In critical illness, the glutamine concentration in plasma may be reduced and considered an expression of the severity of the disease and infection [69]. Supplementation of glutamine may possibly lead to a reduction in bacterial translocation from the gut, improved immune cell function, decreased proinflammatory cytokine production, and increased antioxidant capacity. The clinical impact of these findings, however, has not yet been clearly established and in most meta-analyses, no statistical significance was reached. Because a high dosage in patients with (multi-)organ dysfunction may be detrimental [70,71], in unstable and complex ICU patients, particularly in those suffering from liver and renal failure, parenteral glutamine shall not be administered [2]. An "umbrella" overview of 22 meta-analyses and a current meta-analysis of 15 randomized studies have shown again benefits for glutamine supplementation in ICU patients with regard to the rate of infectious complications and the hospital LOS [72–74]. Reference was also made to the considerable and statistically significant heterogeneity of the studies and metaanalyses [72]. The new ESPEN practical guideline "clinical nutrition in surgery" states parenteral glutamine may be considered in patients requiring exclusive PN [12].

Fish oil or ω-3 fatty acids may have a high anti-inflammatory potential due to the shift in inflammatory mediator synthesis but may intensify an already existing immunosuppression. A recent meta-analysis of 49 RCTs, risk of infection was 40% lower with ω-3 fatty-acid enriched PN than standard PN (RR 0.60, 95% CI 0.49 to 0.72; *p* < 0.00001). Patients given ω-3 fatty-acid enriched PN had reduced ICU LOS (*p* = 0.01) and reduced length of hospital LOS (*p* < 0.00001). Risk of sepsis (9 RCTs) was reduced by 56% in those given ω-3 fatty-acid enriched PN (RR 0.44, 95% CI 0.28–0.70; *p* = 0.0004) [75]. Focusing on enrichment with omega-3 fatty acids in EN and supplemental PN in a recent RCT with 100 mechanically ventilated ICU patients, neither improvement in lung function, nor decrease of complications were observed. However, the supplemented group could be weaned earlier from catecholamine treatment and PN [76]. In patients requiring PN, the new ESPEN practical guideline "clinical nutrition in surgery" states postoperative PN including ω-3 fatty acids should be considered [12].

#### *8.2. Selenium*

Selenium is a known antioxidant and decreases in septic patients and after major surgery. Current evidence for the use of intravenous selenium has been inconclusive. An RCT (SISPCT) administering high-dose selenium to 1089 patients with severe sepsis or septic shock, the 28-day mortality rate in the selenium group was not significantly affected (*p* = 0.30) [77]. A recent meta-analysis focusing on eight RCTs with low risk of bias did not find effects of antioxidant micronutrient supplementation on the reduction of mortality [78]. Currently, an international multicenter RCT of selenium in cardiac surgery (SUSTAIN-CSX, NCT02002247) is undergoing statistical evaluation [79].

Currently the guidelines do not recommend pharmacological supplementation with selenium [1,2].

#### *8.3. Vitamin D*

Vitamin D exerts pleiotropic effects with actions far beyond its classic role in mineral homeostasis. Tissue actions require two enzymatic conversions to 25-hydroxyvitamin D and 1,25-dihydroxy (OH) vitamin D after which vitamin D has been shown to modulate the immune response amongst others. Vitamin D deficiency is highly prevalent across all age groups and countries [80]. Although vitamin D deficiency was further determined to be associated with greater illness severity (also in patients with COVID 19), a causal relationship between vitamin D deficiency and multiple organ dysfunction has not been established [81–84]. Thus, the efficacy of vitamin D as a therapeutic in critically ill patients remains controversial [85].

While in a previous phase 2 trial (underpowered for mortality as endpoint [VITdAL-ICU], involving 475 patients), vitamin D supplementation administered to vitamin D– deficient, critically ill patients was associated with lower observed mortality than placebo at 28 days (21.9% vs. 28.6%, *p* = 0.14) and at 6 months (35.0% vs. 42.9%, *p* = 0.09) [86]. The subsequent randomized, double-blind, placebo-controlled, phase 3 (VIOLET) trial including 1360 patients (1078 vitamin D deficient at baseline defined as 25-hydroxyvitamin D level, <20 ng/mL) receiving a single enteral dose of 540,000 IU of vitamin D or matched placebo did not reveal clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality.

In a recent sub-study of the VIOLET trial, long-term cognitive outcomes were measured. The adjusted median score at follow-up (median 443 days) was not significantly different (adjusted OR, 0.83; 95% CI, 0.50 to 1.38) [87].

Another randomized, placebo-controlled, double-blind, multicenter, international trial, is ongoing with planned recruitment of 2400 adult patients with severe vitamin D deficiency (25-OH Vit D ≤ 12 ng/mL) receiving a enteral loading dose of 540,000 IU cholecalciferol within 72 h after ICU admission, followed by 4000 IU daily for 90 days or placebo [88].

So far, there is no clear evidence for pharmacological vitamin D supplementation in patients with established deficiency.

Given the controversial evidence, different recommendations can be found among the guidelines (1, 2) (see Table 1).

**Table 1.** Current guideline recommendation regarding micronutrients, vitamins, and antioxidants.

DGEM, German Society for Nutritional Medicine; ESPEN, European Society of Enteral and Parenteral Nutrition; A.S.P.E.N, American Society of Enteral and Parenteral Nutrition.

#### *8.4. Vitamin C*

Vitamin C is a pleiotropic nutrient and powerful antioxidant. While suboptimal vitamin C status is common among critically ill patients, vitamin C is currently not recommended as pharmacotherapy for these patients. Nevertheless, a very recent meta-analysis from Patel et al. (acceped for publication, registered at PROSPERO: CRD42021244074) could demonstrate with a trend towards reduction in overall mortality (RR 0.88, 95% CI 0.75 to 1.02, *p* = 0.09), which became significant when comparing high dose vitamin C supplementation (≥10,000 mg/d) with placebo (RR = 0.70, 95%, CI 0.52 to 0.96, *p* = 0.03). In the CITRIS-ALI Trial from Fowler et al., in 2019, vitamin C–infused patients exhibited a significant reduction in 28-day all-cause mortality (χ2 = 4.84; *p* = 0.03) [89].

Regarding the "Marik cocktail", a treatment with intravenous hydrocortisone, ascorbic acid (vitamin C) and thiamine (HAT) [90], a current meta-analysis from 2021 in septic patients found no significant difference between both groups in long term mortality, ICU mortality, or incidence of acute kidney injury, hospital and ICU LOS, and ICU free days on day 28 between the intervention and control groups [91]. There was, however, a significant difference in the reduction of SOFA score on day 3 from baseline (MD −0.92; 95% CI −1.43 to −0.41; *p* < 0.05).

In the before-mentioned meta-analysis (PROSPERO: CRD42021244074), vitamin C monotherapy was associated with a significant reduction in overall mortality (RR 0.66,95% CI 0.49 to 0.89, *p* = 0.006), while there was no effect on overall mortality in the trials administering vitamin C in combination with thiamine and hydrocortisone (RR 0.99, 95% CI 0.82 to 1.19, *p* = 0.91, test for subgroup differences was significant, *p* = 0.02).

**Pragmatic recommendations:**

#### **9. Monitoring and Complications**

In addition to the clinical examination of the patient's abdomen, blood chemistry includes serum glucose, triglycerides, lactate, and procalcitonin should be measured. Phosphate should be controlled to detect and treat a potential refeeding syndrome. To avoid measurement of nitrogen balance, urea excretion rate per 24 h will help to estimate the extent of catabolism. For the estimation of intestinal function, the potential impact of biomarkers as citrulline and fatty acid binding protein plasma level have to be validated in clinical studies.

#### *9.1. Gastrointestinal Intolerance*

There is a variety of definitions for feeding intolerance including a lot of uncertainty for the clinical management [92]. Many critically ill patients experience feeding intolerance, motility disorders, which include delayed passage with slow gastric emptying and constipation, and accelerated passage with impaired small intestinal nutrient absorption or nutrition-related diarrhea [92,93]. According to the ERAS Society's (Enhanced Recovery After Surgery) various guidelines [94–96], causes of GI intolerance include opioid analgesia, sedation, edema, and insufficient stimulation. Treatment options are oral/EN, prokinetics, mobilization and physical therapy, prokinetics and optimization of sedation and volume status. Clinical observation of the patient's abdomen, bowel motility, and gastric reflux is mandatory.

While measurement of GRV is not standardized the optimal threshold is uncertain. Therefore, the impact of the measurement of GRV has been controversial. The monitoring of GRV is considered still relevant in surgical ICU patients and severely critically ill patients with a high risk for GI dysfunction. A GRV of more than 500 mL/6 h may be considered critical [93]. In two controlled studies non-monitoring of GRV was without significant effect on the risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and EEN [97,98].

Additional possibilities to monitor GI tolerance include sonography and CT scans. If the latter shows bowel loops with intramural air accumulation, bowel ischemia must be considered. Intramucosal phi tonometry as a tool for the measurement of splanchnic perfusion has not been used frequently in clinical practice.

A research agenda has been proposed by the working group GI failure of the European Society of Intensive Care Medicine (ESCIM) including the core set of monitoring and outcomes [99].

#### *9.2. Metabolic Intolerance*

Hyperglycemia may be due either to hyperalimentation in the (acute) phase of insulin resistance or underlying subclinical diabetes. Hyperglycemia is associated with increased mortality, which has been the rationale for intensified insulin therapy [100]. To avoid any life-threatening hypoglycemia, nowadays, glucose levels up to 180 mg/dL (10 mmol/L) are accepted [5,101]. Reduction of glucose calories should be considered before insulin is administered in nondiabetic patients with moderate dosages of 0–4 IU/h. An intensive insulin therapy is not recommended to avoid the potential consequences of hypoglycemia [5].

To circumvent hypertriglyceridemia, bolus application of lipids should be avoided. During continuous lipid infusion serum triglyceride levels should not exceed 400 mg/dL [101]. Reversible liver steatosis or hypertriglyceridemia-induced acute pancreatitis may develop if metabolic control cannot be achieved within several days.

In severely malnourished patients and patients after long starving periods, a refeeding syndrome may occur within the first few days after starting MNT. Supply of carbohydrates and fluid will stimulate insulin secretion and intracellular shift of glucose and electrolytes. The decrease of serum potassium, magnesium, and phosphate levels will lead to impaired neuromuscular transmission causing life-threatening arrhythmias, and convulsions. Calories and fluid administration should be increased slowly under electrolyte- and preferably ECG monitoring [102]. In high-risk patients, a preventive thiamine administration 200 mg once daily for 2 days is necessary.

**Pragmatic recommendations:**

#### **10. Tailoring MNT to the Individual Patient's Needs**

The heterogeneity of the patients in the ICU complicates MNT and many different factors such as primary disease, comorbidities, phase of critical illness influence the patient's individual requirements. The most important aspects of the different patient groups are summarized in Figure 1 to give a pragmatic overview.

**Figure 1.** Overview important aspects of medical nutrition therapy in different patient groups. Abbreviations: EN: enteral nutrition, GI: gastrointestinal, PN: parenteral nutrition, RRT: renal replacement therapy.

#### *10.1. Adapting MNT to the Phase of Critical Illness*

MNT must be adjusted to the metabolic tolerance which may considerably alter in the different phases of critical illness and resulting catabolic response [1,2]. While metabolic tolerance may be extremely limited by severe inflammation in the early acute phase bearing the high risk of overfeeding, it is different in the post-acute phase according to chronical inflammation or beginning resolution and recovery—the shift to anabolism includes the risk of underfeeding. Therefore, the guidelines recommend an individualized approach due to specific pathophysiologic and resulting metabolic changes, the guidelines recommend an individual adaptation of MNT to the different phases of critical illness [1,2].

Immediately after onset of the critical illness, the 'acute' phase begins that can be divided into an 'early acute' phase (about 1–3 days post-onset with the possibility of fatality due to the most severe illness entity) and a 'late acute' phase (approximately lasting for 2–4 days if the patient survives the early acute phase). The post-acute phase can be described as a 'recovery' phase (duration >7 days), which is usually spent in the primary care hospital. During this phase of recovery from catabolic critical illness, substrate tolerance has been normalized with a metabolic shift to anabolism. From a nutritional point of view, sufficient macronutrient supply in this period may be considered pivotal to the patient's recovery and long-term outcome. The amount of administered calories are considered to be 1.2–1.5 fold the calculated energy requirement. Because these patients are weaned from ventilation and able to eat, it will be frequently—and falsely—assumed that they will manage to cover these requirements by the oral route. It has been recently shown that this may be achieved only by a combination of oral and enteral feeding [103]. It has been shown that after extubating, many patients will receive no more than 700 kcal/d [104]. Reasons may be early discontinuation of MNT in favor of oral nutrition (especially in case of discharge to standard care), limited oral intake due to post-critical weakness, fatigue, anorexia, and isolation. Documentation of the amount of oral intake is mandatory, supplementation with oral nutritional supplements (ONS), in some cases enteral or even SPN should be considered.

After the recovery phase, the 'rehabilitation' phase (lasting several months) follows, in which, among others, the metabolic damage suffered initially is repaired slowly. Usually, patients will not go through this phase in the primary care hospital. Alternatively, the 'post-acute' phase may merge into a 'chronic' phase (of uncertain duration) characterized by persistent organ dysfunction and an uncertain prognosis. This particular course may be described as a "persistent inflammatory immunosuppressed catabolism syndrome" [105,106]. If there is a new disturbance of homeostasis, the process will start again with the acute phase.

**Pragmatic recommendations:**

#### *10.2. Critically Ill Patients with Altered Nutritional Status*

Malnutrition is a common phenomenon and includes under- as well as overnutrition. While undernourished patients with low weight and BMI can be easily recognized during clinical routine, malnutrition may be underestimated in patients with normal or elevated BMI [3]. An obese patient with weigh loss in the past months or with reduced intake of nutrition is at risk for malnutrition, which may not be diagnosed at first sight. Therefore, a combination of clinical evaluation and the use of a validated screening tool may be recommended [1–3,107]. If the patient is at nutritional risk, a detailed nutritional assessment should follow.

#### 10.2.1. Undernourished Patients

In patients with preexisting malnutrition, according to the DGEM guideline, the same energy and protein targets may be used, as in other patients, as there is still a lack of data concerning the therapeutic relevance of MNT in this patient cohort although the prognostic relevance of malnutrition is clear [1]. In these patients, an MNT should be commenced early to avoid large cumulative macronutrient debts. This may be achieved through ONS or though SPN. Should an EN not be feasible, an early hypocaloric PN should be administered (75% of caloric target, protein ≥ 1 g/kg/d) [1].

In severely malnourished patients, according to the DGEM guideline, a more aggressive MNT is not recommended to avoid GI and metabolic intolerance and potential complications such as acute hyperalimentation, refeeding syndrome, or increased rates of infection [1].

Contrasting this recommendation, the A.S.P.E.N. suggests a rapid progression of preferably EN with the aim to reach the target within 24–48 h under careful monitoring. Within 48–72 h, >80% of energy and protein goals should be achieved [3]. However, these recommendations of the A.S.P.E.N. rely on debatable evidence.

While the essential role of micronutrients for many biological processes in the human body is accentuated in current literature, reliable evidence remains sparse. Therefore, micronutrients in pharmacological dosages should only be administered after clinically raised assumptions or measured micronutrient deficiencies as stated by the DGEM [1].

Special attention should be paid to the occurrence of a refeeding syndrome in severely malnourished patients.

#### 10.2.2. Obese Patients

Obese patients do not have 'reserves', as often assumed, but in contrast they frequently suffer from disturbances in substrate utilization, leading this patient group to be predisposed to loss of muscle mass during an ICU stay. Increased attention should be paid to the monitoring of metabolism, markers of metabolic syndrome and possible comorbidities [3]. While there is only weak evidence, the goal of an MNT is avoidance of muscle catabolism, improvement in body composition, reduction of insulin resistance and hyperglycemia and reduction of infection rates.

For obese patients with BMI ≥ 30 kg/m2, similar guideline recommendations were issued as for other ICU patients [1–3]. The best MNT for obese patients is still debated particularly because evidence remains weak from smaller and quite older observational studies, as are formulas to calculate energy demand in these patients, but indirect calorimetry should be used to measure EE [1,2]. Otherwise, obese patients should be nourished weight-adapted hypocalorically and high in protein (1.5 g protein (1.8 g amino acids)/kgideal BW/d) [1–3,108]. For calculation of ideal BW, the so-called Peterson formula is recommended in a slightly different modification by the ESPEN and DGEM guideline (DGEM: ideal BW = 48.4 + 77.0 × (height-1.50 m) related to a BMI of 22 kg/m2; ESPEN: adjusted BW = (current BW-ideal BW) × 0.33 + ideal BW, ideal BW = 2.2 × BMI + 3.5 × BMI × (height-1.50 m) related to an "overweight" BMI of 25 kg/m2) [109]. In clinical routine, a hypocaloric high-protein nutrition may be achieved via enteral or parenteral protein supplements. Additionally, patients who experienced weight loss in the past months or who underwent bariatric surgery, should receive vitamin and trace element supplements with special focus on thiamine [1,3].

**Pragmatic recommendations:**

#### *10.3. Elderly Critically Ill Patients*

In elderly patients, the most important goal is to optimize the functional capabilities to achieve the best possible quality of life and autonomy [110]. Elderly patients have higher incidences of comorbidities, malnutrition, sarcopenia, and cachexia, which may be regarded as the frailty syndrome [110]. Because the multidimensional syndrome "frailty" and other reasons for malnutrition, such as depression, anorexia, polypharmacy, low activity and catabolism of chronic diseases, and inflammation are so common in elderly patients and affects nutritional status, all elderly patients should be screened for malnutrition and be treated accordingly [111,112]. If the elderly critically ill patient is able to feed orally, sedative measures and dietary restrictions should be minimized to avoid a reduced food intake, which may negatively affect patient outcome [110]. In obese elderly patients, a weightreducing diet should be circumvented, to avoid muscle catabolism [110]. Possibilities to optimize an oral nutrition include enriched nutrition, several small meals, ONS, monitoring of food intake and company during meals. If oral nutrition is insufficient, EN and or PN should be administered with the same indications as in other critically ill patients, while minding an early start of a MNT if indicated [110].

In the absence of methodologically sound clinical evidence, the DGEM chose not to give special recommendations for this patient group [1]. The ESPEN assumes that an adequate macronutrient supply may lower the incidence of frailty in elderly patients and recommends higher protein target (1.2–1.5 g/kg/d) for elderly malnourished patients [2]. In elderly critically ill patients a hypercaloric and high-protein supplementation (30 kcal/kg/d energy and ≥1 g/kg/d protein) is recommended by the ESPEN as well [110]. Micronutrients should be supplied as for healthy elderly patients, special micronutrient deficits shall be counterbalanced [110]. The A.S.P.E.N. does not provide special recommendations for elderly ICU patients.

In addition to an effective MNT, the focus should be on adequate hydration, potential refeeding syndrome [113], as well as on preservation of muscle mass physical activity to allow for an independent living after hospital discharge [110].

**Pragmatic recommendations:**

#### *10.4. Critically Ill Patients in Shock*

Physiologic advantages or an EN are the maintenance of the gut mucosa and the GI barrier, the modulation of an inflammatory reaction and the reduction of insulin resistance. In case of compromised hemodynamics, the concern for mesenterial ischemia due to the increased demands for the gut system is voiced in the guidelines [2,3]. Cautious EN in patients with the need for catecholamines or vasopressors may be considered [114], but there is still a risk for nonocclusive bowel disease and a lack of data from controlled randomized trials [115–117]. In the NUTRIREA-2 trial including 2410 patients, early EN did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric PN [22].

In the concept of "minimal trophic nutrition" it is recommended to start EN with a low flow rate (10–20 mL/h) [118]. In case of hemodynamic instability and the administration of catecholamines, limited enteral tolerance should be anticipated. Careful clinical examination of the abdomen must be performed and keeping in mind that the energy target cannot be achieved in such patients via the EN in most cases within the first ICU week. Complete stop of enteral supply should be avoided whenever possible [23].

The guidelines recommend EEN in septic patients after achieving hemodynamic stability [1–5]. The MNT should be progressed slowly to achieve more than 80% of the nutritional target within the first week [3]. If EN is contraindicated, PN should be used. An SPN shall be administered according to the ESPEN after day 3 [2]. Contrasting the ESPEN guideline, the A.S.P.E.N. and Surviving Sepsis Campaign (SSC) do not recommend SPN or PN in the acute phase of a severe sepsis due to the limited substrate utilization [3,5]. Because septic patients in the hypermetabolic phase may have an increased need for vitamins and trace elements, these should be supplemented in physiological dosages after a proven deficit or of PN is needed [1]. Immonutrition, as well as micronutrients—such as selenium, glutamine, arginine, or carnitine—should not be administered [3,5].

Attention should be paid to the macronutrient balance in the first week of sepsis, because EN alone is often hypocaloric due to limited GI and metabolic tolerance. Whether this is advantageous or not remains controversial. The GI tolerance may be improved through prokinetics and postpyloric nutrition tubes, according to the SSC guideline [5].

The guidelines furthermore state, that patients with septic shock can receive EEN after stable hemodynamics are ensured (mean arterial pressure ≥60 mmHg and stable/falling lactate/need for vasopressors) but should progress slowly and be adapted to the patient's tolerance [2,3]. In patients with uncontrolled shock, no EN should be given [2,3].

**Pragmatic recommendations:**

#### *10.5. Critically Ill Patients after Trauma and Burn Injury*

Due to insufficient data in these patient groups, they should be treated according to the general recommendations for ICU patients [1]. The A.S.P.E.N. recommends EN should be preferred to PN [3].

Patients with burn injury and exudative losses through wound surfaces have an increased need for vitamins and trace elements. A highly variable EE leads to inaccuracy of estimation formulas regarding macronutrient needs. Therefore, indirect calorimetry shall be preferred [1,3]. The ESPEN recommends—contrasting the DGEM—enteral glutamine to be supplemented (0.3–0.5 g/kg/d) for 10–15 days [2] and the A.S.P.E.N. a higher dosage of protein (1.5–2 g/kg/d) [3]. According to DGEM, protein losses via drains and dressings should be compensated [1].

For trauma patients, the ESPEN recommends glutamine (0.2–0.3 g/kg/d) for the first 5 days (10–15 days if wound healing is complicated) [2]. Immunomodulating solutions with fish oil and arginine may be considered for patients after severe trauma according to the A.S.P.E.N. [3]. The DGEM advises against the use of these substrates in the sense of pharmacotherapy [1].

**Pragmatic recommendations:**

#### *10.6. Critically Ill Patients with Central Nervous Diseases*

The guidelines state that patients with head trauma, ischemic or hemorrhagic stroke and spinal trauma should receive EEN [2–4].

Patients with **stroke** are especially vulnerable for malnutrition, dehydration, and aspiration pneumonia due to impaired consciousness, swallowing problems as well as cognitive and perceptive deficits [119]. Therefore, all stroke-patients should be screened for swallowing problems and malnutrition and treated accordingly [120]. ONS may support the individualized therapy [119,120]. In patients, where impaired consciousness or dysphagia prohibit oral nutrition, an EN should be started within 72 h via nasogastric tube [119].

Young patients with **head trauma** are usually not malnourished at ICU admission but have an increased nutritional risk due to long ICU stays, variable EE (up to 200%) and frequently experienced a profound muscle catabolism. A higher protein supplementation 1.5–2.5 g/kg/d may therefore be considered [2,3]. The A.S.P.E.N. suggests the administration of formulas including arginine and omega-3-fatty-acids [3].

Patients with a diagnosed **swallowing disorder**, which make up to 60% of the general ICU population [121], should receive a logopedic therapy and an optimization of food texture to optimize oral food intake as stated in the ESPEN guideline "clinical nutrition in neurology" [119]. Special attention should be paid to oral and pharyngeal residue of food, sufficient food and fluid intake and aspiration [119,120]. If no safe and sufficient nutrition can be ensured, EN via nasogastric route shall be added to the oral nutrition [2, 119,120]. If there is additional risk of aspiration, EN boles should be avoided, a postpyloric tube should be placed, the head should be elevated by 30◦, and prokinetics should be considered [2,3,120]. PN is another option for these patients, especially in cases with preexisting malnutrition or if an EN is not sufficient to ensure adequate nutrition and hydration [2,120].

**Pragmatic recommendations:**

#### *10.7. Critically Ill Patients with Cardiac Diseases*

Malnutrition, cachexia, and sarcopenia are common comorbidities in patients with cardiac failure [17,122,123]. In contrast to often quickly recovering patients after elective "simple" cardiac surgery, patients with preexisting malnutrition, complex heart surgery and elevated risk for prolonged ICU stays should receive regular screenings for nutritional risk [123,124]. At the same time, these patients are vulnerable for fluctuation of the volume status, which is why the use energy-dense formulae seems reasonable.

For patients with mechanical assist devices (extracorporeal membrane oxygenation (ECMO)/ extracorporeal life support (ECLS), or ventricular assist devices (VAD)), the same recommendations apply as for other critically ill patients. According to the guidelines, in patients with stable hemodynamics and intact GI system, EN should be preferred [1,2,4]. Regarding monitoring, special attention should be paid to GI bleeding during therapeutic anticoagulation. In patients on ECMO/ECLS, diagnostic measures and therefore interruptions of EN are frequent. Although evidence remains sparse, SPN seems safe and should be infused via central venous catheter (as opposed to directly into the ECMO circuit [1]. Indirect calorimetry is not reliable in this patient group due to the extracorporeal CO2-elimination, therefore weight-based formulas should be used to estimate energy targets [1].

**Pragmatic recommendations:**

#### *10.8. Critically Ill Patients with Respiratory Diseases*

In patients with respiratory failure, in theory, formulae with increased fat content and reduced carbohydrates may be useful to influence the respiratory quotient and decrease CO2-production. The A.S.P.E.N. advises against these formulae in patients with acute respiratory failure due to the lack of evidence, but recommends avoiding hyperalimentation, because lipogenesis increases CO2-production [3].

According to the guidelines, EN should not be administered to patients with lifethreatening hypoxia, hypercapnia, and acidosis as sign of respiratory decompensation. In patients with stable and compensated respiratory failure, EN can be commenced [2,4]. A restriction of fluids seems reasonable to avoid aggravating overhydration and edema. Therefore, energy-dense formulae (1.5–2 kcal/mL) are recommended [3]. Hypophosphatemia is a common (and commonly unrecognized) problem and may lead to weakness of respiratory muscles and weaning-failure. Therefore, phosphate should be monitored

closely and replaced as necessary [3]. A functional GI-System should be used, so EEN should be performed in patients managed in prone position [2]. The hypothesis that the abdominal compression leads to problems with transport and resorption has not been proven [1,2,4]. One possibility to increase tolerance and avoid aspiration of EN is to bring the entire bed in a 30◦ head elevation. Measurements of intraabdominal pressure may aid in the early detection of an abdominal/GI problem (not only) in patients in prone position.

#### Critically Ill COVID-19 Patient

Most COVID-19 patients admitted to the ICU are at high risk of or have preexisting malnutrition [125]. According to Ochoa et al., COVID-19 patients present with three different phenotypes of nutrition risk: (1) the frail older patient, (2) the patient with severe ongoing chronic illness, and (3) the patient with severe and morbid obesity [126]. The measurement of the upper waist circumference of COVID-19 patients has recently shown that with every centimeter increase there is a 1.13-fold higher probability of intensive treatment and a 1.25-fold higher probability of mechanical ventilation [127].

Regarding MNT in this patient cohort, no RCTs exist so far. Instead, the ESPEN and A.S.P.E.N. have published expert statements as an adaptation of their existing guidelines [128,129].

Before admission to the ICU, anorexia secondary to infection, dyspnea, dysosmia, dysgeusia, and impaired meal preparation during quarantine may have reduced food intake. Therefore, upon ICU admission, nutritional assessment is mandatory. An individualized approach including indirect calorimetry is recommended, because persistent hypermetabolism was observed in these patients [130,131].

While EN may be performed even in prone position, Martindale et al. recommend a lower threshold for switching to PN in cases of intolerance, high risk of aspiration, or escalating vasopressor support [129]. In case of ARDS, Thibault et al. have recommended the use of EN enriched with omega-3 fatty acids, and for PN fish oil-enriched intravenous fat emulsions [125].

In a multicenter, double-blind, RCT conducted at two sites in Sao Paulo, Brazil, 240 hospitalized patients with COVID-19 being moderately to severely ill were randomized to receive a single oral dose of 200,000 IU of vitamin D3 or placebo [132]. LOS defined as the primary endpoint was not significantly different between the vitamin D3 and placebo groups (log-rank *p* = 0.59; unadjusted hazard ratio for hospital discharge, 1.07 [95% CI, 0.82 to 1.39]; *p* = 0.62). Furthermore, there were no significant differences for in-hospital mortality, admission to the ICU (*p* = 0.30), or need for mechanical ventilation (*p* = 0.09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D3 vs. placebo (44.4 ng/mL vs. 19.8 ng/mL; difference, 24.1 ng/mL [95% CI, 19.5 to 28.7]; *p* < 0.001).

**Pragmatic recommendations:**

#### *10.9. Critically Ill Patients with Abdominal Diseases*

Critically ill patients requiring abdominal surgery often present anatomical and functional characteristics that require a critical evaluation and adaptation of MNT. Compromised functions are GI-motility, digestion, and absorption of nutrients, which often leads to a reduced tolerance of EN. On the other hand, EN also nurtures the gut mucosa, increases intestinal perfusion and peristalsis [3,17].

#### 10.9.1. Patients after GI-Surgery

If the GI system is functional, it shall be used in patients after **GI surgery** as recommended uniformly by all guidelines [1–4]. Therefore, in most abdominal-surgery patients an EEN within 24–48 h is recommended [1,12]. Even if the nutrition of these patients

remains a controversially debated topic, it is not necessary to withhold EN as per standard or administer clear liquids only [3]. The MNT should be discussed in the interdisciplinary teams to optimize the nutrition for each individual patient [12].

In patients after **upper GI-surgery,** an intraoperatively placed nasojejunal or percutaneous postpyloric tube can allow for EN of the distal GI parts without risking injury of a fresh anastomosis during feeding tube placement and without risk of regurgitation and aspiration. In general, fresh anastomoses *per se* are not a contraindication for EN, whereas the individual therapy needs to be decided in the interdisciplinary team [2].

Abdominal surgery patients with **complicative courses** often accumulate great energy debts. Therefore, the ESPEN recommends to consider an early SPN [2]. In patients with leaky anastomoses, with internal or external fistulas, an access to the distal part of the gut shall be used for EN. Enteroclysis shall be considered and re-evaluated on a regular basis, to increase resorption of nutrients and prevent mucosal atrophy as well as bacterial overgrowth with the risk of bacterial translocation and bacteriemia [2]. If EN is insufficient, the patient needs PN [2].

Patients with **open abdomen** should receive an EEN (24–48 h postinjury) in the absence of bowel injury [3,4]. Protein losses via drains and dressings should be compensated in the form of enteral protein supplements or parenteral albumin (15–30 g protein/ liter exudate) [1,3]. In addition to the above-mentioned guideline recommendations, an algorithm was proposed by Friese et al. in 2012 [133] and Moore and Burlew in 2016 [134].

#### 10.9.2. Patients with Liver Failure

According to the ESPEN guideline on clinical nutrition in liver disease [135] and the A.S.P.E.N. [3], patients with liver failure have an increased risk for malnutrition and may develop severe disturbances regarding carbohydrate, protein and fat metabolism with impeded hepatic gluconeogenesis and lactate clearance, as well as catabolism [3,135]. Therefore, all patients with liver disease should be screened for malnutrition and treated accordingly [135]. EE may be highly variable in these patients; therefore, indirect calorimetry should be used [3,135]. If the latter is not possible, the patient's dry weight shall be used to estimate energy and protein targets and 1.3× resting EE should be supplied [135]. Patients with acute liver failure should receive oral nutrition as long as possible, or in case of hepatic encephalopathy, EEN [135]. A generalized protein restriction is not recommended prevent muscle degradation, which contributes to the development of a hepatic encephalopathy [3]. In patients with encephalopathy and high ammonia, the protein supplementation can be delayed for 24–48 h [135]. A normal EN formula shall be used, because of insufficient evidence for the use of branched chained amino acids [3,135].

#### 10.9.3. Patients with Acute Pancreatitis

In patients with acute pancreatitis, there is a great range of severity. Therefore, the MNT should be re-evaluated frequently. In mild cases, patients can receive oral nutrition ad libitum. In medium or severe cases, EEN should be commenced with a low infusion rate via gastral or jejunal path. If the patient undergoes surgery for necrosectomy, placement of needle catheter jejunostomy should be considered [136]. Before PN is considered one week after onset of pancreatitis, measures to increase GI-tolerance can be performed, according to A.S.P.E.N. [3].

**Pragmatic recommendations:**

#### *10.10. Critically Ill Patients with Renal Diseases*

Patients with renal failure represent a heterogeneous group with different needs regarding macro- and micronutrients. EN should be preferred in this patient group. If an EEN is not possible, SPN or TPN should be started early according to the German guideline for Patients with Kidney Disease [137].

A patient with acute kidney failure has the same needs for energy and protein and should be treated according to the standard of other critically ill patients—compared to patients with chronic kidney failure, who have increased energy demands as stated in the guidelines [1,3,137]. Even when deranged values for potassium and phosphate are rare in patients with acute-on-chronic kidney failure, a careful electrolyte monitoring is important. In case of electrolyte derangements and no indication for RRT, special renal formulae can be used [3]. These formulae contain less fluid and protein, are high in calories and have lower potassium and phosphate content and can contain additional substances such as carnitine [137].

A RRT increases losses of energy, water soluble molecules—such as amino acids, electrolytes, trace elements, and vitamins—and induces systemic inflammation and protein catabolism. On the other hand, substances sch as lactate and citrate are added excessively with the dialysis or hemofiltration solution. This needs to be minded for calorie calculations. The guidelines vary in their recommendations regarding energy supplementation for ICU patients with kidney failure during RRT. The DGEM guideline recommends macronutrient calculation as per the standard in other ICU patients, which should be ramped up slowly while considering macronutrient losses. The A.S.P.E.N guideline suggests administration of high protein dosages of 2.5 g/kg/d, to achieve nitrogen balance [1,3,137]. To cope with the increased need of vitamins and trace elements, an increased supply is recommended, with special regard to vitamin C, folate and thiamine [1,137].

**Pragmatic recommendations:**

#### **11. Summary and Conclusions**

Despite ongoing research activities, the level of evidence remains often low due to a lack of data from large RCTs.

Evidence based international guidelines are available. Nevertheless, the implementation of the different recommendations into clinical routine remains often insufficient.

It should be kept in mind that every ICU-patient is at risk for malnutrition, regular screenings for malnutrition should be performed, close monitoring and frequent adaptation of nutrition is necessary. An early enteral nutrition with a standard formula is preferred in almost all critically ill patients. The addition of parenteral nutrition and micronutrients should be considered individually. Feeding protocols which are tailored to the treating units will improve the nutritional performance.

Due to the heterogeneity of the patients, MNT should be carefully adapted to the individual patient with special focus on phase of critical illness, metabolic tolerance, leading symptoms, and comorbidities. Nutrition in the ICU is a complex therapy requiring an interdisciplinary approach and frequent reevaluation. This article can only be regarded as an introduction and summary for the complex topic of nutrition in the critically ill patient and may be of help for the clinical routine.

Appreciating recent advances, the long-lasting open questions will remain:

**Author Contributions:** Conceptualization, A.H. and A.W. together with G.E.; Writing—original draft preparation, A.H. and A.W. together with G.E.; Writing—review and editing, A.H. and A.W. together with G.E.; Visualization, A.H.; Supervision, A.W. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** A.H. is currently supported by a stipend from the Ministry of Culture and Science of the State of North Rhine-Westphalia "Landesprogramm für chancengerechte Hochschulmedizin".

**Conflicts of Interest:** G.E. received lecture fees, travel support and advisor honoraria from Fresenius Kabi within the last three years, A.W. received lecture fees from Baxter, B. Braun, Fresenius Kabi, Ethicon, and Falk Foundation, Research grant from Baxter, Mucos. A.H. received a research grant from Fresenius Kabi.

#### **Abbreviations**

#### **Appendix A**

**Table A1.** Weight based calculation of macronutrient requirements, \*, recommendation for acute phase, use actual body weight for calculation.

#### **References**

## *Review* **Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome**

**Sara D'Imperio 1, Michelle M. Monasky 1, Emanuele Micaglio 1, Gabriele Negro 1 and Carlo Pappone 1,2,\***

**Abstract:** A healthy regime is fundamental for the prevention of cardiovascular diseases (CVD). In inherited channelopathies, such as Brugada syndrome (BrS) and Long QT syndrome (LQTS), unfortunately, sudden cardiac death could be the first sign for patients affected by these syndromes. Several known factors are used to stratify the risk of developing cardiac arrhythmias, although none are determinative. The risk factors can be affected by adjusting lifestyle habits, such as a particular diet, impacting the risk of arrhythmogenic events and mortality. To date, the importance of understanding the relationship between diet and inherited channelopathies has been underrated. Therefore, we describe herein the effects of dietary factors on the development of arrhythmia in patients affected by BrS and LQTS. Modifying the diet might not be enough to fully prevent arrhythmias, but it can help lower the risk.

**Keywords:** Brugada syndrome; long QT syndrome; diet; ingredients; glucose; ketone bodies; ROS; sudden cardiac death

#### **1. Introduction**

A healthy regime is fundamental for the prevention of cardiovascular diseases (CVD). CVD are widely known to be responsible for 33% of all deaths worldwide [1]. One of the multiple types of cardiac disorders is arrhythmia, which refers to a group of several conditions that interfere with heart rhythm. Among different types of cardiac arrhythmias, there are inherited channelopathies (IC), including long QT syndrome (LQTS), short QT syndrome (SQTS), Asian sudden unexplained nocturnal death syndrome (SUNDS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS). Unfortunately, sudden cardiac death (SCD) could be the first symptom of patients affected by IC. Risk stratification and current diagnosis have been primarily focused on clinically detectable changes and abnormalities in the heart structure and function [2,3]. Several known markers are used to predict cardiac arrhythmias, although none are specific for patients affected by inherited channelopathies.

Several risks factors, such as obesity, diabetes, sleep apnea, anorexia nervosa, electrolyte imbalances, and unhealthy food consumption, are associated with these inherited channelopathies (Figure 1). Therefore, it is very important to address these risk factors in order to manage and prevent adverse outcomes. Most of the correlations are well established, and, indeed, these risks factors can be affected by adjusting lifestyle habits, such as a particular diet, impacting the risk of arrhythmogenic events and mortality. Thus, the aim of this review is to present objective insights into different daily diets. Specifically, here, we highlight the effects of various dietary factors and their suspected roles in the development of arrhythmias in BrS and LQTS, providing a summary of current literature and presenting questions that need to be the subject of future studies. This information is desperately needed to advise the patients diagnosed with these syndromes in the clinic.

**Citation:** D'Imperio, S.; Monasky, M.M.; Micaglio, E.; Negro, G.; Pappone, C. Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome. *Nutrients* **2021**, *13*, 2482. https:// doi.org/10.3390/nu13082482

Academic Editor: Ina Bergheim

Received: 24 June 2021 Accepted: 19 July 2021 Published: 21 July 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Figure 1.** Cardiac arrhythmias, such as Brugada syndrome and long QT syndrome, can be triggered by a variety of factors, but maintaining a certain lifestyle may reduce these risks.

#### **2. Brugada Syndrome and Long QT Syndrome**

Brugada syndrome and long QT syndrome are among the most common inherited cardiac arrhythmias, with high risks of malignant arrhythmias, and they present with abnormalities in the 12-lead electrocardiogram (ECG): ST-segment elevation and prolonged QT interval, respectively.

BrS is associated with right ventricular conduction abnormalities and coved-type STsegment elevation in the right precordial leads of the ECG [4]. The syndrome is clinically characterized by syncope episodes and SCD due to ventricular fibrillation [5]. The majority of the patients are asymptomatic, and they are usually diagnosed by chance due to the dynamicity of the BrS ECG pattern, since it fluctuates throughout the day [6]. Moreover, these fluctuations can be induced by several factors, such as fever, hypercalcemia, diabetes, excessive consumption of food or alcohol, hyperkalemia, and certain drugs [7]. The covedtype ST-segment elevation is diagnostic when the "Type 1" Brugada pattern is seen, which can be found either on a spontaneous ECG or after a drug challenge with a class Ia antiarrhythmic drug, such as ajmaline, which can provoke the Type 1 pattern so that the syndrome can be discovered [8]. The true incidence of BrS is currently unknown, due to the lack of availability of centers that can perform the drug challenge to unmask the syndrome. This is because these tests must be performed in specialized centers capable of specialized resuscitation due to the risks associated with the drug ajmaline [9], which can potentially induce life-threatening ventricular arrhythmias (VAs). For this reason, although used widely in Europe, the drug ajmaline is not used in the United States of America, due to risks associated with this drug. The BrS is believed to be genetic in nature, described as being oligogenic in nature, although it may occur in a minority of families as a Mendelian condition [10,11].

LQTS is defined by a variable degree of QT prolongation, absence of structural heart diseases, and it can manifest in three different subtypes (LQTS1, LQTS2, and LQTS3). The syndrome is clinically characterized by syncope episodes and SCD due to ventricular tachyarrhythmias [12]. LQTS can be congenital or acquired, therefore, a prolonged QT interval may result from genetic abnormalities, mineral imbalances, or certain medications [13]. It manifests as ECG abnormalities, including prolonged QT-interval, Torsade de Pointes (TdP), and ventricular fibrillation (VF) [14]. LQTS is usually diagnosed by measuring the QT interval on the ECG and it can include adrenalin and isoproterenol test. Moreover, epinephrine test is able to unmask the prolongation of the QT intervals in patients with

'concealed LQTS' [15]. The ECG may result normal at rest but based on the subtype, ECG abnormalities can be triggered by physical stress, emotional stress, dietary changes, certain drugs, or during sleep or at rest [16,17], and it has also been associated with metabolic syndromes and eating disorders [13]. LQTS primarily affects young people and is one of the main causes of SCD in this population [18].

#### **3. BrS ECG Pattern Triggered by Food or Alcohol Intake**

Several studies have repeatedly stressed that the BrS ECG pattern can appear after the consumption of alcohol [19,20] or caused by glucose-induced insulin secretion after the ingestion of a meal [21]. A 29-year-old BrS patient experienced several episodes of palpitation and syncope after alcohol consumption [22]. Another case report described a 25-year-old man who experienced three syncope events while consuming alcohol [23]. In yet another study, a 21-year-old man was diagnosed with BrS after he developed two episodes of syncope after the consumption of a high quantity of alcohol; specifically, his ECG, during the syncope, revealed ventricular fibrillation and the elevation of the ST-segment at high intercostal space [24]. In addition, a 56-year-old male experienced cardiac arrest while asleep after the consumption of one bottle of wine. The patient, five years previously, already had an abnormal ECG showing an elevation of the ST-segment, however, unfortunately, this abnormality was not considered important as a diagnostic criteria for BrS [25]. A nine-year-old boy, who was diagnosed with BrS by an ajmaline test, experienced syncope and cardiopulmonary arrest after the ingestion of a large hot dog [26]. Another case report of a 53-year-old man, who had been diagnosed with BrS after four weeks of Ramadan-fasting, had syncope events and several sudden cardiac arrests after the ingestion of a large meal [27].

Glucose and insulin intravenous infusion in patients affected by BrS results in a significant accentuation of the abnormal J-ST configuration [26]. In one study, 75% of BrS patients, compared to the controls, had a higher incidence of ECG fluctuation after an oral glucose tolerance test (OGTT) [28]. Although it is widely understood that large meals can trigger the BrS ECG pattern, the cellular mechanism responsible for the appearance of this ECG pattern by high levels of glucose and/or insulin concentration in BrS is still unclear.

In conclusion, the relationship between large meal intake, alcohol, and the development of the BrS ECG pattern is still unclear. However, it seems that the interplay between them is very relevant and should be investigated further.

#### **4. Cortisol and Sudden Death**

The majority of sudden cardiac deaths seem to occur from 4 am to 6 am, so in a period of nocturnal sleep in which cortisol concentration tends to be lower than in other periods of the day [29]. This observation suggests a role for abnormal sympathetic activity, which has been observed in a SUNDS cohort (sudden unexplained death during nocturnal sleep), and SUNDS is still considered to share common genetic causes with BrS [30,31].

Moreover, it is very well known that cortisol can affect the incidence and the clinical manifestations of sudden cardiac death. More recently, the role of the enzyme 11βhydroxysteroid dehydrogenase (11β-HSD1) has been considered [32]. This enzyme is one of the most promising molecular targets to treat Type 2 diabetes mellitus and its complications [33]. Basically, 11β-HSD1 is able to catalyze the production of cortisol, and the levels of 11β-HSD1 correspond to the levels of cortisol concentration [29]. High concentrations of cortisol have already been demonstrated to be associated with both cardiac arrhythmias and diabetes mellitus [34]. The drug-mediated 11β-HSD1 inhibition alleviates most metabolic abnormalities associated with both diabetes and a cortisol concentration beyond normal levels [32]. The expression of 11β-HSD1 can be induced by high-fat diet in mouse models [35], suggesting the usefulness to assess the activity of 11β-HSD1 among human patients with BrS. Therefore, these mechanisms should be further explored to better understand why the majority of sudden deaths occur during this time period.

#### **5. The Mechanisms behind Food and Alcohol Intake as a Trigger for BrS ECG Pattern Manifestation**

The mechanism behind the manifestation of ventricular arrhythmias after ingestion of alcohol or large amounts of food is still uncertain. The main product produced by the metabolism of fatty acids (FA), carbohydrates, ketones, and amino acids [36] is adenosine triphosphate (ATP), which is essential as energy source for cardiac work. The energy metabolic pathways include (1) glycolysis, where ATP is produced by glucose oxidation, (2) the citric acid cycle (Krebs cycle or TCA cycle), where guanosine-triphosphate (GTP), nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) are produced by acetyl-CoA oxidation, (3) the electron-transport chain (ETC), where most of the ATP is produced, and (4) fatty acid beta-oxidation, where FAs breakdown into acetyl-CoA and they are used by the TCA cycle. Acetyl-coenzyme A (CoA) is produced by either oxidative decarboxylation of pyruvate from glycolysis, beta-oxidation of long chain fatty acids, or oxidative degradation of some amino acids [37]. CoA is synthesized within the mitochondria, and it is the main substrate for the TCA cycle, which is a series of enzyme catalyzed reactions that generate energy sources via oxidative reactions. NADH and FADH2 are generated, then they enter into the ETC and, together with oxygen, they generate ATP through a redox reaction. The ATP level in the cells is maintained constant via two mechanisms: the production of ATP by oxidative phosphorylation and the hydrolysis of ATP [38]. In order to sustain normal cardiac activity in a healthy human heart, if there is an increase of fatty acid oxidation, there is also a decrease of pyruvate oxidation, and thus a glucose oxidation, and vice versa [39].

However, dysfunction of glucose metabolism, whether hypoglycemia or hyperglycemia, could have detrimental effects on cardiomyocytes. Several studies describe the deleterious effect of high glucose and alcohol on cardiomyocytes. In addition, the deprivation of glucose results in cardiac myocyte apoptosis [40–42]. A study conducted on rat cardiomyocytes demonstrated that high glucose-induced mitochondrial hyperpolarization increases cell injury [43]. Moreover, an in vitro induction of high glucose resulted in cardiomyocyte apoptosis [44]. Furthermore, several studies have demonstrated that ethanol depresses myocardial contractility both in humans and animals [45,46]. The first enzyme involved in alcohol metabolism is alcohol dehydrogenase (ADH), which catalyzes the conversion of ethanol into acetaldehyde, which is a reactive and toxic product that contributes to the formation of reactive oxygen species (ROS) and reduces the oxidation process in liver cells; the second enzyme involved is aldehyde dehydrogenase 2 (ALDH2), which converts acetaldehyde into acetate, which is then ready to be incorporated into Acetyl CoA and then entered into the TCA cycle. Indeed, a study conducted on 198 Japanese patients affected by BrS demonstrated that arrhythmic events caused by the consumption of alcohol were associated with the increased activity of the alcohol-metabolizing enzyme ADH1B in BrS patients [47].

BrS is a complex disease that has been described to have an oligogenic model of inheritance [10,48], and several possible genetic causes have been proposed, reviewed elsewhere [10,49]. It has also been hypothesized that, when people are overstressed by large meals and alcohol, especially during festivities, possible mutations in genes encoding for SULT1A enzymes result in the inability of those enzymes to deactivate catecholamines in the intestine, possibly inducing cardiac arrhythmia [50]. Finally, another hypothesis could be that glucose metabolism dysfunction can interfere with the homeostasis of ATP and ROS within the cardiomyocytes [51], possibly leading to arrhythmic events via mitochondria defects and impaired intracellular cation homeostasis.

Adhering to the "Mediterranean diet" may reduce the risk of cardiovascular disease. However, unfortunately, this diet is not clearly defined. However, generally, it consists of eating smaller portions throughout the day, such as eating five smaller meals instead of three larger ones. The Mediterranean diet could allow for max one glass of red wine per day, but patients with cardiac arrhythmias are probably best to abstain completely from alcohol, especially if even low amounts of alcohol make them feel unwell. In our

experience, even one glass of alcohol can make some patients with BrS fell unwell. In these cases, it is best to avoid alcohol completely. The Mediterranean diet includes a lot of plant-based foods and olive oil, but tends to be low in saturated fat, meat, and dairy products. Red meat could be eaten once per week. Fish are generally included minimum twice per week, but oily fish, such as salmon, which are larger fish and could contain a higher amount of mercury, should be limited to only once per week, although it is still good because it contains a high amount of omega-3 fatty acids. Nuts are also good for omega fatty acids and legumes are good for proteins.

#### **6. Sudden Cardiac Death and QT Prolongation Triggered by Ketogenic Diet**

While carbohydrates provide a readily available fuel for our body, fats and oils (lipids) are considered our primarily source of stored energy. Fat enters into the body through food and breaks down into triglycerides, and then into fatty acids and glycerol. Mitochondria provide the main source of energy, and, therefore, the dysfunction of the two metabolic pathways of β-oxidation of fatty acids (FAO) and oxidative phosphorylation (OXPHOS) can lead to mitochondrial remodeling and the manifestation of heart failure, arrhythmias, and ventricular hypertrophy [52,53].

Acute arrhythmic events associated with a ketogenic diet and calorie-restricted diets can include QT prolongation, leading to sudden cardiac death, and these phenomena have been described in children, adolescents, and adults [54–56]. A ketogenic diet is characterized by very low carbohydrate intake, with 75% of calories derived from fat. This carbohydrate (CHO) restriction helps to reduce blood glucose and insulin [57]. However, it is known that, among several complications related to a ketogenic diet, there is selenium deficiency, QT prolongation, and SCD [58–60]. A case report described a Torsades de Point (TdP) event in a patient with a dual-chamber implantable cardioverter-defibrillator (ICD) affected by LQT2 triggered by an uncommon factor: the ketogenic diet. Specifically, while the patient was following a ketogenic diet, she experienced four episodes of ventricular fibrillation, due to TdP, over the course of only three weeks. Selenium, ketone bodies, and alcohol levels were all within normal limits. One month later, she stopped the ketogenic diet, and the ICD showed no further arrhythmic episodes [17].

The majority of SCD cases of pediatrics patients are associated with QT interval prolongation and ketosis. In a report about two cases of death in two children on a ketogenic diet for seizure control, both patients experienced QT prolongation and suffered from selenium deficiency [58]. However, another case described a correlation between a QT interval prolongation and ketogenic diets in the absence of electrolyte imbalance in children [60]. Specifically, a direct correlation was observed between QT interval prolongation and β-hydroxybutyrate concentrations, and between QT interval prolongation and systemic acidosis [60]. Interestingly, in a study of 70 children with drug-resistance epilepsy, receiving a ketogenic diet for a 12-month period, no deleterious effects on corrected QT interval, QT dispersion, and Tp-e interval were reported [61]. Finally, another case described a five-year-old boy who developed selenium deficiency, acute reversible cardiomyopathy and ventricular tachycardia with prolonged QT interval after following a ketogenic diet to treat refractory epilepsy. Then, his clinical status improved and got back to normal after selenium supplementation [62].

In conclusion, the extended association between QT interval prolongation and/or SCD and ketosis conditions/ketogenic diet has been described, and it raises the question of whether ketosis may directly affect cardiac repolarization.

#### **7. The Mechanisms behind Ketosis as a Trigger for the Manifestation of QT Prolongation**

The relationship behind the manifestation of ventricular arrhythmias and high-fat and low-carbohydrate diet is still unclear. However, it is known that the heart uses fatty acids as a main substrate for source energy, but it can also use ketone bodies. Ketone bodies are produced by breaking down fatty acids and ketogenic amino acids in a process called ketogenesis, previously reviewed elsewhere [63]. Briefly, ketogenesis involves the

anabolic hormone insulin, and the catabolic hormones glucagon, cortisol, catecholamines, and growth hormone, of which insulin and glucagon are considered the most crucial for this pathway [64,65] (Figure 2). Ketone body concentration is lowered by insulin, which promotes glucose uptake and oxidation. The reduction of circulating insulin levels is the principal triggering event for accelerating ketogenesis [63]. Insulin acts on the adipose tissue, liver, and the periphery; specifically, the low amount of insulin and a high amount of glucagon in our blood stream trigger the augmentation of free fatty acids (FFAs), increase uptake of FFAs into the mitochondria, and increase production of ketones in the liver, by activating the acyltransferase system through the inhibition on malonyl-CoA synthesis. Indeed, the ketogenesis pathway occurs primarily in the mitochondria of hepatocytes. FFAs are converted into fatty acyl CoA (Acyl CoA), which enters into the hepatic mitochondria through CPT1-mediated transport. Then Acyl CoA undergoes β-oxidation to produce Acetyl CoA, which is only employed to generate ATP if there is enough oxaloacetate. When carbohydrate intake is limited, such as in the ketogenic diet, the liver uses the majority of oxaloacetate to produce glucose through gluconeogenesis; therefore, the liver diverts the acetyl CoA to form ketone bodies. Thiolase enzyme (acetyl coenzyme A acetyltransferase (ACAT)) catalyzes the reversible reaction where two molecules of acetyl CoA are combined to generate acetoacetyl CoA. At this point, mitochondrial β-Hydroxy β-methylglutaryl-CoA (*HMG*-CoA) synthase catalyzes a condensation reaction by adding an extra acetyl CoA molecule onto the acetoacetyl CoA. Then, the enzyme *HMG*-CoA lyase cleaves the *HMG*-CoA, which releases CoA and forms acetoacetate, the metabolized ketone body. Within the mitochondrial matrix, 3-hydroxybutyrate dehydrogenase can reduce the acetoacetate into two other ketone bodies: acetone and β-hydroxybutyrate (β-HB), through non-enzymatic decarboxylation or by beta-hydroxybutyrate dehydrogenase, respectively. Moreover, the ratio of NADH/NAD+ helps to maintain an equilibrium between acetoacetate and β-HB within the mitochondria matrix. Both acetoacetate and β-HB are considered fuel molecules normally found in the heart and renal cortex. Acetone cannot be metabolized. At this point, due to the fact that the liver does not have enzyme beta ketoacyl-CoA transferase, and it cannot utilize ketone bodies [66], acetoacetate and β-HB reach the extrahepatic tissues. β-HB is converted into acetoacetate, which is then converted back to acetyl-CoA. Acetyl-CoA goes through the TCA and produces 22 ATP by oxidative phosphorylation. Therefore, due to the acid nature of ketone bodies, this causes an anion gap metabolic acidosis. This condition usually results in electrolyte imbalances, especially a reduction in K+, Mg2+, and P.

**Figure 2.** Ketogenesis pathway in hepatic mitochondria. Low amounts of insulin and high amounts of glucagon in our blood stream trigger the augmentation of free fatty acids (FFAs), and increase uptake of FFAs into the mitochondria. Acetyl CoA is generated from beta-oxidation of Acyl CoA, which derives from FFAs. The production of ketones (acetoacetate, acetone, β-HB) in the liver is then increased.

A metabolomic study on individuals with arrhythmogenic cardiomyopathy (AC) identified as a possible biomarker β-HB, due to its elevated amount in the plasma and hearts [67]. Specifically, the β-HB produced by cardiomyocytes of AC patients is released into the blood, and its levels are significantly higher compared to controls [67]. Therefore, it was demonstrated that cardiac ketogenesis occurs in CA, and β-HB may be used as a potential metabolic marker to predict CA.

#### **8. Oxidative Stress**

Oxidative stress is usually considered a state in which the production of ROS and antioxidant defenses are not balanced [68]. ROS are derivatives of molecular oxygen, such as superoxide (O2 −), hydrogen peroxide (H2O2), peroxynitrite (ONOO–), and hydroxyl radicals (OH) [69]. ROS are mainly produced by mitochondria, and their homeostasis is maintained by the enzyme glutathione peroxidase (GSH-Px). In damaged mitochondria, the calcium ions are overloaded and drive the augmentation of ROS concentration, which leads to excitotoxicity damage [70]. Indeed, excessive generation of ROS, impaired calcium homeostasis, and diminished ATP production directly impact mitochondrial function [71].

Repetitive or prolonged oxidative stress can damage proteins and lipids within the cell, and it might result in a contractile dysfunction, a downregulation of gene expression, and also a disrupted energy transfer, which could induce cardiomyocyte apoptosis, followed by heart failure [72]. There have been limited studies into the mechanisms linking oxidative stress and arrhythmias, but it has been shown that cardiac conditions with increased arrhythmic risks are associated with an unbalanced production of ROS [73]. ROS, in addition to their role as a messenger in cell signal transduction and the cell cycle, regulate both cellular metabolism and ion homeostasis in excitable cells. An elevated presence of ROS within the cells can be highly toxic, and they can lead to arrhythmogenic triggers, such as alterations of ion channels (Na, Ca2+, and K+), dysfunction of the mitochondria, and gap junction remodeling [74]. Therefore, an excessive production of ROS and ineffective ROS scavenging can culminate in cell death [52].

It is well known that ketone bodies are always present in the blood, and their concentration increases during prolonged exercise and fasting. In vitro studies demonstrated that KBs stimulate insulin release [75,76], cause lipid peroxidation, and generate oxygen radicals [77]. It is also known that KBs are able to reduce oxidative stress, due to the activation of multiple protective antioxidant pathways. However, we hypothesize that patients affected by inherited channelopathies could have a potential dysfunction of these pathways, and they are not able to reduce the levels of ROS. To sustain our hypothesis, there are some studies suggesting that exposure to high concentrations of KBs could provoke oxidative stress. A study conducted on calf hepatocytes suggested that both β-HB and acetoacetic acid decrease the activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and increase malondialdehyde (MDA) and nitric oxide (NO), which are markers of oxidative stress [78,79]. Another study attributed acetoacetate treatment to the activation of mitogen-activated protein kinase (MAPK) pathway, which is known to be activated by oxidative stress in rat hepatocyte cells [80]. Therefore, even if there are several studies associating KBs with the inhibition of oxidative stress and ROS production, there are still some studies showing a correlation between KBs and the induction of oxidative stress.

It is known that a nutrient overload helps to release free fatty acids and can also induce damages to the mitochondria [81]. Therefore, free fatty acids might be related to the excess production of oxidative stress. Indeed, there is a lot of evidence suggesting that conditions of high levels of glucose, lipids, or their combination can interfere with mitochondria metabolism, and they may modulate mitochondrial ATP synthesis capacity and increase ROS production [71]. Moreover, in patients with inherited channelopathies, malignant ventricular arrhythmias and SCD occur before overt structural changes of the heart. To prevent the arrhythmogenic substrate progression, more studies to understand the electrical instability of cardiomyocytes are needed. At present, a lot of studies are

focused on the connection between metabolic disease and the manifestation of arrhythmic events. Specifically, the attention is focused on the mitochondrial dysfunction, which can drive the manifestation of arrhythmic events by interfering with the electrical activity of the cardiomyocytes. The role of mitochondrial dysfunction in inherited channelopathies is still unclear and will be the subject of future studies.

#### **9. Vitamin D**

Vitamin D, also known as calciferol or hydroxyvitamin D (25-OHD), is a fat-soluble vitamin that is naturally found in a few foods and is also produced endogenously by the exposure of the skin to sunlight ultraviolet rays [82]. Vitamin D is responsible to increase the intestinal absorption of calcium and to maintain the serum calcium and phosphate concentration [82]. Vitamin D is also involved in the reduction of inflammation, cell growth, neuromuscular, immune function, and glucose metabolism [83–85].

Vitamin D deficiency has been related to different cardiovascular disorders, including SCD [86]. Moreover, a decreased level of 25-OHD has been linked to structural and ionic channel remodeling, which may increase arrhythmic events [87]. Indeed, prolonged QTc is commonly induced by hypocalcemia, which can be caused by vitamin D inadequacy or resistance.

In a case of a patient with severe vitamin D deficiency, hypocalcemia and prolonged QTc resulted in TdP and cardiac arrest. After the administration of vitamin D and calcium supplements, the QTc interval became normal, and the patient did not experience additional arrhythmic events [88]. A hypocalcemic teenage girl affected by hypoparathyroidism experienced a few episodes of syncope during exercise, and the ECG on admission showed prolonged QTc. After the treatment with alphacalcidol, which is an analog of vitamin D, and calcium supplements, the QTs of the patient became normal [89]. Moreover, in a case of a 40-year-old woman, who followed a vegan diet, she was affected by hypocalcemia, due to severe deficiency of vitamin D. The patient manifested symptoms of palpitations, presyncope, and a long QT (556 ms). Therefore, she was first treated with calcium gluconate, then by vitamin D and calcium oral supplementation. After the treatment, the QTc normalized, and the symptoms disappeared [90].

Vitamin D deficiency can not only induce the prolongation of the QTc, but it can also promote inflammatory reactions. It is known that cardiac contraction is affected by an overload of Ca2+ ions in myocardial cells. Studies have hypothesized that lack of vitamin D could interfere with the function of Ca2+ in myocardial cells; specifically, it can induce hypertrophy [91], increase anti-inflammatory cytokines [92], increase fibrosis [93], and impact the production of ROS in the atria [94].

The correlation between atrial fibrillation and vitamin D is poorly understood. Some studies suggest a direct correlation between atrial fibrillation and vitamin D deficiency [95–97]. However, other studies did not find a connection between vitamin D levels and the incidence of atrial fibrillation [98–100]. It would be important to better understand the link between vitamin D and calcium, because it is known that calcium overload causes myocytes apoptosis and cardiac failure [101,102]. Oxidative stress associated with cardiovascular risks factors is real, and, therefore, further studies are needed to investigate this aspect.

In conclusion, vitamin D deficiency appears to play an important role in CVD, and it is important to investigate the possible role of vitamin D deficiency in the development of arrhythmic events.

#### **10. Omega-3 Fatty Acids**

Omega-3 fatty acids, also called ω-3 (n-3) fatty acids, are polyunsaturated fatty acids (PUFAs), and they are essential nutrients involved in lipid metabolism. It has been demonstrated that n-3 PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid (ALA), play an important role in the human diet and cellular physiology, and they may have beneficial effects against CVD and risks factors, including arrhythmias, probably by the modulation of cardiac ion channels [103]. DHA and EPA fatty

acids are mostly found in seafood, seaweed, and algae, while ALA is in nuts and seeds. ALA might improve cardiac function by inhibiting apoptosis through anti-inflammatory and anti-oxidative stress effects in diabetic, but not normal, rats [104].

An investigation into whether a diet enriched with fish and PUFAs could be associated with changes in QT duration on a resting ECG showed that long-term consumption of fish could positively influence the duration of QTc by lowering it; therefore, fish intake may be considered an antiarrhythmic protection [105]. A retrospective study of men affected by BrS evaluated the correlation between the serum levels of EPA and DHA and the risks factors for SCD. A multivariate logistic regression analysis showed that low levels of EPA and DHA were linked to the incidence of syncope in patients affected by BrS. This same study suggested that all levels of omega-3 PUFAs may play an important role in preventing ventricular fibrillation in BrS [106]. Furthermore, a study on 123 Langendorff-perfused rabbit hearts, used to mimic LQT2 and LQT3 syndrome, showed that PUFAs were able to prevent TdP by reverting the AP prolongation. This effect was stronger in LQT2 than in LQT3 syndrome, and the antitorsadogenic effect was more distinctive with DHA and EPA compared with ALA [107].

A recent review demonstrated that n-3 PUFAs have no significant effect on mortality or cardiovascular health [108]. For example, in a study investigating the correlation between n-3 PUFAs from fish and risks of CVD, including SCD, PUFAs were inversely related to QTc and JTc intervals. However, QTc and JTc did not reduced the inverse relationship between n-3 PUFAs and SCD risks, suggesting that this association cannot explain the prevention of prolonged ventricular repolarization [109]. Moreover, in a study investigating the association between mercury (Hg), EPA, and DHA, and large seafood consumption and heart rate variability (HRV) and QT interval duration, the authors found a possible association between specific seafood types and arrhythmias, such as tuna steak with QTc and anchovies with HRV [110]. Finally, data from four trials suggested that a high dose (4.0 g/d) of n-3 PUFAs could increase the risk of atrial fibrillation development [111].

In conclusion, data on the effects of omega-3 are still inconsistent, requiring further studies to assess their beneficial effects on preventing arrhythmic events.

#### **11. Arrhythmogenic Ingredients**

Several factors can increase the risk of the development of arrhythmias in BrS and LQTS. Although not well studied in these two specific syndromes, one of the factors that could result in arrhythmias is the consumption of specific foods, which are considered to be arrhythmogenic [112,113], as described in Table 1, which lists both arrhythmogenic and anti-arrhythmogenic dietary factors.

Several case reports have described patients experiencing arrhythmic events and cardiac arrests after the consumption of energy drinks [114–117]. Taurine has been shown to modulate ion channel activity by suppressing the activity of sodium, calcium, and potassium channels [118]. Moreover, it shortens the action potential duration and decelerates the rate of terminal repolarization of the cardiac action potential, inducing atrial and ventricular arrhythmias or cardiac arrest [116]. Furthermore, atrial and ventricular arrhythmias can also be induced by caffeine, which is able to interfere with calcium homeostasis [115,119] by increasing intracellular calcium concentration [115]. Indeed, it was demonstrated that caffeine is able to stimulate calcium release from the sarcoplasmic reticulum [120], and calcium imbalances, particularly sarcoplasmic reticulum calcium stores, may be altered in BrS [121–123]. A 24-year-old male developed arrhythmias and collapsed after the ingestion, for the first time, of a small quantity of an energy drink combined with alcohol; specifically, the drink contained 80 mg of caffeine and 1000 mg of taurine, plus Vodka. He was then diagnosed with BrS [116]. Another case report showed that energy drinks could have triggered an abnormal QT response in a 13-year-old female affected by LQTS1. Moreover, a 22-year-old female affected by LQTS1 experienced cardiac arrest after the consumption of an elevated quantity of energy drink [124].

Grapefruit has been identified as an inhibitor of drug-induced TdP and QTc prolongation, thus enhancing their pharmacokinetics [113]. Specifically, naringenin, which is a flavonoid found in grapefruit, is able to block the hERG channel and induce TdP and/or QTc prolongation [113,125]. These hERG channels are known receptors of the drug ajmaline, which is used to provoke the diagnostic type-1 BrS ECG pattern [126]. Therefore, other ingredients could be suspected to be arrhythmogenic, because they contain flavonoids: citrus fruit, parsley, onions, berries, bananas, red wine, chocolate, grains, nuts, tea, coffee, and various other fruits and vegetables [127–129], including spinach, cauliflower, broccoli, black beans, and chickpeas [130–134]. Moreover, additional ingredients like lemon, lime, clementine, oranges, and bergamot oil could be considered a risk, due to the same organic compounds of grapefruit: furanocoumarins [129]. However, other studies have suggested that flavonoids could actually be beneficial for cardiovascular health by reducing inflammation. Flavonoids, polyphenolic compound derivatives, reduce inflammation and risk of cardiovascular disease by reducing NFκB and its resulting transcription factors involved in the inflammatory pathway [128]. Many other natural products, which have polyphenols as their major compound, have been shown to have anti-inflammatory effects, such as mushrooms, honey, plant extracts, plant juices, plant powders, and essential oils [128,135,136]. Thus, further studies are needed to understand these foods and the resulting effects, in order to better advise the patients about dietary supplements or restraints.

**Table 1.** Arrhythmogenic and anti-arrhythmogenic dietary factors.

§ Honey and mushrooms have been described as both arrhythmogenic and anti-arrhythmogenic, depending on the study.

#### **12. Ingredients That Suppress Cardiac Arrhythmogenesis**

An interesting review showed that 18 active ingredients such as alkaloids, flavonoids, saponins, quinones, and terpenes, Wenxin-Keli, and Shensongyangxin could have antiarrhythmic effects [143]. In particular, the Chinese herb extract, Wenxin-Keli (WK), has been reported as an effective treatment of atrial and ventricular fibrillation by inhibiting the transient K+ outward current (Ito) [144]. The experiments were conducted in a canine experimental model of BrS, and the authors observed an inhibition of Ito and indirect adrenergic sympathomimetic effects using WK in combination with quinidine [144]. However, the 18 ingredients described in the review, with the exception of omega 3, have been tested in vitro or in animal models as natural drugs or in combination with other antiarrhythmic treatments, and not as ingredients for regular meals. Therefore, further studies are needed.

Another ingredient with the potential to prevent antiarrhythmic events, in moderate doses, is resveratrol, a stilbenoid polyphenol found in grapes. It has been described as a potential inhibitor of intracellular calcium release able to eliminate calcium overload in AF, and, therefore, able to preserve the cardiomyocyte contractile function [140]. Finally, based on an interesting review on antioxidant therapies for atrial fibrillation [138], it would

be interesting to further study the role of vitamin C, vitamin E, and carotenoids, found in fruits and vegetables, and their role as suppressors of ROS, and, therefore, their role as anti-arrhythmic nutrients.

#### **13. Electrolytes**

Food is the main source of electrolytes, essential minerals for life. Electrolytes are required for maintaining osmotic pressure in cells and generating action potentials in nerves and muscles. In particular, sodium, calcium, potassium, and magnesium play an important role in the heart. Indeed, it has been demonstrated that electrolyte imbalance can have detrimental effects on the heart, such as triggering cardiac arrhythmias or cardiac arrest [141], including what has been coined "BrS phenocopies" [145], which may provide important insights into the mechanisms involved in BrS [11]. It is important to understand better the connection between food intake, electrolyte imbalance, and BrS or LQTS.

#### **14. Vagal Tone Activity and Arrhythmic Events**

The heart rhythm is regulated by cardiac parasympathetic (vagal) nerves, the sympathetic nerves, and the pacemaker cells [121]. Autonomic activity can influence the elevation of the ST-segment [146–148]. Indeed, late in the 1990s, it was shown that the nocturnal vagal activity may be involved in the cardiac arrhythmic events of BrS [149]. Moreover, the high vagal activity could lead to the manifestation of ventricular tachyarrhythmias in patients with BrS or LQTS [150,151].

The relationship between the autonomic modulation and arrhythmic events is very complex and still unclear. However, based on the studies presented in this review, the association between the vagal activity and the consumption of large meals may contribute to the manifestation of arrhythmic events.

#### **15. Conclusions**

We describe herein the effects of dietary factors in patients affected by cardiac arrhythmias, specifically BrS and LQTS. To date, the importance of understanding the relationship between diet and inherited channelopathies has been underrated. It is evident that dietary factors can influence the risk of the development of arrhythmic events. Therefore, we recommend eating and drinking small portions throughout the day and to try to limit certain types of ingredients in order to prevent arrhythmic events. Modifying the diet might not be enough to fully prevent arrhythmias, but it can help lower the risk.

**Author Contributions:** S.D. conceived and drafted the paper. M.M.M. revised the paper. M.M.M., E.M. and G.N. provided useful feedback. C.P. secured funding for the project. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was partially supported by Ricerca Corrente funding from Italian Ministry of Health to IRCCS Policlinico San Donato.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

#### **References**

## *Review* **Relationship between Dietary Patterns with Benign Prostatic Hyperplasia and Erectile Dysfunction: A Collaborative Review**

**Giorgio Ivan Russo 1,\*, Giuseppe Broggi 2, Andrea Cocci 3, Paolo Capogrosso 4, Marco Falcone 5, Ioannis Sokolakis 6, Murat Gül 7, Rosario Caltabiano 2 and Marina Di Mauro 8,†**

**Abstract:** Interest in the role of dietary patterns has been consistently emerging in recent years due to much research that has documented the impact of metabolism on erectile dysfunction (ED) and/or benign prostatic hyperplasia (BPH). We conducted a non-systematic review of English articles published from 1964 to September 2021. The search terms were: ("dietary patterns" OR "diet") AND/OR ("erectile dysfunction") AND/OR ("benign prostatic hyperplasia"). In the present review, we have highlighted how the association between dietary patterns and two of the most frequent pathologies in urology, namely erectile dysfunction and benign prostatic hyperplasia, is present in the literature. The data suggested that a diet that is more adherent to the Mediterranean diet or that emphasizes the presence of vegetables, fruits, nuts, legumes, and fish or other sources of long-chain (n-3) fats, in addition to reduced content of red meat, may have a beneficial role on erectile function. At the same time, the same beneficial effects can be transferred to BPH as a result of the indirect regulatory effects on prostatic growth and smooth muscle tone, thus determining an improvement in symptoms. Certainly, in-depth studies and translational medicine are needed to confirm these encouraging data.

**Keywords:** prostate; diet; metabolism; benign prostatic hyperplasia; erectile dysfunction

#### **1. Introduction**

The interest in the role of dietary patterns has been consistently emerging in recent years due to much research that has documented the impact of metabolism on erectile dysfunction (ED) [1] and benign prostatic hyperplasia (BPH) [2,3].

Although much research has already demonstrated a significant association between dietary patterns and prostate cancer, including polyphenols, phytoestrogens or phenolic acids [4–6], the evidence regarding ED and BPH have not been fully investigated.

It is estimated that the worldwide prevalence of erectile dysfunction will likely increase to 322 million men by 2025 [7]. These results also explain the increase in interest over the years in Google trend searches for many terms such as prosthetic surgical treatment (+1.7%), for prostaglandins (+0.7%), for traction (+0.6%), and for shock wave therapy (+1.8%) [8].

**Citation:** Russo, G.I.; Broggi, G.; Cocci, A.; Capogrosso, P.; Falcone, M.; Sokolakis, I.; Gül, M.; Caltabiano, R.; Di Mauro, M. Relationship between Dietary Patterns with Benign Prostatic Hyperplasia and Erectile Dysfunction: A Collaborative Review. *Nutrients* **2021**, *13*, 4148. https:// doi.org/10.3390/nu13114148

Academic Editor: Lynnette Ferguson

Received: 7 November 2021 Accepted: 17 November 2021 Published: 19 November 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Although many modifiable risk factors for ED have been investigated, such as cardiovascular disease (CVD), smoking, obesity, sedentary behavior, diabetes, hypertension, hyperlipidemia, and metabolic syndrome [9], it is still unknown whether healthy dietary patterns are associated with a reduced risk (Figure 1).

**Figure 1.** Overview of mechanisms associated with erectile dysfunction.

In addition to these concepts, it is interesting to state that men with ED are 1.33–6.24 times more likely to have BPH than men without ED [10].

In fact, data from the literature have shown a close relationship between BPH and ED, suggesting that pathophysiological mechanisms involved in the metabolic syndrome are key factors in both disorders [11].

In particular, several possible pathophysiological mechanisms have been discussed, including the NOS/NO (the nitric oxide synthase) and the Rho-kinase activation pathways, autonomic hyperactivity, pelvic ischemia and microvascular dysfunction, inflammatory pathways, sex hormones, and psychological factors [11].

All these premises lay the groundwork for the hypothesis that dietary patterns may have a role in exacerbating or even preventing ED and BPH [12].

For these reasons, in this non-systematic review, we aimed to address current evidence on the role of dietary patterns on ED and BPH. We also addressed the impact of diabetes, atherosclerosis, and metabolic syndrome on ED and BPH.

#### **2. Materials and Methods**

We conducted a non-systematic review of English articles published from 1964 to September 2021. The search terms were: ("dietary patterns" OR "diet") AND/OR ("erectile dysfunction") AND/OR ("benign prostatic hyperplasia").

#### **3. Erectile Dysfunction**

In recent years, interest in the quality of food has grown, paying attention not only to the individual food, but also to the micronutrients contained in the food [13,14].

#### *3.1. Studies in Animal Models*

In recent years, there have been important advances in the study of the molecular pathways that regulate the association between diet, exercise, and endothelial function in the penis.  They also reported that exercise of pigs counteracted these abnormalities [15].

These data demonstrated that unhealthy diets determine a detrimental impact in endothelial cells by the increase in oxidative stress and significant reduction in nitric oxide, an essential molecule that maintains erectile function [16].

Akomolafe et al. evaluated the effect of a diet supplemented with raw and toasted pumpkin seeds on some key biochemical parameters relevant to erectile function in the body cavernous tissues of male rats. Animals were divided into six groups (10 animals per group) for the evaluation of adenosine deaminase (ADA), phosphodiesterase-5 (PDE-5), arginase, and acetylcholinesterase (AChE) activity, including nitric oxide level and malondialdehyde (MDA). Group I: normal control rats fed with a basal diet; Groups II and III: (5% and 10% pumpkin seeds [PS]) rats fed with diet supplemented with 5% and 10% raw pumpkin seeds, respectively; Groups IV and V: (5% and 10% roasted pumpkin seeds [PS]) rats fed with diet supplemented with 5% and 10% roasted pumpkin seeds, respectively; Group VI: rats treated with Sildenafil citrate (5 mg/kg). The diet supplemented with roasted pumpkin seeds showed better PDE-5, ADA, and arginase activities, as well as NO and MDA levels. No significant differences were observed in the AChE activities of rats treated with raw and roasted pumpkin seeds. The authors concluded that the modulatory effects of raw and roasted pumpkin seeds on enzymes associated with erectile dysfunction suggest the biochemical rationale for their therapeutic role in improving erectile function. However, it appears that roasted pumpkin seeds (10%, *w*/*w* of the diet) have more beneficial effects than raw seeds [17]. In addition, a 2016 study by Akomolafe revealed that pumpkin seeds contain phenolic acids and flavonoids and prevent oxidative damage to testicular tissues [18].

Recent studies have suggested that the treatment of ED may benefit from the modulation of other enzymes such as ectonucleotidases (E-NTPDase) and ADA [19–21], which are involved in the regulation of biomolecules such as cGMP (cyclic guanosine monophosphate), NO (nitrogen oxide), ATP, and adenosine that are involved in penile erection [22,23].

In a study conducted in rats with ED, the authors investigated the effects of quercetin as a promising source of dietary phytochemicals for ED management.

The authors divided the rats into different groups by the administration of normal saline, cyclosporine-induced hypertension, rats administered with sildenafil (5 mg kg−1 day−1), and rats administered quercetin 25 mg kg−1 day−1 or Q 50 mg kg−1 day−1 (50 Q). They demonstrated that quercetin improved the activities of enzymes associated with better ATP bioavailability (E-NTPDase and 5 -nucleotidase). Its effects were able to decrease ADA activity and increase NO levels [24].

These findings highlighted the concept that polyphenols are phytochemicals and can promote good health and improved erectile dysfunction [25].

#### *3.2. Studies in Humans*

The importance of diet on ED arises from the assumption that this pathology is often the first symptom of coronary heart disease (CHD) [9,26,27]. In fact, the pathophysiology of ED is similar to that of atherosclerosis [28,29]. The correlation between diet and diseases of the cardiovascular system has been known for years [1]. Therefore, a possible correlation between erectile dysfunction and dietary factors is conceivable.

In the study by Nicolosi et al., it is shown that 31.8% of men with a below-average level of physical activity demonstrate ED, compared to 17.5% of men with an average activity level and only 13.9% of men who have an above-average level of physical activity, thus demonstrating a linear association between the level of physical activity and ED [30].

Lu et al. recently studied the relationship between a plant-based diet and erectile dysfunction in 184 Chinese patients. The ED group (92 subjects) and the free ED group (92 subjects) were similar in terms of baseline characteristics (*p* > 0.05), with the exception of lifestyle (*p* < 0.05). The plant diet index (PDI) and the healthy plant diet index (hPDI) in the ED group were significantly lower than those of the control group (*p* < 0.001). Adjusted multivariate analysis indicated that the presence of ED was negatively associated with nitric oxide, PDI, and hPDI levels (all *p* < 0.05) and was positively related to body mass index, metabolic syndrome and E-selectin levels. Additionally, both PDI and hPDI significantly increased with increasing International Erectile Function Index (IIEF-5) scores within the ED group (*p* < 0.05). Finally, multimodal multivariate analysis was performed, which indicated the robustness of the results [31].

From previous studies, we know that ED is less frequent in patients who adhere to the Mediterranean diet model, characterized by the prevalent presence of fish, vegetables, fruit, whole grains, and nuts, compared to those who mainly consumed a diet containing red and processed meats and refined cereals [16,32].

Giugliano et al. assessed the relationship between adherence to the Mediterranean diet and sexual function among 555 men with type 2 diabetes, showing that men with the highest scores of adherences to the Mediterranean diet had lower overall prevalence of erectile dysfunction. Additionally, men in the middle and highest tertiles had a lower prevalence of severe ED compared to men in the lowest adhesion tertile [33].

Sticking to an unhealthy diet pattern can cause early endothelial damage through oxidative stress, which results in a reduction in the availability of nitric oxide, indispensable in the physiology of erection [34].

Food antioxidants have been shown to improve erectile dysfunction in men. A rich source of polyphenols is represented by the standardized French maritime pine bark (Pinus pinaster) Pycnogenol (PYC) extract. The main constituent of the polyphenols in PYC is made up of 70% procyanidins. PYC has significant antioxidant and multiple power biomodulatory effects, such as transcription factor inhibition NF-κB, cyclooxygenase, NO stimulation of the hypertensive effect by inhibition of the angiotensin converting enzyme, antimutagen effects, and alleviation of allergic and anti-glycemic asthma symptoms. Trebaticky enrolled 53 patients with ED who were divided into two groups (32 with diabetes mellitus, 21 non-diabetes mellitus) in a randomized, blinded, placebo-controlled study. During the 3-month intervention with Pycnogenol or placebo and one month after the end of the intervention, the patients were investigated for ED with a validated International Index of Erectile Function-5 (IIEF-5) questionnaire. Lipid profile and blood glucose were analyzed in each group. The results showed that of the natural polyphenols extracted, Pycnogenol improved erectile function in the DM group by 45% compared to the NDM group, where the improvement was also significant, but only 22%. The levels of total cholesterol, LDL cholesterol and glucose were lowered by Pycnogenol in patients with DM. Glucose level was not affected by Pycnogenol in non-DMs. The placebo showed no effect on the monitored parameters in both groups [35].

In a recent study, Salas-Huetos et al. (2019) reported that the consumption of walnuts increased sexual function. Indeed, a secondary outcome analysis of the FERTINUTS study, a 14-week randomized controlled trial with 83 subjects consuming a Western-style diet, reported that consuming 60 g/day of nuts was associated with increased orgasmic function and sexual desire compared with the control group (avoiding nuts), but no significant differences in erectile function were observed [36].

Previously, Mykoniatis et al. enrolled 350 adult men who were asked to complete an anonymous web-based questionnaire. Erectile dysfunction was diagnosed with the International Erectile Function Index (IIEF) and flavonoid intake was recorded using foodfrequency questionnaires, with a focus on flavonoid-rich foods such as coffee, fruit, etc. Participants were divided into two groups based on the IIEF scores: control group without ED (IIEF score 26; n = 264) and the case group with ED (IIEF score < 26; n = 86). Men with erectile dysfunction reported a lower median monthly intake of total flavonoids (*p* < 0.001) and all flavonoid subclasses (*p* < 0.001) than the controls. Adjusting the intake for age and body mass index, it was found that the consumption of 50 mg/day of flavonoids reduced the risk of erectile dysfunction by 32% (odds ratio = 0.68, *p* < 0.001). Of all the flavonoids recorded, flavones appeared to contribute the most to healthy erectile function. Controls

reported higher consumption of fruit and vegetables, lower consumption of dairy products and alcoholic beverages, and less intense smoking than the cases (*p* < 0.001) [37].

Cassidy et al. were among the first authors to evaluate the intake of flavonoids in erectile dysfunction. The results of the Health Professions Follow-up study showed that a reduced incidence of ED was associated with increased habitual intake of specific foods rich in flavonoids. The greatest benefits from the increase in the consumption of flavonones, flavones, and anthocyanins were observed in overweight or obese young men. Of all the flavonoids recorded, flavones appeared to contribute the most to healthy erectile function [38], according to Mykoniatis's study [37].

Bauer also conducted a population-based prospective cohort study which included men from the Health Professionals Follow-up Study with follow-up from January 1998 through January 2014, demonstrating that a higher-quality diet based on adherence to a Mediterranean diet or alternative to the Healthy Eating Index diet, which emphasize eating vegetables, fruits, nuts, legumes, and fish or other sources of long-chain (n-3) fats, as well as avoiding red and processed meats, was found to be associated with a lower risk of developing erectile dysfunction [39].

Taking together all these considerations, we postulate that dietary patterns have a significant role in ED severity (Figure 2) and should be investigated further in future studies.

**Figure 2.** Relationship between dietary patterns and erectile dysfunction. Relationship between dietary patterns and erectile dysfunction. PDE5 = phosphodiesterase-5 inhibitors; ADA = adenosine deaminase; NO = nitrogen oxide; MDA = Malondialdehyde; ED = erectile dysfunction.

#### **4. Benign Prostatic Hyperplasia**

The histopathology of BPH characteristically consists of a dual hyperplasia of the epithelial and stromal compartment of the transitional zone of the prostate. Epithelial hyperplastic features include nodules composed of variably sized and sometimes cystically dilated prostatic glands with a retained basal cell layer, often exhibiting corpora amylacea and/or calcifications; stromal hyperplasia consists of nodular proliferation of bland-looking spindle cells with rounded to ovoid nuclei, frequently resembling smooth muscle cells [40].

Several biological factors, including oxidative stress, inflammation, androgens, and enhanced expression of multiple growth factors, have been associated with benign and malignant prostatic disorders [41–45] (Figure 3).

**Figure 3.** Overview of mechanisms associated with benign prostatic hyperplasia.

In this regard, as some evidence has suggested that a high-fat diet is intrinsically correlated with BPH by stimulating inflammation and oxidative stress [46], in recent decades, the potential association between different dietary patterns, including both macroand micronutrients, and incidence of BPH has become one of the most debated topics in scientific literature [47–49].

#### *4.1. Studies in Animal Models*

Numerous advances have been made in the comprehension of the molecular basis of the relationship between diet and BPH in animals.

Zhang et al. found that Vitamin D (VD) deficiency in early life promoted BPH in middle-aged mice [50]; male pups, whose dams were fed with VD-deficient diets during pregnancy and lactation and continued to receive VD-deficient diets after weaning. Higher incidences of BPH were observed in this group of mice, compared to a control group of dams and male pups that received a standard diet. In addition, the authors [50] found that VD-deficient diets induced prostatic inflammation and fibrosis through the activation of the NF-κB-mediated pathway and the production of IL-6, as well as upregulation of the STAT3-mediated pathway that stimulates cell proliferation and growth. Interestingly, these prostatic effects were partially reversible if the standard diet was restored.

Li et al. showed that the combination of androgens and a high-fat diet-induced hyperinsulinemia promoted BPH in rats and the activation of p-ERK1/2 could be implicated in this process [51]. In particular, higher immunohistochemical and Western blot levels of p-ERK1/2 were observed both in rats with BPH plus a high-fat diet and rats with BPH compared to those found in rats with a high-fat diet and in a control group. However, it has also been reported that the administration of flaxseed reduced epithelial cell proliferative activity in rats with BPH [52,53]; this finding led to the supposition that different fat types and contents are involved in BPH onset and maintenance. As further evidence for this hypothesis, Kayode et al. emphasized that a ketogenic diet, consisting of high fat, moderate protein and low carbohydrate consumption, ameliorated testosterone propionate-induced BPH in male Wistar rats [54]. Similarly, epigallocatechin-3-gallate (EGCG), a green tea component, has been found to play an antioxidative and anti-BPH role in a metabolic syndrome rat model [55].

Recently, Aljehani et al. investigated the role of icariin (ICA), a flavonol glycoside with marked phytoestrogenic activity in rats with metabolic syndrome (MS)-induced BPH [56]. Animals were divided into five groups (two out of five groups were fed a standard diet and MS was induced in the remaining three groups). MS rat groups were given vehicle, 25 mg/kg of ICA and 50 mg/kg of ICA, respectively. The authors found that the administration of both ICA doses had positive effects on prostate weight, prostate index, and histopathologic features of BPH. Furthermore, ICA seemed to play antiproliferative, proapoptotic, antioxidant, and anti-inflammatory functions by regulating cyclin D1, Bax, Bcl2, and tumor necrosis factor-α expression.

Mangosteen pericarp powder (MPP), which originates from Mangosteen, a tropical fruit from the Malay islands and the Indonesian Moluccas, has been traditionally used for wounds and cutaneous infections. Recently, the consumption of MMP, whose xanthones are the main polyphenol compounds, has been found implicated in the decrease in prostate weight, serum testosterone, and attenuation of BPH in F344 male rats [57].

#### *4.2. Studies in Human*

BPH is a very frequent and age-related disease as it is estimated that about 50% of men over the age of 50, and 80% of those older than 70 suffer from it [58,59]. Patients with BPH often exhibit acute urinary symptoms deriving from urethra compression and/or lower urinary tract symptoms (LUTSs) [59]. Due to the huge impact of BPH on populations, multiple studies have investigated its relationship with environmental factors, including the effects of several macro- and micronutrients [60,61].

A statistically significant correlation between higher risk of BPH and high consumption of fats and red meat or low consumption of proteins and vegetables has been found by the Prostate Cancer Prevention Trial (PCPT) within a cohort of 18,800 patients aged more than 50 years. A slight relationship between lower risk of BPH and multiple nutrients, such as lycopene, VD and zinc was also established for this group; conversely, no association between this disease and antioxidant consumption was identified. Total but not dietary vitamin D was associated with reduced risk. Compared with men in the lowest quintile of total vitamin D intake, those in the highest quintile had an 18% reduced BPH risk (*p*-trend = 0.032). Compared with men eating red meat less than once per week, men eating red meat at least daily had a 38% increased BPH risk (*p* = 0.044) and, compared with men eating fewer than one serving of vegetables per day, men eating four or more servings had a 32% decreased BPH risk (*p* = 0.011) [62]. The protective role of lycopene supplementation on BPH has been also shown by Schwarz et al. who enrolled 40 patients with histologically proven BPH. The authors divided their patients into two groups: (i) lycopene at a dose of 15 mg/d for 6 months, (ii) placebo for 6 months, and found that patients who received lycopene had decreased PSA levels. No evidence of further prostate enlargement nor higher amelioration in symptoms of the disease were found, as assessed by the International Prostate Symptom Score (IPSS) questionnaire, compared to those who were given the placebo [63]. Further evidence of the anti-BPH effect of lycopene has been previously provided by Kim et al. from a clinical study on prostate cancer patients in which lycopene was found capable of inducing apoptosis in tumor-free prostatic tissue exhibiting the histologic features of BPH [64].

Rohrmann et al. prospectively investigated the effects of fruits, vegetables and micronutrients on BPH and found an inverse correlation between intake of vegetables, especially those rich in beta-carotene, lutein, vitamin C (VC), and BPH. Interestingly, fruit intake resulted to be unrelated to the onset of the disease [65]. Conversely, the study by Lagiou et al., through the administration of a food frequency questionnaire, reported for a cohort of 420 patients, all permanent residents in Athens area, that fruit consumption with high levels of beta-carotene, lutein and VC were inversely correlated with BPH risk, while a high-fat diet, especially with increased intake of butter and margarine, had a positive correlation with the disease [66]. Based on these findings, the exact effects of a fruit-rich diet on BPH is still to be elucidated. It may be hypothesized that fruit consumption, according to the type and quantity, influences BPH onset and progression in a diversified manner. Similarly, little is known about the usefulness of polyphenols contained in green tea; in

this regard, it has been suggested that they could be used for the treatment of BPH-related symptoms, due to their positive effects on LUTS [67].

Even with regard to the role of a high-fat diet, the evidence from the literature is not unique; although some of the above-mentioned studies stated an increased risk of BPH in patients with high fat consumption [62,66], Suzuki et al. found that BPH risk was modestly associated with intake of eicosapentaenoic, docosahexaenoic, and arachidonic acids, but not with energy-adjusted total fat intake [68].

Similar to what has been reported on animal models [52,53], a strong utility of dietary flaxseed lignan extract in improving BPH-related LUTSs, compared to that of alpha1A-adrenoceptor blockers and 5alpha-reductase inhibitors, has been reported by Zhang et al. [69]. These authors conducted a randomized clinical trial in which a placebo, 300, or 600 mg/day of secoisolariciresinol diglucoside, a flaxseed extract, were administered to 87 patients affected by BPH and found a decrease in IPSS and improvement of quality of life score and LUTSs, respectively [69]. Conversely, it has been shown that pumpkin seed extract did not have any benefits on BPH compared to the placebo over a 1-year period [70].

The above-mentioned findings led us to emphasize that the exact relationship between different dietary patterns and BPH has not yet been fully elucidated; this is probably due to the fact that BPH is a multifactorial disease, whose pathogenesis seems to be correlated with different biological factors, including oxidative stress, androgenic stimulation and inflammatory and growth factors. Finally, recent advances have also highlighted the potential role of statins in reverting BPH symptoms by the improvement of hypercholesterolemia and metabolic syndrome [71]. As far as we are aware, as most macro- and micronutrients that have been associated with BPH risk also influence steroid concentrations, oxidative stress level and inflammation, it is reliable to suppose that they also have positive effects on BPH, regulating prostatic growth and smooth muscle tone (Figure 4).

**Figure 4.** Relationship between dietary patterns and BPH. Relationship between dietary patterns and BPH. STAT3 = Signal Transducer And Activator Of Transcription 3; BPH = benign prostatic hyperplasia.

#### **5. Conclusions**

In the present review, we have highlighted how the association between dietary patterns and two of the most frequent pathologies in urology, namely, erectile dysfunction and benign prostatic hyperplasia, is present in the literature. Evidence comes from both animal studies and in part from human studies. The data suggested that a diet that is more adherent to the Mediterranean diet or that emphasizes the presence of vegetables, fruits, nuts, legumes, and fish or other sources of long-chain (n-3) fats, in addition to reduced content of red meat, may have a beneficial role on erectile function. At the same time, the same beneficial effects can be transferred to the BPH side due to the indirect regulatory

effects on prostatic growth and smooth muscle tone, thus determining an improvement in symptoms. Certainly, in-depth studies and translational medicine are needed to confirm these encouraging data. Studies could address the relationship of dietary patterns and tissue expression as a marker of disease severity, such as NO and cAMP for ED and markers of inflammation for BPH.

Finally, clinical studies investigating the role of specific drugs for metabolic syndromes, such as statins or hypoglycemic drugs, together with investigations of dietary patterns could be beneficial in better understanding how to counteract ED and BPH.

**Author Contributions:** Conceptualization, G.I.R.; methodology, G.I.R.; writing—original draft preparation, G.I.R., G.B., M.D.M.; writing—review and editing, A.C., M.F., P.C., I.S., M.G., R.C., EAU-YAU Sexual, Reproductive Health Group. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Acknowledgments:** We would like to thank Giorgio Ivan Russo, Paolo Capogrosso, Marco Falcone, Ioannis Sokolakis, Murat Gül as member of the EAU-YAU Sexual, Reproductive Health Group.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

## *Review* **Nutrition and Kidney Stone Disease**

**Roswitha Siener**

University Stone Center, Department of Urology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany<EMAIL_ADDRESS>Tel.: +49-228-287-19034

**Abstract:** The prevalence of kidney stone disease is increasing worldwide. The recurrence rate of urinary stones is estimated to be up to 50%. Nephrolithiasis is associated with increased risk of chronic and end stage kidney disease. Diet composition is considered to play a crucial role in urinary stone formation. There is strong evidence that an inadequate fluid intake is the major dietary risk factor for urolithiasis. While the benefit of high fluid intake has been confirmed, the effect of different beverages, such as tap water, mineral water, fruit juices, soft drinks, tea and coffee, are debated. Other nutritional factors, including dietary protein, carbohydrates, oxalate, calcium and sodium chloride can also modulate the urinary risk profile and contribute to the risk of kidney stone formation. The assessment of nutritional risk factors is an essential component in the specific dietary therapy of kidney stone patients. An appropriate dietary intervention can contribute to the effective prevention of recurrent stones and reduce the burden of invasive surgical procedures for the treatment of urinary stone disease. This narrative review has intended to provide a comprehensive and updated overview on the role of nutrition and diet in kidney stone disease.

**Keywords:** calcium oxalate stone formation; diet; dietary assessment; fatty acids; fluid; oxalate; protein; sodium; uric acid; water

#### **1. Introduction**

The prevalence of urolithiasis of the general population has increased worldwide in the past decades and was reported to be 4.7% in Germany and up to 10.1% in the United States [1–3]. The recurrence rate of urinary stones is high and is estimated to be approximately 50% at 10 years [4]. Nephrolithiasis is associated with an increased risk of chronic and end-stage kidney disease, probably due to kidney injury from obstructive nephropathy [5,6]. The most common stone type is calcium oxalate (67%) followed by calcium phosphate (17%), uric acid (8%), struvite (3%), and cystine (0.4%) [7]. Urinary stone formation is a multifactorial process to which metabolic derangements, genetic factors, anatomical and functional abnormalities may contribute, whereby nutrition plays a crucial role. Diet composition can affect urine risk profile and the supersaturation with the stone-forming salt, which can modify the risk of urinary stone formation [8,9].

A reliable stone analysis is an essential precondition for specific treatment regimens, because urinary risk factors for stone formation vary with the type of stone [10,11]. Moreover, a thorough metabolic evaluation of the stone patient is required, including detailed medical history, dietary assessment as well as blood and urine analysis [11–17]. To reduce the risk of recurrent stone formation, targeted dietary treatment should be individually adjusted to the metabolic risk profile of each patient. The collection of two consecutive 24 h urines is recommended to detect frequent metabolic disturbances such as hypercalciuria, hypocitraturia, hyperoxaluria, and hyperuricosuria and to identify dietary risk factors for kidney stone formation. Specific nutritional therapy, based on dietary assessment and metabolic evaluation, has been demonstrated to be more effective than general dietary measures in preventing recurrent stone formation [18]. The aim of this narrative review is to summarize the current knowledge of the role of nutrition in kidney stone formation.

**Citation:** Siener, R. Nutrition and Kidney Stone Disease. *Nutrients* **2021**, *13*, 1917. https://doi.org/10.3390/ nu13061917

Academic Editor: Ina Bergheim

Received: 2 May 2021 Accepted: 31 May 2021 Published: 3 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **2. Fluid Intake**

A low urine volume caused by insufficient fluid consumption or excessive fluid loss is one of the most crucial risk factors for kidney stone formation [19]. Numerous physiological and pathological conditions may lead to dehydration that modifies water needs. These factors include excessive sweating due to heat exposure, mental stress, high physical activity level, and occupation as well as chronic diarrhea in the setting of fat malabsorption due to different gastrointestinal disorders [19–21]. A study of 100 steel plant workers reported a history of stone disease in 16%, with a urine osmolality of more than 700 mOsm, defined as dehydration, in more than 50% of workers [22]. Occupations at elevated risk for stone formation also include health care professionals with limited access to water. A survey of employees found that physicians working in the operating room had the highest prevalence of nephrolithiasis (17.4% vs. 9.7%) and reported higher stress levels and lower fluid intake compared to those who work at other locations [23]. Poor access to fluids or to bathroom facilities are other circumstances, in which occupation can affect urolithiasis, such as, for example, in professional drivers, airplane pilots or schoolteachers [24].

A randomized controlled study of 199 first-time idiopathic calcium oxalate stone patients evaluated the impact of a high fluid intake in preventing stone recurrence [25]. Patients were randomly assigned to a high water intake to achieve a urine volume of at least 2 L/day or to a control group without specific instructions. After the five-year follow-up period, the intervention group was found to have a 2.5-fold higher urine volume, a lower recurrence rate (12% vs. 27%; *p* = 0.008) and a longer time to recurrence (38.7 months vs. 25.1 months; *p* = 0.016) than the control group. Several systematic reviews and meta-analyses on the role of fluid intake in the secondary prevention of urolithiasis concluded that high total fluid intake to achieve a urine volume of greater than 2.0 to 2.5 L/day decreases the risk of stone recurrence [26–31]. While fluid intake was reported to be a protective factor in the primary prevention of kidney stone formation in cohort studies [30], no evidence was found from randomized controlled trials [31].

An adequate fluid intake is the most important nutritional measure to prevent kidney stone recurrence, regardless of urine stone composition and individual risk factors for stone formation [19]. The intake of an adequate amount of fluid increases urine dilution, thereby reducing the concentration of lithogenic constituents and encouraging the expulsion of crystals by decreasing the renal intratubular transit time [32]. According to the guidelines on urolithiasis, a copious fluid intake to maintain a urine volume of at least 2.0 to 2.5 L/24 h is recommended for most types of stones [15,16]. For the recurrence prevention of patients with cystinuria, excessive urine dilution is of the utmost importance. In adult cystine stone patients, urine volume of at least 3.0 L/24 h should be achieved to decrease urinary cystine concentration to below the solubility limit of 1.3 mmol/L at pH 6.0 [14,15,33]. A study of 27 adult patients with cystinuria demonstrated that maintaining a urine volume of more than 3.0 L/day significantly reduced recurrent stone formation [34]. The specific recommendations regarding fluid intake are summarized in Table 1.

**Table 1.** Recommendations for fluid intake—adapted from [14–16].

**Table 1.** *Cont.*

While the benefit of high fluid intake has been confirmed, the effect of different beverages is still debated. The constituents of different beverages can affect urine composition and consequently the risk of stone formation.

#### *2.1. Tap Water and Mineral Water*

The impact of the composition of tap water and mineral water on kidney stone formation is still a matter of debate. The composition of drinking water, predominantly the content of the divalent cations calcium and magnesium, varies widely between geographic regions within the same country [35]. Hard tap water, defined as a calcium carbonate concentration above 120 mg/L [36], can contribute to the daily dietary calcium intake. A study on 2295 patients from two regions in the United States found an increased risk of urinary stone formation for individuals consuming tap water from a private well [37]. However, the cause of elevated risk by private well users is unknown. Other cohort studies have not identified an association between the hardness of water from public water suppliers and urinary stone disease [37–39].

In contrast to tap water, bicarbonate is a natural constituent of mineral water besides calcium, magnesium and other ions. The intake of bicarbonate increases the buffering capacity of the body and is a strong alkalizing agent. Mineral water rich in bicarbonate can support alkalinization therapy and contribute to inhibitory potential of urine by increasing urine pH and citrate excretion [40]. A randomized crossover trial of healthy subjects compared the effect of an equimolar alkali load in form of bicarbonate-rich mineral water or potassium citrate on the urinary risk profile for calcium oxalate and uric acid stone formation [41]. The intake of 2 L/day of mineral water containing 1715 mg/L bicarbonate or 2.55 g/day potassium citrate significantly increased urine pH and citrate excretion and decreased oxalate excretion. The relative supersaturation of calcium oxalate and uric acid declined significantly in both groups. A study of healthy individuals conducted under controlled dietary conditions demonstrated that a mineral water rich in bicarbonate, calcium and magnesium increased urine pH, as well as the excretion of the urinary inhibitors of calcium oxalate stone formation citrate and magnesium [42]. Despite the significant increase in calcium excretion, no change in the relative supersaturation of calcium oxalate occurred.

A study of 22 idiopathic calcium oxalate stone patients evaluated the impact of three mineral waters with different contents of bicarbonate and calcium. The intake of the mineral water rich in bicarbonate and calcium resulted in a significant increase in urinary citrate and decrease in urinary oxalate excretion, while urinary calcium excretion and the supersaturation of calcium oxalate did not change [43]. A study by Rodgers [44] found that the intake of 1.5 L/day of a mineral water with high calcium content (202 mg/L) compared to 1.5 L/day of a tap water with low calcium content (13 mg/L) significantly increased calcium excretion in 20 healthy individuals of each sex as well as 20 female calcium oxalate stone formers but not in male patients. Urinary oxalate excretion and the relative supersaturation of calcium oxalate did not change in any of the four groups. A double-blind crossover study of 34 recurrent calcium oxalate stone patients under a regular diet examined the effect of 1.5 L/day of a bicarbonate-rich mineral water (2673 mg/L) vs. 1.5 L/day of a mineral water with a low bicarbonate content (98 mg/L) on the risk of urinary stone formation [45]. The intake of the bicarbonate-rich mineral water resulted in a

significant rise in urine pH, citrate and magnesium excretion compared to the control. The relative supersaturation of calcium oxalate decreased to a similar extent in both groups.

The impact of mineral water on the risk of calcium oxalate and uric acid stone formation is mainly determined by the presence of bicarbonate [40,41,45]. The effect of bicarbonate-rich mineral water corresponds to that of sodium bicarbonate in galenic form [46]. If calcium in high concentration is present in the water, the positive effect of increased urine pH and citrate excretion is neutralized by an increased urinary calcium excretion [42,44]. A randomized trial of 129 healthy women and men found that the consumption of at least 1.5 to 2.0 L/d of mineral water rich in bicarbonate (>1800 mg/L) can decrease the net acid excretion by reducing the dietary acid load [47]. Urine alkalinization is an important nutritional measure in the treatment of patients with calcium oxalate, uric acid and cystine stones, but it is not indicated in calcium phosphate and struvite stone disease [14]. Comparisons of the composition of commercial bottled 'still', 'carbonated' and 'sparkling' water from 10 European countries found a wide variation in the calcium content, with concentrations reaching up to 581.6 mg/L [48,49]. As the dietary reference intake of calcium of a total of 1000 to 1200 mg per day are already achieved by consuming 2 L of calcium-rich water, patients should be aware of the calcium content of the water.

#### *2.2. Fruit Juices and Fruit Juice Beverages*