**4. MSCs in meniscus injury**

Meniscus injury in the knee joint is probably the most frequent intra-articular damage. The typical treatment is a partial surgectomy, but it can lead to degeneration of articular cartilage, narrow joints, and early osteoarthritis. Intra-articular injection of MSCs could be a simple treatment with little damage since MSCs might promote the regeneration of meniscus. Indeed, it was found that when MSCs were injected directly into the articular cavity, they could migrate to the lesion site, directly participate in the tissue repair, and induce the repair of the host through the collateral secretion, and replace the injured tissue [36]. Murhpy et al. reported the first study of injection of BMSCs in sheep articular cavity [37], and observed the obvious repair of cartilage damage in meniscus injury, 6 and 12 weeks after injection. Whitehouse et al. also reported that undifferentiated MSCs/collagen-scaffold implant could provide a safe way to augment avascular meniscal repair in some patients [38]. Another study investigating the injection of allogenic MSCs in the context of post-subtotal meniscectomy found that there was evidence of meniscal regeneration in the two groups treated with MSCs [39]. However, Hong et al. used arthroscopic surgery to repair the meniscus of the posterior articular cavity with or without BMSCs after meniscus injury [40], and found that the meniscus and tibial plateau were not fully integrated, and the efficacy of MSCs treatment group was not significantly different from that of the control group. They argued that MSCs may differentiate into other tissue cells if they were not effectively induced to differentiate into specific cell types. Therefore, it is still a challenge to induce the cells into the meniscus cartilage phenotype in this context.

due to limited clinical case number [46]. Therefore, further high-quality studies for OA with high internal and external validity are still required. In addition, Shi et al. compared the clinical results of platelet-rich plasma (PRP) and MSCs treatments for osteoarthritis of the knee in a systematic review and pointed out MSCS provide more significant disease therapeutic

Auto\_BM\_MSC, Autologous Bone Marrow-derived MSCs. Auto\_AT\_MSC, Autologous Adipose Tissue-derived MSC.

Avascular necrosis of the femoral head (ANFH) is a serious clinical problem. If untreated, about 80% of ANFH progresses to the collapse of the head within 1–4 years [48]. Numerous clinical methods have been tried, including core decompression (CD), a commonly used method for treating the early stages of ANFH. The presumption is that CD can reduce the intraosseous pressure and also stimulate stem cell regeneration. But the outcome of CD is variable and is

With the development of non-biological materials, MSCs and tissue engineering techniques, the treatment of ANFH has been significantly improved recently [49]. For example, it was

effect [47].

a

b

c

still controversial.

**6. MSCs in femoral head necrosis**

**References Location BMCSa Follow-up**

BM\_MSC

AT\_MSC

BM\_MSC

BM\_MSC

BM\_MSC

The WOMAC index (pain subscale) has been used; scale 0–100.

The VAS index (pain subscale) has been used; scale 0–10.

**Table 1.** Summary of MSCs as the treatment of osteoarthritis.

[41] knee Auto\_

[42] knee Auto\_

[43] knee Allo\_

[44] knee Auto\_

[45] Hip Auto\_

Allogeneic Bone Marrow-derived MSC.

**time**

**No. of cases** **Pain subscale Outcomes**

http://dx.doi.org/10.5772/intechopen.76868

**values**

improvement, higher cartilage quality (MRI)

215

improvements

improvement, higher cartilage quality (MRI)

improvement, higher cartilage quality (MRI)

improvement, improved function

**Pre-infusion values Post-infusion**

Clinical Applications of Mesenchymal Stromal Cells (MSCs) in Orthopedic Diseases

1 year 12 24 ± 14b 6 ± 6b pain

6 months 12 56 ± 19b 34 ± 23b clinical

1 year 15 46 ± 15b 30 ± 16b pain

24 weeks 2 4c 0.38c pain

3 years 10 34.5 ± 8.2b 19.2 ± 6.1b pain


**7. Conclusion**

Mineral diet can have a significant impact on animal reproduction, as evidenced by the current review. This study would highlight the role of soil minerals in farm animal reproductive function, including infertility, met energy-protein requirements, and mineral deficits. Mineral deficiencies may be a major cause of infertility in dairy cows in different parts of the country. Exotic and crossbreeds showed increased severity of infertility than local breeds. This reflected the increased mineral requirements of these breeds. Compared to milkers, dry cows had severe trace element deficits.

The bulk of the animals with low fertility was found to be weak in P, Cu, Zn, Mn, and Co. Analysis of soils and plants could provide some insight into mineral levels in animal blood. With the use of clinical symptoms and serum analysis, an accurate picture of the animals' mineral status could be established. Satisfying the animal's energy-protein requirements is insufficient to express the animal's maximum reproductive potential. Mineral supplementation in animal diets, particularly those of plant origin, should be addressed.

*The Interactions of Some Minerals Elements in Health and Reproductive Performance of Dairy… DOI: http://dx.doi.org/10.5772/intechopen.101626*


**Electropolymerization of Some Ortho-Substituted Phenol Derivatives on Pt-Electrode from Aqueous Acidic Solution; Kinetics, Mechanism, Electrochemical Studies and Characterization of the Polymer Obtained**

S.M. Sayyah\*, A.B. Khaliel, R.E. Azooz and F. Mohamed *Polymer Research Laboratory, Chemistry Department, Faculty of Science, Beni-Suef University 62514, Beni-Suef City, Egypt*


# **Ischemic Heart Disease in the Context of Different Comorbidities**

Edited by Irina-Iuliana Costache, Bogdan-Mircea Mihai and Minerva Codruta Badescu Printed Edition of the Special Issue Published in *Life*

www.mdpi.com/journal/life


**9. References**

[1] Muşuroi, S.; Vătău, D.; Andea, P.; Şurianu, F.D.; Frigură, F. & Bărbulescu, C. (2007). Analysis of the Magnetic Losses from the Induction Machines Supplied by Inverters**,** *Proceedings of EUROCON 2007 International Conference on Computer as a Tool*, pp. 1800-1809, ISBN 978-1-4244-0812-2, Warsaw, Poland, September 9-12, 2007

**Chapter 3**

© 2012 Mirošević, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 Mirošević, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**The Dynamics of Induction Motor Fed**

Additional information is available at the end of the chapter

Marija Mirošević

**1. Introduction**

intermittently.

http://dx.doi.org/10.5772/49973

**Directly from the Isolated Electrical Grid**

An induction motor is the most common machine used for industrial drives. It is used in variety of drives due to its robust construction, relatively low cost and reliability. In isolated electrical network, such as marine and offshore power systems and emergency generation plant, induction motors are the most power consuming loads and are used for winches, water pumps, compressors, fans and for other on-board applications, in continuous mode or

In many applications induction motors are direct-on-line switch-started. Their dynamic characteristics have an obvious influence on the transient process of power system; however, they cause a significant disturbance in transients (significant impacts loads) that can produce disturbances in the isolated electrical network, which in turn affects the quality

Direct-on-line starting represents the simplest and the most economical system to start squirrel-cage induction motor. During starting induction motors draw high starting currents which are several times the normal full load current of the motor. This current causes a significant voltage dip on the isolated electrical grid until the induction motors reach nearly full speed. This voltage drop will cause disturbances in the torque of any other motor running on the isolated electrical grid. Significant disturbances in transients are caused by direct-on-line switch-started induction motors, especially if the load torque on the motor shaft is increased and beside that, also by the sudden change load, such as the impact load on the motor shaft (McElveen, et al., 2001; Cohen, 1995). This situation is particularly difficult because of relatively strong electrical coupling between electrical grid and loads. Besides the voltage dips, an interruption can also appear, which further affects on the fatigue of induction motors connected to the grid. When an interruption of the supply lasts longer than one voltage period, many AC contactors will switch off the motor. In some

of electric power system and thus, on the dynamic behavior of induction motors.


6. Bat conservation in the context of forest management

#### 6.1. The impacts of silviculture

Figure 1. The spatial distribution of foraging bats in a forest stand. Gleaners (Myotis and Plecotus) forage within the foliage of the trees and around shrubs and bushes in the understory, whereas hawkers (Nyctalus, Eptesicus, Barbastella and Pipistrellus) are distributed above and under the canopy (a). When a tree dies, (b) a space free of vegetation forms. This clearing is generally avoided by gleaners and possibly exploited by hawkers where the space is not too cluttered by dead branches. Barbastella barbastellus may take advantage of any peeling bark for potential diurnal roosts. Once the dead tree has fallen, (c) hawkers distribute at the top of the clearing. The forest gap allows light to penetrate to the ground level, favouring the development of low vegetation. Certain gleaners (Myotis nattereri and Plecotus auritus) take advantage of this opportunity by foraging in the understory while others (Myotis myotis) require bare ground, and Myotis bechsteinii continues to exploit the foliage of the canopy. Bb: Barbastella barbastellus; Es: Eptesicus serotinus; Mb: Myotis bechsteinii, mm: Myotis myotis; Mms: Myotis mystacinus; Mn; Myotis nattereri; Nl: Nyctalus leisleri; Nn: Nyctalus noctula; Pa: Plecotus auritus;

Pk: Pipistrellus kuhlii; Pp: Pipistrellus pipistrellus.

70 Bats

Regardless of the type of silvicultural practice undertaken in forests around the world, biodiversity will be affected. Harvest exclusion areas or setting aside reserves within production forests constitute sites that are richer in terms of species present, whereas timber plantations with more economically profitable methods employed, notably short rotation forestry, are the most impacting of approaches [1, 26, 71]. For bats, silvicultural logging reduces food resources, destroys breeding sites, and can kill individuals or colonies when trees are felled [2, 5, 6, 71]. Females of Plecotus auritus have been shown to entirely avoid forests recently logged during lactation periods even if mature trees have been preserved [32]. The same avoidance has also been observed in juveniles of Myotis bechsteinii and Myotis nattereri probably due to the decrease in the volume of foliage, which is an important source of insect production for these species [31]. More generally, logging forests for timber induces a net loss of prey-bearing mature broadleaves causing an immediate reduction in food resource. Therefore, bats are forced to move to new habitats next to their previous foraging grounds that are already occupied by other individuals, reducing the carrying capacity of the milieu. The silvicultural harvesting of mature trees that possess cavities inevitably leads to a reduction of the total number of roosts available to bats. Even if the natural ageing of trees continues and is accompanied by the gradual formation of new cavities, principally by woodpeckers, the setting aside of areas of unlogged mature forest to protect habitat diversity must still be maintained in order to ensure the temporal and spatial continuity of bat colonies [2, 6, 31]. Indeed, only harvest exclusion areas where the natural forest cycle is allowed to continue without the intervention of man represent truly ideal habitats for bats [80]. However, strict protection obviously remains an unrealistic measure across the European forest scale, implying a need for other forest management strategies.

maintain a group of trees, ensuring a forest ambience, around a cavity while, again, limiting the potential risk of injury to forestry workers or public. Maintaining quantities of deadwood, where possible both snags and ground-lying, should target the minimal threshold of

In Europe, the accumulation of knowledge over the last decade on the relationships between bats and forests has orientated programmes geared towards a greater consideration for bats. In addition, the Natura 2000 network has been adopted in the European Community making it possible to designate numerous sites considered as fundamental for these animals [2, 13]. Forests being a key issue for the conservation of bats need to be taken into account as part of regional planning and forest management policies [2]. However, even though the number of appropriate management recommendations has increased in recent years the implementation of concrete conservation strategies is challenging, and unfortunately slow. Furthermore, forest managers must meet society's growing demand for wood products among other objectives such as reducing fossil fuel consumption, curtailing the impacts of

Of the 15 million hectares of forests in France (including overseas territories), 4.5 million hectares are managed by the French Forest Office who are mainly financed by timber production. This management body has integrated key conservation issues for biodiversity at various spatial scales within production forest systems. First, a number of harvest exclusion areas, whereby no silvicultural intervention occurs, have been created, each area ranging in size from ten to hundreds of hectares, totalling nearly 50,000 ha. Second, 3% of managed forests are "habitat islands" (generally ranging from 1 to 10 ha in size) where a true naturalness approach allows the natural cycle of forests to ensue ageing and decomposition of trees. Third, three microhabitat-bearing trees or dead trees are systematically protected per hectare. Fourth, at least one-third of a mature broadleaved forest's area is maintained in each forest canton as often as possible. The exploitation by clearcutting cannot exceed a few dozen hectares for any single block and the natural regeneration of the ecosystem is favoured, which is thus less degrading to biodiversity than plantations. Lastly, a team of 45 conscientious forest engineers, technicians and ecologists set up in 2004 carry out forest inventories and studies to improve knowledge on the relations between bats and forests and to evaluate the impact of forestry in this Office. They convert the collected information into management guidelines that favour bat conservation. These people are trained in forestry and have years of experience in managing forest plots, and can use the technical terminology required when communicating appropriate strategies to silviculture. The internalisation of these issues by teams dedicated to the preservation of bats within forest management organisations is the best assurance of successful bat conservation within exploited forest systems

/ha. Finally, diversity in tree species, a diversity in the vertical stratification and structure of a forest stand can only further support a diversity and abundance of food resources

Bat Conservation Management in Exploited European Temperate Forests

http://dx.doi.org/10.5772/intechopen.73280

73

25m3

climate change.

worldwide.

for the various species of bats.

7. The involvement of forest managers in France

#### 6.2. Forest management orientations in favour of bats

Given the major differences in the ecological functioning of forest habitats, i.e. different compositions and structures, combined with a diverse range of silvicultural techniques employed to manipulate growth conditions, it becomes difficult for the conservation biologists to propose bat-friendly management measures [2, 81]. The growing literature comparing managed and non-managed forests demonstrates that bats do have the ability to occupy exploited forest systems, which gives hope for improving the conservation status of many species throughout European forests [1]. However, so as to implement effective conservation measures for bats, it is vital to know what habitat parameters to conserve and balance this with appropriate silvicultural treatments that ensure the continuing exploitation of wood while assuring the safety of the loggers themselves and the public who use the forests for recreational purposes. Although it is necessary to further improve knowledge on the relationship between bats and forest management [2], some recommendations can already be put forward. In order to conserve both roosts and foraging habitats, it is imperative that the manager ensures the temporal and spatial continuity of mature broadleaved stands composed of native species by maintaining at least 35% of the surface area of each forest (about 1000 ha). One way of maintaining suitable habitats for bats in forests would be by setting aside a number of small sites of no more than a few hectares in size, leaving the forest within each site to complete its natural cycle. By doing so, this would assure the presence of tree cavities, deadwood, and certain heterogeneity to naturally occur across an entire forest mosaic. In addition, within production forest plots, maintaining a small number of live or dead trees possessing cavities even after felling treatments have been carried out can ensure a minimum continuation of usable roosts. This can be of particular ecological interest: live trees possessing cavities surrounding a dead tree form a group of trees representing a particularly attractive habitat for bats. Also, a tree possessing a large voluminous cavity at a high position can accommodate certain species for an extended period of time such as Nyctalus noctula. Because isolated trees are at a greater risk of falling (due to abiotic factors) it is possible and recommended to

maintain a group of trees, ensuring a forest ambience, around a cavity while, again, limiting the potential risk of injury to forestry workers or public. Maintaining quantities of deadwood, where possible both snags and ground-lying, should target the minimal threshold of 25m3 /ha. Finally, diversity in tree species, a diversity in the vertical stratification and structure of a forest stand can only further support a diversity and abundance of food resources for the various species of bats.


*4.8. DN*2*PCIoT 30R*

The fifth approach that we used for the experiments was the application of DN2PCIoT starting from random-generated partitionings. This approach executed DN2PCIoT 30 times starting from different random-generated partitionings and we report the best value achieved in these 30 executions. It is worth noting that this approach was only executed for the LeNet 2:1 model due to the more costly execution of LeNet 1:1 starting from a random partitioning. This was the only approach that did not employ LeNet 1:1. Furthermore, DN2PCIoT can discard some devices when they are not necessary, i.e., if DN2PCIoT finds a better partitioning with fewer devices.


**3.1 Significance of phagocytosis**

Phagocytosis of pathogens is one of the most important features of the hostpathogen communications and interactions mediated by macrophages. This element of host defense by macrophages not only operates toward host protection at the onset of infection but also makes room for the initiation and amplification of intracellular signals that can potentially mature to the generation of antigen-specific T cell responses and creation of immunological memory (explained in **Figure 4**).

As described earlier in this chapter, Wnt5A signaling aids in maintaining a steady-state expression of CD14 and IFNβ, two of the many molecules involved in innate immune defense. Although it is not exactly clear how CD14 and IFNβ fit into the program of phagocytosis in exact molecular terms, it is documented that while CD14 is instrumental in the recognition of structural motifs like lipopolysaccharide (LPS) intrinsic to certain pathogens, both CD14 and IFNβ facilitate pathogen clearance through the initiation and propagation of macrophage TLR signaling during phagocytosis and activation of immune responses [10, 13] (**Figure 3**). Following pathogen engulfment and phagosome formation during phagocytosis, macrophages rely mostly on endosomal and lysosomal proteases and NADPH oxidase-generated reactive oxygen species for both pathogen clearance as well as processing and presentation of antigenic peptides to MHC molecules for presentation to T lymphocytes [31, 46] and translation to memory.

## **3.2 Need for Wnt5A signaling-assisted actin rearrangement/assembly**

At the core of all phagocytosis-related processes lies the involvement of the actin cytoskeleton through its influence on protein sorting/trafficking and intracellular organelle fusions that are crucial for the activation of phagosomal enzymes such as

#### **Figure 4.**

*A schematic of maturation of pathogen containing vesicle and its outcome: After phagocytosis of pathogen there is fusion of early endosome and endoplasmic reticulum (ER) with the phagosome which helps in the maturation of the phagosome and fusion with lysosome. This is important for both innate and adaptive immunity.*

NADPH oxidase and phagosome maturation [31, 47]. Several cytoskeletal GTPases such as Rac1 and Disheveled, lipid rafts, and actin-nucleating proteins such as Arp2/3 and formins partake of the cytoskeletal actin modulations that accompany macrophage phagocytosis and phagosome maturation [47–50]. There is evidence that Wnt5A signaling is important for such rearrangements of the actin cytoskeleton. Accordingly, Wnt5A signaling facilitates Rac1- Disheveled-lipid raft-dependent phagocytosis of bacteria and other foreign matter through modulations of the actin cytoskeleton [9]. Blockers of any of the cytoskeletal actin-associated signaling intermediates—Rac1, Disheveled, or lipid raft and cytochalasin-D, an inhibitor of actin assembly—are antagonistic to the effect of Wnt5A signaling on phagocytosis [9]. The influence of Wnt5A signaling on phagocytic uptake is usually dependent on the microbe under consideration, because while most bacterial species tested undergo facilitated phagocytic uptake by Wnt5A signaling in macrophages, phagocytic uptake of *Leishmania donovani* remains unaffected by it [11]. Perhaps Wnt5A-facilitated internalization encompasses distinct membranous domains depending on the availability of cognate receptors, which are not equally compatible with all microbes. That Wnt5A signaling also facilitates phagosome-lysosome fusion during phagosome maturation which is evident from the augmented appearance of lysosomal markers such as cathepsins in Wnt5A-induced phagosomes of bacteria-infected macrophages [12]. Wnt5A-facilitated alteration in cytoskeletal actin assembly that correlates with phagosome-lysosome fusion is concomitant with the killing of several microbes including bacterial pathogens (*Pseudomonas aeruginosa*, *Streptococcus pneumoniae*, etc.) and even *Leishmania donovani*, although it gets internalized independent of Wnt5A signaling [11, 12]. The mechanism of microbial killing is discussed at greater length in the following section of this chapter. Microbial killing is furthermore facilitated by Wnt5A-responsive NADPH oxidase activity, which is associated with cytoskeletal actin-dependent assembly of NADPH oxidase subunits [11]. Interestingly, nonpathogenic laboratory strains of bacteria that are engulfed by macrophages in increased numbers by Wnt5A signaling are not necessarily killed by it like the pathogenic bacterial strains [9, 12]. Such discrepancy in the fate of internalized microbes may be an outcome of notable differences in the interaction of different microbial components with Wnt5A-regulated cytoskeletal actin rearrangements. The interrelation between Wnt5A signaling and Ehrlichia infection is especially noteworthy in this context [51].

In light of the fact that the cytoskeletal actin-assisted phagosome is the originator and communicator of many signals generated by phagocytozed cargorecognizing molecules such as TLR, NOD1, and NOD2 [35, 52, 53] (**Figure 4**), it is quite likely that the consequences of Wnt5A-assisted phagocytosis are numerous. Association of Wnt5A signaling with TLRs has already been reported [54]. Careful analysis of the consequences of such associations is important.

#### **3.3 Role played by other Wnts and costimulatory molecules of Wnt signaling**

Wnts other than Wnt5A are known to regulate macrophage phagocytosis as well. For example, the Drosophila Wnt has been reported to stimulate phagocytic uptake in the S2 cell, a macrophage-like line [55]. Moreover, Wnt1, Wnt7A, and Wnt3A have been reported as phagocytic modulators [56, 57]. The association or relation of these different modes of phagocytosis with Wnt5A signaling and cytoskeletal actin rearrangements is yet to be explored. At this point of our understanding of Wnt signaling with respect to phagocytosis, regulatory roles played by LRP5/6 and ROR, which act as co-receptors to Wnts [22, 58], remain unclear. It also remains to be seen if the influence of Wnt5A signaling on phagocytosis is in the canonical or noncanonical mode or is in fact an intermediary between the two depending on the context of infection, the available receptors, and coactivators.

*Wnt Signaling Regulates Macrophage Mediated Immune Response to Pathogens DOI: http://dx.doi.org/10.5772/intechopen.86433*

## **4. Wnt signaling-induced actin-dependent autophagy-assisted xenophagy by macrophages and the potential link with antigen processing/presentation**

#### **4.1 Autophagy-assisted xenophagy**

Several pathogenic microorganisms try to adapt to the intracellular milieu of macrophage creating a niche for their survival [59–61]. Nevertheless, as described earlier in this chapter, the host macrophage tries maneuvering elimination of infection by pathogens by several means. It has been reported that following phagocytosis of microbes by macrophages, the host autophagy machinery comes into play in the ultimate event of clearance of bacteria and other engulfed microbes (xenophagy) through coordinated alterations of the actin cytoskeleton. Autophagy involves the turnover and clearance of damaged organelles and proteins by the cell under both normal conditions as well as under stress in the maintenance of cellular homeostasis [62, 63]. During infection with pathogens, the autophagy program is often utilized for the incapacitation and eradication of engulfed pathogens [26, 64].

#### **4.2 Role of Wnt signaling and cytoskeletal actin in autophagy-assisted xenophagy**

Wnt signaling has been reported to play a significant role in the autophagyassisted xenophagy of engulfed microbes by macrophages. Wnt5A signaling, for instance, has been documented to be an integral component of this theme in the killing of several bacterial pathogens through utilization of a Rac1-Disheveled-actin cytoskeleton circuit that involves interactions among several autophagy-associated proteins like microtubule-associated protein 1B-light chain 3B (LC3B), autophagyrelated 5 (ATG5), ATG7, and Unc-51-like autophagy-activating kinase 1 (ULK1) [12]. The different nuances of Wnt5A signaling in connection with the actin cytoskeleton are depicted in **Figure 5**. Pathogen killing through autophagy machinery is blocked with the use of cytochalasin-D, an inhibitor of actin assembly as well as with inhibitors to Rac1 and Disheveled [12]. Although Wnt5A-assisted killing of *L. donovani* in macrophages has not been shown to directly involve autophagy, electron micrographs of *L. donovani* harboring parasitophorous vacuoles, which display distinct membranous aggregates, suggest that *L. donovani* containing parasitophorous vacuoles may be subjected to lysis by the host autophagy circuit activated by Wnt5A signaling [11]. The inactivation or lysis of microbe-carrying vacuoles, which happens in due course through fusion of autophagy-destined phagosome or autophagosome with the lysosome, may also be facilitated by Wnt5A signaling [12]. Although cholesterol and other lipids are known to partake of both Wnt5A signaling and actin dynamics [65, 66], at this stage much remains unknown about the specific roles of cholesterol and other lipids in the process of actin modulation during phagocytosis and autophagic clearance of bacteria and other microbes. It also remains to be seen if Wnt5A signaling during autophagy belongs strictly to the noncanonical mode or canonical mode based on the involvement of β-catenin.

#### **4.3 Potential link with antigen presentation/adaptive immunity**

In view of the fact that the autophagic or rather xenophagic removal of pathogens by macrophages involves reorganization and fusion of intracellular vesicles associated with at least partial lysis of pathogens, the processing and presentation of pathogen antigens to MHC molecules are a likely event during xenophagy in infected macrophages [67, 68]. Thus, autophagosome formation, autophagosome lysosome fusion, and T cell activation by the presentation of processed pathogenic

**Figure 5.**

*Schematic of Wnt5A signaling aided bacterial killing: Both autocrine and paracrine modes of Wnt5A signaling can lead to increase in phagocytosis of pathogenic bacteria. After phagocytosis, the Wnt5A mediated cytoskeletal modulation leads to fusion of early endosome and lysosome with the pathogen containing phagosome. Wnt5A signaling also activates Rac1 and Unc like kinase 1 (Ulk1) for initiation of autophagy. The subsequent steps of maturation lead to killing of pathogen in an autophagy dependent process (xenophagy).*

antigens may prevail as a continuum during immune defense depending on the nature and degree of the infection. Given the intrinsic association of Wnt signaling with cytoskeletal dynamics and autophagy [11, 12], it is quite likely that Wnt signaling will influence the antigen processing and presentation linked with autophagy in infected macrophages. Detailed investigation in this respect, although important, remains to be documented.

#### **5. Concluding remarks**

Given the important role played by Wnt ligands in the transmission of signals associated with cytoskeletal modulation and transcriptional regulation which are part and parcel of host-pathogen communications [27–29, 69], a combination of Wnt signal transduction cascades is expected to hold a fundamental standing in the immune defense program operated by macrophages in both innate and adaptive immunity. Phagocytosis, autophagy/xenophagy (intracellular microbial killing), and a steady-state expression of immune defense molecules through transcriptional regulation appear as some of the major players of the immune defense program operated by Wnt signaling.

In respect of transcriptional regulation of immune defense molecules by steadystate Wnt5A-signaling as described in this chapter [10], it is not understood exactly what dictates the nuclear translocation of p65 and not the other NFκB isoforms for specific modes of gene expression. Additionally, how this regulation fits in with the activity of other major transcription factors like NFAT and AP1 in the macrophage is also not clearly understood. Moreover, details of the context dependence of

#### *Wnt Signaling Regulates Macrophage Mediated Immune Response to Pathogens DOI: http://dx.doi.org/10.5772/intechopen.86433*

Wnt5A signaling, wherein a certain level and mode of signal transmission will be beneficial for immune response, but excess will cause inflammation and disorder [70–72], remain largely unclear. Besides, a clear concept of how actin cytoskeletonassociated proteins such as Rac1 promote both NFκB activity as well as cytoskeletal rearrangements for phagocytosis and autophagy is yet to be achieved [10, 12]. Whether nuclear translocation of NFκB is a natural function of actin assembly or is executed by a separate pool of Rac1 associated cytoskeletal proteins is an important matter that deserves investigation.

With regard to phagocytosis and autophagy-assisted xenophagy, the molecular details of the actin rearrangements with actin binding proteins and the processing and presentation of antigens remain to be deciphered. This brings into question how different host-pathogen interactions within macrophages are guided by modulations of the actin cytoskeleton. Of special interest in this context is the interaction of the actin cytoskeleton with pathogenic mycobacteria, which thrive in self-generated niches within macrophages [60, 73]. The interrelation between different modes of Wnt signaling and mycobacterial infection, although much studied [74, 75], needs to be better understood with respect to actin dynamics. Now that Wnt5A signaling has been shown to play a major role in the regulation of actin cytoskeletal modulation and autophagy [11, 12, 76], future experiments addressing whether this can also facilitate the adaptive immune response through antigen processing and presentation may prove fruitful.

At this juncture of our understanding of Wnt signaling and immune response by macrophages, it is important to know how the different Wnt ligands operate in the regulation of immune response by the different types of macrophages that are distributed in different tissues under the varied conditions of intracellular milieu and infection. Macrophages (microglia) present in the brain and spinal cord maintain an active immune defense scheme against pathogens that affect the central nervous system. Alveolar and airway macrophages likewise protect the respiratory tract and lungs from the toxic effect of infectious agents. Peritoneal macrophages of the peritoneum and Kupffer cells of the liver also encounter and confront infectious agents for host protection. Quite naturally, the roles played by Wnt signaling in the combat mechanism of each macrophage type in its paradigm of immune defense is expected to be different at least to some extent on account of potential variations in cellular environmental cues and modes of host-pathogen interactions.


**Ischemic Heart Disease in the Context of Different Comorbidities**

**Irina-Iuliana Costache 1,2,\*, Bogdan-Mircea Mihai 3,4 and Minerva Codruta Badescu 1,5**

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide. Since coronary atherosclerosis is its main substrate, IHD generally affects the geriatric population [1]. As aging is associated with an increased number of comorbidities, IHD further negatively influences these patients' quality of life and longevity.

Ilie et al. debated the strong relationship between frailty and chronic coronary syndromes [2]. They discussed the mechanisms of the bidirectional interaction between frailty—a complex geriatric syndrome with many phenotypes—and increased risk of ischemic coronary events. They also highlighted the key roles of sarcopenia, systemic inflammation, endothelial dysfunction, and impaired lipid and glucose metabolisms. The authors also provided useful guidance for risk assessment, diagnosis, and treatment of old and frail patients with stable IHD.

Epidemiological studies have shown a decrease in the age at which risk factors for atherosclerosis begin to accumulate. In this context, the age at which the incidence and prevalence of IHD begin to increase has shifted to younger ages, causing the impact of the disease on public health to become even greater [3]. Approximately 1.72% of the world's population is currently affected by IHD, and the prevalence is still rising. As the global distribution map of IHD demonstrates, Eastern European countries contribute by far the highest prevalence [4].

Although myocardial infarction is only the tip of the iceberg, its consequences have a significant negative impact on morbidity and mortality in patients with IHD. Leancă et al. [5] provided an excellent review on adverse cardiac remodeling in survivors of acute myocardial infarction. The authors performed an in-depth analysis of the pathophysiological mechanisms involved in this process, and systematized the complex methods of evaluation by biomarkers and both conventional and high-performance imaging. The main goals of treatment were to avoid the progression of IHD to heart failure and to reduce mortality. The article provides strong evidence to guide individualized treatment aimed at counteracting adverse ventricular remodeling and promoting reverse ventricular remodeling.

Cancer is highly prevalent in the elderly, and cardiac toxicity of antineoplastic agents is currently a topic of major interest. Badescu et al. have shown that some commonly used oncological treatments have adverse effects on coronary arteries, as they induce endothelial dysfunction, coronary artery spasm, thrombosis, and fibrosis [6]. These harmful structural and functional changes lead to cardiovascular events that require reduction or temporary or permanent stop of antineoplastic therapy, and all of these events have a negative impact on cancer outcomes. The authors provided a comprehensive, systematized, structured, and upto-date analysis of the available literature regarding the optimal measures to mitigate the

**Citation:** Costache, I.-I.; Mihai, B.-M.; Badescu, M.C. Ischemic Heart Disease in the Context of Different Comorbidities. *Life* **2022**, *12*, 1558. https://doi.org/10.3390/life12101558

Received: 28 September 2022 Accepted: 4 October 2022 Published: 7 October 2022

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toxic effects of major antineoplastic therapies on coronary arteries. Sorodoc et al. focused on chemotherapy-induced cardiotoxicity and discussed the value of troponin as a biomarker of myocardial injury in oncologic patients [7]. The authors highlighted that troponin is a sensitive indicator of myocardial injury, as well as a marker for increased risk of developing left ventricular systolic dysfunction and progression to heart failure. The assessment of troponin levels enables early detection of cardiac injury and identification of patients that could benefit from the implementation of prevention measures. Moreover, the authors warn that troponin has no diagnostic value for cardiotoxicity and should not be used to modulate chemotherapy in cancer patients.

The cross-talk between the heart and the liver is the main focus of the articles of Cazac et al. and Gîrleanu et al. Non-alcoholic fatty liver disease reflects a disrupted lipid and carbohydrate metabolism, and it is perceived today as the hepatic manifestation of the metabolic syndrome [8]. The authors emphasize that in the presence of a common pathogenic substrate, this liver disease should be considered a marker of an increased risk for atherosclerotic cardiovascular disease. It is highlighted that patients with non-alcoholic fatty liver disease have an increased prevalence of subclinical atherosclerosis, a higher risk for the development of acute coronary syndromes (ACS), a need for more revascularization procedures, and an increased risk of fatal and non-fatal cardiovascular outcomes.

Vascular inflammation, endothelial dysfunction, and procoagulant status are present in both liver cirrhosis and coronary artery disease [9]. Along with the main pathogenic mechanisms, the authors discuss the specifics of the diagnosis and treatment of IHD in cirrhotic patients, taking into account the fragile balance between thrombosis and bleeding, as well as the limited amount of evidence from clinical studies, especially in patients with advanced liver disease.

The link between inflammatory bowel disease and IHD is systemic inflammation. The article by Jucan et al. provides robust data regarding the elevated risk of IHD in inflammatory bowel disease patients, based on an in-depth analysis of the relevant literature [10]. The crucial role of chronic inflammation is extensively debated. The authors showed that the disruption of the intestinal mucosal barrier allows microbial translocation and other endotoxins to reach the blood. These events are followed by multi-pathway activation of systemic inflammation that leads to endothelial dysfunction, changes in the vascular smooth muscle, reduction in vessels elasticity, medial calcification, and atherosclerotic plaque formation and progression.

Cardiovascular complications of the SARS-CoV-2 infection have troubled the medical community for more than two years now, and not all questions have yet been answered. An impressive amount of data was systematized in the article by Timpau et al., covering all known mechanisms by which the infection with COVID-19 causes cardiac injury, expressed as ACS, heart failure, myocarditis, and stress cardiomyopathy [11]. The diagnostic role and prognostic value of inflammation and myocardial damage biomarkers are commented on from the perspective of an in-depth and comprehensive study of the dedicated literature, offering a robust conclusion that guides the practitioners. Duca et al. focused their research on myocardial ischemia in patients with the COVID-19 infection, and highlighted not only its complex pathophysiology, but also the diversity of its electrocardiographic expression [12]. The authors showed that myocardial ischemia is the result of endothelial damage mediated by the virus, cytokine storm caused by hyperactivation of the immune system, and oxygen supply–demand imbalance due to extensive pulmonary lesions. Moreover, they emphasized that the electrocardiographic aspects of myocardial ischemia were generally severe, and occurred even in younger and healthier patients.

A very particular aspect regarding IHD is presented by Haliga et al., namely the ACS precipitated by carbon monoxide (CO) poisoning [13]. This original research article demonstrated that the development of myocardial injury in these patients is the combined result of hypoxia, direct CO-mediated cell damage, coronary spasm, and intracoronary thrombosis. The authors showed that ACSs occur irrespective of the poisoning severity, some in the absence of significant cardiovascular risk factors and in both normal coronary

arteries and non-critical atherosclerotic plaques. Among the many interesting results of the study, we want to draw attention to the young age of STEMI patients, with a mean of 27.7 years, and the absence of comorbidities.

As medicine advances and knowledge deepens, one non-modifiable cardiovascular risk factor, namely the genetic substrate, is studied with increased interest. It seems that it will become a major landmark in the implementation of preventive measures in the future. Butnariu et al. provided a state-of-the-art analysis of the data available in the literature on the role of genetic factors in the etiology of IHD [14]. The authors discussed the phenotypic variability and the genetic heterogeneity of the disease, suggesting that genetic and genomic studies may provide the highly sought-after and awaited answers about what makes us unique in the face of the disease. The multiple facets of monogenic and polygenic coronary artery disease are emphasized, with the hope that the identification of individuals at high risk for IHD will be facilitated. The door toward the medicine of the future is now open, and gene therapy strategies no longer seem to be an unattainable desideratum.

We may conclude that this Special Issue excels through multidisciplinarity, integrating into a unified whole the experience of various specialists whose common interest is IHD. We consider that the goal has been fully achieved, and we have succeeded in drawing attention to the multiple diagnostic and therapeutic challenges determined by the association of IHD with a series of comorbidities, as well as providing useful guidance for practice.

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

#### **References**

### *Review* **Chronic Coronary Syndrome in Frail Old Population**

**Adina Carmen Ilie , Sabinne Marie Taranu \*, Ramona Stefaniu, Ioana Alexandra Sandu , Anca Iuliana Pislaru, Calina Anda Sandu, Ana-Maria Turcu and Ioana Dana Alexa**

> Department of Medical Specialties II, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Ias,i, Romania<EMAIL_ADDRESS>(A.C.I<EMAIL_ADDRESS>(R.S<EMAIL_ADDRESS>(I.A.S<EMAIL_ADDRESS>(A.I.P<EMAIL_ADDRESS>(C.A.S<EMAIL_ADDRESS>(A.-M.T<EMAIL_ADDRESS>(I.D.A.)

**\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** The demographic trend of aging is associated with an increased prevalence of comorbidities among the elderly. Physical, immunological, emotional and cognitive impairment, in the context of the advanced biological age segment, leads to the maintenance and precipitation of cardiovascular diseases. Thus, more and more data are focused on understanding the pathophysiological mechanisms underlying each fragility phenotype and how they potentiate each other. The implications of inflammation, sarcopenia, vitamin D deficiency and albumin, as dimensions inherent in fragility, in the development and setting of chronic coronary syndromes (CCSs) have proven their patent significance but are still open to research. At the same time, the literature speculates on the interdependent relationship between frailty and CCSs, revealing the role of the first one in the development of the second. In this sense, depression, disabilities, polypharmacy and even cognitive disorders in the elderly with ischemic cardiovascular disease mean a gradual and complex progression of frailty. The battery of tests necessary for the evaluation of the elderly with CCSs requires a permanent update, according to the latest guidelines, but also an individualized approach related to the degree of frailty and the conditions imposed by it. By summation, the knowledge of frailty screening methods, through the use of sensitive and individualized tools, is the foundation of secondary prevention and prognosis in the elderly with CCSs. Moreover, a comprehensive geriatric assessment remains the gold standard of the medical approach of these patients. The management of the frail elderly, with CCSs, brings new challenges, also from the perspective of the treatment particularities. Sometimes the risk–benefit balance is difficult to achieve. Therefore, the holistic, individualized and updated approach of these patients remains a desired objective, by understanding and permanently acquiring knowledge on the complexity of the frailty syndrome.

**Keywords:** frailty; chronic coronary syndrome; elderly

#### **1. Introduction**

#### *1.1. The Demographic Trend of Aging*

The old population continues to increase worldwide, being highly influenced by important regressions in the main causes of mortality. The demographic changes are reflected in society, raising the needs and costs of health care yearly. Worldwide, the proportion of people over the age of 65 is expected to exceed 25% by 2030, and in Europe, the number of older people will increase to 152.6 million in 2060 from 87.5 million in 2010 [1]. At the same time, the growing trend of demographic aging is associated with a high prevalence of coronary artery disease (CAD) in both men and women. The mortality risk and morbidity attributed to chronic coronary syndromes are increased due to aging (especially after 75 years) and due to a high incidence of comorbidities (e.g., hypertension, diabetes, chronic kidney disease, etc.).

**Citation:** Ilie, A.C.; Taranu, S.M.; Stefaniu, R.; Sandu, I.A.; Pislaru, A.I.; Sandu, C.A.; Turcu, A.-M.; Alexa, I.D. Chronic Coronary Syndrome in Frail Old Population. *Life* **2022**, *12*, 1133. https://doi.org/10.3390/ life12081133

Academic Editor: Alexey V. Polonikov

Received: 23 June 2022 Accepted: 25 July 2022 Published: 27 July 2022

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

**Copyright:** © 2022 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/).

With global aging, frailty has become a common condition in the old population. Frailty is highly related to the incidence and unfavorable prognosis of atherosclerotic coronary heart disease [2].

The literature reports two-way associations between cardiovascular disease and frailty. Although peripheral arterial disease and heart failure have been more frequently linked to frailty, current studies focus on broader directions, considering the impact and relationship between chronic coronary syndromes and frailty [3].

#### *1.2. Chronic Coronary Syndromes. Definition, Prevalence and Features in Senior Patients*

Of all types of cardiovascular diseases, coronary syndrome showed the highest mortality rate, resulting in approximately 659,000 deaths and 805,000 coronary events yearly in the United States [4].

The pathological foundation of coronary heart disease is based on the permanent accumulation of atherosclerotic plaque in the epicardial arteries. It can manifest as obstructive or non-obstructive. Lifestyle regulations, medication and invasive procedures having therapeutic and diagnostic roles can influence the evolution of this process, by stabilizing or regressing the disease. CAD is known by its long periods of stability, but we have to consider the possibility of an acute atherothrombotic event due to plaque rupture or erosion. This event will increase the risk of turning into unstable angina, at any time. Even in apparently silent clinical periods, the disease is usually progressive, and therefore severe. The fact that this pathology implies a dynamic manifestation, we can integrate it in two different clinical presentations known as acute coronary syndromes (ACSs) and chronic coronary syndromes (CCSs) [5,6].

To briefly define chronic coronary syndromes is a challenge, as they are identified by the different evolutionary stages of coronary heart disease, excluding the states in which an acute coronary artery thrombosis dominates the clinical presentation (i.e., ACS) [5,7].

Studies show an increased risk in the old population to develop CCSs. Despite this fact, it seems like this group mostly remains insufficiently diagnosed and treated. The atypical character of the symptoms in a senior patient is recognized, thus delaying the timing of the definite diagnosis [5].

#### *1.3. Frailty. Definition, Prevalence and Features in Senior Patients*

Frailty is a geriatric syndrome, encompassing different and complex phenotypes, from the physical to the immunological and cognitive components. Frailty is identified by the state of gradual and absolute decline, regardless of the aspects in which it occurs. Geriatric syndromes such as functional dependence, cognitive impairment and malnutrition are in most cases caused by physical frailty which implies decreased muscle strength, a loss of endurance, decreased physiological function and a decreased ability to adapt to stress. Studies have shown clear interactions between frailty status and the complications of coronary heart disease [2,8,9]. Therefore, the evaluation of frailty in seniors has become an indirect way of assessing the true adverse events associated with chronic coronary syndromes.

Fried et al. proposed five dimensions of frailty, which continue to be the diagnostic criteria for this syndrome: decreased muscle strength, decreased walking speed, fatigue, decreased physical activity and involuntary weight loss [2]. Despite its wide use, the Fried phenotype only assesses the physical component of frailty [10]. Other methods of evaluation assess other components, but the golden standard in diagnosing or assessing frailty is the geriatric evaluation.

There are also revealing data confirming a relationship of interdependence and mutual empowerment between CCSs and frailty. Plurivascular disease (40%), tortuosity and calcifications (80–90%) have been seen in patients 80 years of age with a high prevalence of obstructive coronary heart disease (60%) in autopsy studies [6].

However, there is a predominant tendency in current studies to speculate on a one-way relationship between CCSs and frailty, so it seems that cardiovascular damage predisposes to frailty rather than vice versa [8,11].

#### **2. Pathogeny, Mechanisms and Associated Factors**

#### *2.1. Pathophysiology of CCSs and Frailty in Senior Patients*

The mechanisms surrounding frailty and cardiac aging require special attention due to their role in senior patients' morbidity, mortality, quality of life and their need for medical assistance and increased medical costs [12].

Frailty often coexists with heart disease due to coexisting pathophysiological changes, aging and numerous comorbidities, all leading to rapid functional decline and sarcopenia. Higher rates of disability, institutionalization and mortality were recorded in senior patients with both frailty and CCSs [12].

In the pathogenesis of CCSs, varied mechanisms were described in which protein degradation, denervation, atrophy and altered fatty acid oxidation played an important role. Moreover, peroxisome proliferation and decreased protein synthesis, commonly in seniors, activate the gamma coactivator-1 alpha receptor (PGC-1α), whose expression is mitochondrial dysfunction. Thus, sarcopenia represented by homeostenosis of muscle metabolism increases predisposition to chronic coronary syndromes. The altered protein, lipid and glucose metabolism (i.e., insulin resistance) and also endothelial dysfunction, a substrate of cardiovascular disease, are precipitated by an ongoing inflammatory process (increased expression of biomarkers), usually encountered in old age [12].

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase increases the production of reactive oxygen species (ROS) and stimulates the ubiquitin-proteasome system in skeletal muscle, leading to the development of sarcopenia and increasing the occurrence of chronic coronary syndromes [12–15].

Elevated levels of C-reactive protein, Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) are also linked to the loss of skeletal muscle mass. At the same time, TNF-α/nuclear factor-κB (NF-kB) catalyzes the synthesis of ROS in mitochondria, leading to the degradation of muscle proteins, sarcopenia and increasing the risk for ischemic events [12,16,17].

The loss of muscle mass and function also contributes to ischemic heart damage. Therefore, knowledge of the pathogenesis of sarcopenia at the cellular mechanism level is important. With aging, the pathways leading to sarcopenia, involving myostatin, phosphatidylinositol 3-kinase and lysosomal catabolism, are affected. Consequently, autophagy as a mechanism of cell preservation is inactivated and damaged. Its constituents remain undegraded, resulting in the alteration of the quality and quantity of muscle mass, leading, in time, to cardiovascular conditions [12,18–20].

The abnormal activation of inflammasome NLRP3, a multiprotein signaling complex found in the cytoplasm of the cell, has also been linked to cardiac inflammation, systolic dysfunction and ventricular remodeling that precipitate the onset of ischemic cardiovascular events [12,21–24].

Vascular aging is defined by mechanisms involving oxidative stress, mitochondrial dysfunction, genomic instability and epigenetic alterations. Moreover, lipid metabolism, extracellular matrix, coagulation/hemostasis impairment and inflammation are considered to have an important role in vascular aging. Lots of the predisposing factors for atherosclerosis, such as the damage to deoxyribonucleic acid from endogenous or exogenous sources, can lead to improper endothelial function, mediated by reduced nitric oxide synthase (eNOS) activity. They promote impaired vasodilator phenomena, the frailty of blood vessels and the growth of the intimal wall, ultimately leading to an increased risk for coronary heart disease. Theories of aging illustrate the mediator role of special proteins known as sirtuins (e.g., SIRT1) in endothelial function, whose impairment leads to increased reactive oxygen reactive species (ROS). The ROS determine the development of vascular senescence and atherosclerosis [6,25].

In addition, research revealed that dehydroepiandrosterone, fibroblast growth factors (e.g., FGF-23), growth-differentiating factor-15 and plasma-associated lipokaline linked to neutrophil gelatinase have been involved in the progression of cardiovascular disease in the senior patient [6].

#### *2.2. Implications of Inflammation in the Pathogenesis of CCSs and Frailty*

Inflammation, represented by an impaired immune status and changes in function of immune cell subpopulations, is revealed to be closely related to frailty [26].

A meta-analysis of 32 cross-sectional studies in a group of 23,910 old people showed higher levels of inflammation, indicated by elevated serum levels of CRP and IL-6, in those with frailty and pre-frailty compared to those without frailty. At the same time, a positive link between high serum levels of IL-6, CRP and a loss of muscle mass was highlighted, with a reduction in the grip force, and correlations between inflammation and atherosclerosis were reported simultaneously [2,27].

In CCS patients as well as in frail ones, chronic low-grade inflammation, namely a lifetime exposure to the antigen, angiotensin activation, high body mass index, glucose intolerance and redox instability, are predominantly reported. Aside from conventional inflammatory markers, in CCSs and frailty syndrome, thrombotic markers such as factor VIII and D-Dimers are also elevated [28].

Inflammation is a key factor in both CCSs and frailty. In the first one, we already established the role of the inflammatory syndrome in lipoprotein oxidation and plaque activation. In the second, inflammation is shown to activate a catabolic neurohormonal process that implies the redistribution of amino acids from skeletal muscle to other organ systems. This is a cause of sarcopenia, represented by a decrease in muscle mass, with the inherent modification in muscle metabolism and impairment to adapt to stress factors [28,29].

Intermediate monocytes contribute to the proinflammatory status by releasing cytokines (e.g., TNF-α, IL-1β and IL-6) and reactive oxygen species. Alongside elevated lipoprotein levels, they constitute a possible marker for atherosclerosis and increased CVD risk [26].

IL-6 was found to directly activate muscle catabolism by stimulating the ubiquitinproteome pathway, annihilating the cytoplasm and nucleoprotein in fibrocytes. In this context, the increase in IL-6 is considered an important predictor of decreased motor capacity, especially in older women. Indirectly, the concentrations of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have lowered, with decreased protein production and sarcopenia [2].

#### *2.3. The Role of Albumin and Vitamin D in the Pathogenesis of CCSs and Frailty*

A cohort study by Johansen et al. revealed that for each 1 g/dL increment in serum albumin levels, the frailty grades in senior hemodialysis patients, lowered by 0.4 points, thus suggesting that old patients with increased serum protein concentrations had a decreased rate of frailty [2,30]. These data are sustained by other studies on old, frail and non-frail patients with different comorbidities. Moreover, Dai et al. showed that blood serum albumin concentrations in senior patients with frailty and CCSs were significantly lower than that in pre-frailty and non-frailty patients. Serum albumin, a marker of nutritional status, may be an indicator of frailty in senior patients with chronic coronary syndrome [2].

A 25 (OH) D deficit is a negative prognostic factor in old patients with chronic coronary syndrome. The level of 25 (OH) D can be utilized as a marker to evaluate the gravity of CAD. Recent data have shown its role in predicting frailty [31]. Although results are not very specific, they indicate a link between the genetic mechanism of action of the vitamin D receptor (VDR) and that of cell differentiation and protein production. Thus, when vitamin D is low, adhesion to its receptor decreases simultaneously with muscle mass and strength [2].

The pathophysiological components between aging, frailty and CCSs in old patients are synthetized in Figure 1. There are three major factors contributing to both frailty and CCSs in old persons: normal aging, accelerated aging and inflammation. Each one can be an independent factor for frailty and/or CCSs, but they can also be found together as coexisting factors. Normal aging contributes to both frailty and CCSs and the cited mechanisms are: insulin resistance, increased production and accumulation of oxygen reactive species, normal changes in body composition which appear with aging (sarcopenia, central adiposity), homeostatic dysregulation, energy imbalance, neurodegeneration and hormonal dysregulation and inflammageing. Accelerated aging (which includes premature or aging at a rapid pace induced by diseases, genetic disorders or external factors) contributes to frailty and/or CCSs and the involved mechanisms are: increased oxidative stress, telomere shortening, immunosenescence, reduced autophagy and cellular senescence. Inflammation contributes to frailty and/or CCSs and the involved biomarkers are: C-reactive protein, Interleukin 6, tumor necrosis factor alpha (TNF-α) and nuclear factor-κB (NF-kB). All three factors contribute in varied degrees to both frailty and CCSs. Moreover, frailty is well-documented as being an important independent risk factor for CCSs in old patients and CCSs have a negative impact on frailty in old persons. The association of frailty and CCSs has a negative impact on the evolution of geriatric syndromes (especially cognitive impairment, immobility, delirium and iatrogenesis) and the development of CCS complications (acute coronary syndrome, heart failure and arrythmias). All these aspects imply polypharmacy, increased morbidity and death. tral adiposity), homeostatic dysregulation, energy imbalance, neurodegeneration and hormonal dysregulation and inflammageing. Accelerated aging (which includes premature or aging at a rapid pace induced by diseases, genetic disorders or external factors) contributes to frailty and/or CCSs and the involved mechanisms are: increased oxidative stress, telomere shortening, immunosenescence, reduced autophagy and cellular senescence. Inflammation contributes to frailty and/or CCSs and the involved biomarkers are: C-reactive protein, Interleukin 6, tumor necrosis factor alpha (TNF-α) and nuclear factorκB (NF-kB). All three factors contribute in varied degrees to both frailty and CCSs. Moreover, frailty is well-documented as being an important independent risk factor for CCSs in old patients and CCSs have a negative impact on frailty in old persons. The association of frailty and CCSs has a negative impact on the evolution of geriatric syndromes (especially cognitive impairment, immobility, delirium and iatrogenesis) and the development of CCS complications (acute coronary syndrome, heart failure and arrythmias). All these aspects imply polypharmacy, increased morbidity and death.

not very specific, they indicate a link between the genetic mechanism of action of the vitamin D receptor (VDR) and that of cell differentiation and protein production. Thus, when vitamin D is low, adhesion to its receptor decreases simultaneously with muscle mass and

The pathophysiological components between aging, frailty and CCSs in old patients are synthetized in Figure 1. There are three major factors contributing to both frailty and CCSs in old persons: normal aging, accelerated aging and inflammation. Each one can be an independent factor for frailty and/or CCSs, but they can also be found together as coexisting factors. Normal aging contributes to both frailty and CCSs and the cited mechanisms are: insulin resistance, increased production and accumulation of oxygen reactive species, normal changes in body composition which appear with aging (sarcopenia, cen-

*Life* **2022**, *12*, x FOR PEER REVIEW 5 of 15

strength [2].

**Figure 1.** The pathophysiological components between aging, frailty and CCS in old patients. CCS chronic coronary syndrome. **Figure 1.** The pathophysiological components between aging, frailty and CCS in old patients. CCS chronic coronary syndrome.

#### **3. Clinical Presentation and Evaluation of the Frail Senior Patient with CCSs 3. Clinical Presentation and Evaluation of the Frail Senior Patient with CCSs**

Diagnosing chronic coronary syndromes in the old aged can be challenging. Senior patients generally have atypical symptoms (e.g., fatigue, dyspnea, nausea, vomiting or postprandial epigastric pain) rather than conventional angina. The presence of hearing or cognitive disorders complicates the anamnesis, and the associated comorbidities delay the diagnosis [6]. Diagnosing chronic coronary syndromes in the old aged can be challenging. Senior patients generally have atypical symptoms (e.g., fatigue, dyspnea, nausea, vomiting or postprandial epigastric pain) rather than conventional angina. The presence of hearing or cognitive disorders complicates the anamnesis, and the associated comorbidities delay the diagnosis [6].

Regarding chronic coronary syndromes, the clinical scenarios reported by the latest guidelines are: (i) patients with suspected coronary heart disease and "stable" angina symptoms and/or dyspnea, (ii) patients with a new decompensation of heart failure or left ventricular dysfunction and suspected coronary heart disease, (iii) asymptomatic and symptomatic patients with symptoms stabilized at <1 year after ACS or patients with recent revascularization, (iv) asymptomatic and symptomatic patients > 1 year after initial diagnosis or revascularization, (v) patients with angina pectoris and suspected vasospastic or microvascular angina and (vi) asymptomatic subjects in whom coronary heart disease is detected on screening [5].

All of these are categorized as chronic coronary syndromes but entail various and timemodifiable risks for possible cardiovascular complications. For example, the installation of an ACS can sharply imbalance each of these clinical situations. Risks, in turn, could

be precipitated by the improper management of cardiovascular risk factors, inadequate lifestyle adjustments, medical treatment or failure of revascularization. Alternatively, appropriate secondary prevention methods can counterbalance the adverse events of chronic coronary syndromes [5].

Frailty, disability or other processes of the disease that exacerbate fatigue (i.e., pulmonary, skeletal and peripheral artery disease) can veil the perception of the typical symptoms of chronic coronary syndrome by assuming increased oxygen demand for the associated pathologies. Although electrocardiographic anomalies could predict possible negative complications, previous pathologies/abnormalities could limit the usefulness of ECG screening. Transthoracic echocardiography, however, has proven useful in screening for global and segmental ventricular function and structural pathology in old patients [5,6].

There are scarce data about diagnostic and prognostic values of imaging modalities in CCS evaluation in frail old patents compared to the standard population. The few data are for the old and very old population compared to the adult population.

Age influences the validity and reliability of diagnostic tests in CCS patients. In the context of advanced age, exercise stress tests are submaximal undertaken by frail seniors, their diagnostic and prognostic value being less than for young adults. In a study of Newman and Phillips, the sensitivity and specificity of the ECG exercise test in patients aged ≥65 years were 85% and 56%, respectively, and data from a metanalysis, including patients regardless of age, reported that the sensitivity and specificity of ECG exercise testing for the diagnosis of stable CAD were 58% and 62%, respectively [32,33]. Independently of age, bicycle echocardiography is more useful clinically than other tests in the diagnosis of CCSs [32]. Generally, stress testing is better at confirming than infirming CCSs [34]. Exercise echocardiography in old patients reveals resting wall motion abnormalities in 36% of the seniors and new or worsening wall motion abnormalities in 41% of patients. Moreover, in the multivariate analysis, exercise echocardiography variables, such as end systolic volume and ejection fraction, added significantly to clinical factors in predicting mortality [35]. Dobutamine stress echocardiography in old patients generally is well-tolerated, but there is a higher risk for side effects. Asymptomatic hypotension occurred more frequently in the elderly (7% in those <55 vs. 13% in the 55–74 age group vs. 25% in those ≥75). Moreover, any ventricular arrhythmia was more common in the elderly patient population (26% vs. 30% vs. 41%) [36].

Although angiography is frequently used in CCS diagnosis in seniors, many times it is temporized due to frailty and some associated conditions, such as anemic syndromes and chronic kidney disease, the latter coming with high risk of contrast substance nephropathy [37]. Major vascular complications may occur in 3.6% of older patients undergoing diagnostic coronary angiography [6]. When considering cardiac catheterization, the probability of hemorrhagic, embolic and neurological events and acute renal damage induced by the contrast substance should be considered, all of which are increased in geriatric patients. In addition, the old aged with rheumatological or orthopaedical comorbidities may have issues maintaining clinostats and anesthesia. Thus, an individualized approach, comparing the possible advantages and disadvantages of invasive assessment, is required before advising cardiac catheterization to seniors [5,6].

Exploring the presence and rate of ischemia in old patients needs a careful analysis of the usefulness of the diagnosis, as well as the patient's preferences and objectives of treatment. It is fundamental to establish if the patient in question is eligible for future treatments. A non-invasive diagnostic stress assessment is very important when the subject's likelihood of developing chronic coronary syndrome is intermediate. Pharmacological stress echocardiography and single-photon emission computed tomography (SPECT), including myocardial perfusion imaging (MPI), have been shown to be effective in stratifying risk in these patients. In those non-eligible for testing, vasoactive agents such as adenosine or dobutamine are needed to cause differential coronary flow or ischemia. This medication associates a high level of iatrogeny, favoring adverse effects such as tachyarrhythmias, hypotension and severe myocardial ischemia. However, depending on the degree of frailty, these agents can be used safely in the old aged [5,6].

The role of magnetic resonance imaging in the evaluation of cardiac ischemia in geriatric patients is still being studied. Stress cardiac magnetic resonance strongly predicted cardiovascular events in people older than 70 years in a cohort of 110 patients. In a cohort of 110 patients who undergo stress CMR, 40.9% of the patients tested positive for ischemia. The median follow-up was 26 months, and in this period, there were 35 cardiovascular events. Therefore, a positive stress CMR with a moderate or severe hypoperfusion defect predicted the appearance of cardiovascular events in the follow-up in patients older than 70 years [38].

Coronary CT angiography is a non-invasive imaging method that can objectify the atherosclerotic rate with no need for pharmacological effort or stress testing. Still, senior people may fail to go through with the test due to their inability to hold their breath. Moreover, they are more likely to acquire atrial fibrillation and renal injury compared to young patients [5,6]. Computed tomography coronary angiography performed in an old population was able to exclude obstructive atheroma in 59% of patients. The positive predictive value of CTCA showing obstructive atheroma was between 74 and 89% when compared with invasive angiography [39].

Regarding the diagnosis of frailty, two main models have been proposed in recent decades. The first is the phenotype model proposed by Fried et al., describing frailty in terms of five physical dimensions: (1) unintentional weight loss of at least 4.5 kg in the last year or ≥5% of body weight in the previous year; (2) self-reported exhaustion identified by two questions from the CES-D depression scale; (3) a reduction in the grip force, adapted according to gender and body mass index (BMI); (4) decreased mobility adjusted to gender and height; and (5) low energy consumption related to physical activity based on the subject's self-report on the Minnesota Leisure Time Physical Activity Questionnaire (MTLAQ-short version). The lack of any of these items defines patients as "robust". "Pre-frail" subjects have low scores of one or two, and "frail" patients meet three or more of these criteria [1].

A Canadian study of the frailty index of health and aging (CFI), proposed by Rockwood et al., is based on a cumulative deficit model, comprising 70 items that include clinical signs, symptoms, diseases and comorbidities, in order to construct an individual FI score, compared to the standard one. Various instruments based on these two main models have been used in cardiac rehabilitation [40].

The gold standard for assessing frailty in an old patient remains the Comprehensive Geriatric Assessment (CGA). The CGA consists of a holistic evaluation in different areas of health in seniors, exploring 10 dimensions (cognition, motivation, disability, communication, mobility, balance, bowel/bladder function, nutrition, social ability and comorbidity). The Frailty Index based on a Comprehensive Geriatric Assessment (FI-CGA) is based on the CGA, evaluates the 10 dimensions and classifies patients into three classes of frailty: mild (0–7), moderate (7–13) and severe (>13) [1,41,42].

The different methods in evaluating frailty and its components are described in Table 1 [8].

**Table 1.** Diagnostic methods of frailty and frailty subtype.

FI-CGA = Frailty Index based on a Comprehensive Geriatric Assessment; CFS = Clinical Frailty Scale; CSHA-FI = Canadian Study of Health and Aging Frailty Index; EFS = Edmonton Frailty scale; CGA = Comprehensive Geriatric Evaluation.

#### **4. Risk Assessment in the Frail Senior Patient with CCS**

A frailty assessment using the Clinical Frailty Assessment Scale (CFS) was separately and closely linked to mortality at 6 months of all causes, including after full adjustment for the initial differences in other risk factors [43].

The advanced age segment, increased comorbidities, recurrence of decompensation and prolonged hospitalization (>10 days) and emergency readmission within 30 days of discharge were associated with a higher degree of frailty and, at the same time, with the mortality of any within 30 days of the date of admission. A higher degree of frailty, according to the CFS, is associated with a more reserved prognosis in terms of mortality or the development of complications [43].

Other data suggested a high probability of readmission to hospital and death in frail patients compared to those who are not frail but who are associated with heart failure or chronic coronary syndromes. Polypharmacy and the lack of individualization of treatment are also factors that affect mortality in senior patients with CCSs and explain some of the differences between mortality from any cause and that linked to cardiovascular disease [4].

In the frail old aged, aging accelerates physical and functional decline, which raise the risk of poor health outcomes. The occurrence of frailty is directly proportional to aging and is related to elevated rates of mortality, morbidity, disability and increased health care costs while also being a predictor of poor surgical and interventional outcomes [4]. One meta-analysis evaluating gender differences between frail seniors showed women were considerably more frail, while men had increased mortality. The same data showed that frail old women with CCSs have a higher death rate than frail men of similar age [4,44,45].

During the 6-year follow-up of the NHATS study, it was revealed that seniors with pre-frailty and frailty have higher incidences of all-cause mortality, mainly due to death, stroke and peripheral vascular disease. The means to include frailty evaluation into the care of seniors at risk for CCSs is limited due to low efficacy in the prevention of frailty, no fully efficient therapies of the frailty and limited access to comprehensive geriatric evaluation [46–48].

The battery of secondary prevention interventions in frail old people with CCS includes: training, management of risk factors (diet management, smoking abstinence), medical treatment and psychological intervention [1]. Because frailty is a predictor of adverse outcomes in patients with CCSs, both the American Heart Association and the European Society of Cardiology recommend frailty screening in seniors with CAD and the development of intervention plans [5,49].

A holistic evaluation of the high-risk old aged can aid to recognize the factors that determine the development of frailty. It has been shown that aging, limited financial resources, malnutrition and depression are key to the development of frailty in patients with CCSs. The results are significant in the identification of frail adults with CCSs and the emerging need to bring forth preventive interventions [49]. A comprehensive geriatric assessment to recognize frailty is fundamental prior to clinical treatment, as are interventions to limit or reverse frailty in old patients with CCSs [49,50].

#### **5. Consequences of the Association of Frailty and CCSs in Senior Patients**

The risk for developing CCSs has raised in frail and pre-frail people > 65 years of age. Both frailty and CCSs in the old aged leads to a higher risk of short-term mortality (3 months). As per the frailty phenotype model, the prevalence of CCSs has led to a two- or three-times growth in frail seniors and a tendency to precipitate pre-frailty [1,51].

In hospitalized seniors, malnutrition and hypoalbuminemia may show either a state of frailty or a complication of CCS. The explanation resides in the resemblance and overlap of biological and pathophysiological mechanisms, such as inflammation and age-related subclinical cardiovascular impairment that leads to both conditions [1,52].

In aging patients with CCSs, heart failure (HF) is widespread, and the risk of frailty is 3.4 times bigger, with a high prevalence of pre-frailty (46%) and frailty (40%) The ischemic cardiovascular state predisposes to HF development [53]. Pathophysiologically, it shares common mechanisms with sarcopenia, related especially to inflammation pathways. Thus, it seems that HF can negatively influence gait speed and precipitate malnourishment, resulting in anemia and negative outcomes [1].

The aging of the world's population is leading to an increase in the incidence and prevalence of geriatric syndromes, such as frailty and disability. The advanced age segment is associated with a series of worsened results related to the link between frailty and CCSs. On these grounds, all other comorbidities, such as sarcopenia, malnutrition, functional dependence, polypharmacy, bleeding risk and thromboembolic events, are precipitated [1,29].

#### **6. Treatment Characteristics in the Fragile Senior Patient with CCS**

#### *6.1. Treatment Goals*

The treatment goals in frail old patients, who are associated with CCSs, include increasing life expectancy, minimizing the risk of cardiovascular events, improving or remitting symptoms and returning to normal activities or a good quality of life [11,54].

In senior patients, improving the quality of life, maintaining independence in daily life and controlling symptoms are priorities. In most cases, these issues are more important than prolonging life [55].

#### *6.2. Pharmacological Treatment*

According to new standards, treatment interventions should take into consideration two ways of approaching frailty. The first one must concentrate on preventing or reducing the progress of frailty while the second will be concerned with the anticipation of side effects in frail seniors. Periodic physical exercise and an adequate diet bring known benefits in the prevention of frailty, but the efficacy of pharmacotherapy is still certain [28].

Concerns have persisted over the past few years that the development of pharmaceutical strategies, such as new lipid-lowering agents in the form of subtilizin/kexin-9 (protein PCSK-9) inhibitors of proprotein convertase, and the use of oral anticoagulants (e.g., Rivaroxaban in patients with increased risk) outshine the role of lifestyle changes. Beta-blockers and calcium channel blockers still are the primary drugs for controlling the symptoms of angina and should be administered depending on the patient's heart rate, blood pressure and left ventricular function. The utilization of other secondary prevention medications (e.g., angiotensin converting inhibitors and statins) also remains the same [56].

The pharmacological treatment in an old patient must be prescribed considering its particularities: pharmacological and pharmacokinetic changes due to aging, body composition which is different in the old aged compared to adult, pre-existing medication for other conditions, the coexisting comorbidities, the presence of impairments, life expectancy, quality of life, polypharmacy and even the financial aspect [57,58].

Compared to young adults, seniors tend not to adhere to medical regimens, including optimal medical therapy for CCSs. Based on the literature, higher medical treatment compliance improves the survivability rate, even for frail seniors with CCSs [59]. The efficiency of antithrombotic therapy in frail senior patients is comparable to that in young adults, but the first group has a higher risk of bleeding [60].

#### *6.3. Interventional Treatment*

In the context of worldwide aging and a life expectancy increase, there appeared to be more and more cases of seniors necessitating advanced cardiovascular procedures, such as coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). Increased comorbidity prevalence associated with CCSs predisposes this group to more revascularization complications and poor outcomes. Thus, there is need to preoperatively assess the physiological status of these patients to establish the eligibility for CABG, PCI or pharmacological treatment. In addition to conventional risk stratification, the assessment of frailty is increasingly recognized as an available indicator for predicting outcomes after cardiac surgery [61].

The treatment of chronic coronary syndromes in the old aged suffers from the impasse of vulnerabilities related to both conservative and invasive strategies, such as bleeding, kidney failure and neurological disorders. According to current guidelines, radial access is recommended to be used, when possible, to lower complications at the entry zone when considering an invasive approach for seniors management. It is indicated that diagnostic and revascularization arguments be based on clinical presentation, the rate of ischemia, frailty, life expectancy and other morbidities [5].

Data report that in old patients with isolated CABG, the Preoperative Clinical Frailty Scale (CFS) was a separate predictor of hospital mortality at 30 days. A slow gait has been reported to have an individual predictive role in poor outcomes, even after adjusting for the Thoracic Surgeons Society (STS) score [61]. Debate yet remains as to whether to consider PCI or CABG for senior patients with CCSs and frailty. The presence of asymptomatic myocardial ischemia can be a complication of the frailty status associated with CCSs. Thus, preoperative screening for the frailty of CCS patients remains crucial [61,62].

The frail senior patient with comorbidities has a higher risk of post-CABG mortality compared to young adults [63,64]. Moreover, data show that age over 65, female sex and the presence of comorbidities are associated with higher rates of rehospitalization after CABG [65,66]. CABG should be used cautiously in the frail senior patient.

A single-center cohort study of 3826 patients undergoing cardiac surgery found frailty to be associated with an increased risk of mortality in hospital (adjusted odds ratio, 1.8; 95% CI, 1.1–3.0) and at 2 years (adjusted HR, 1.5; 95% CI, 1.1–2.2) [67]. Another population-based, retrospective, cohort study included 40083 patients undergoing CABG. A total of 8803 (22%) were frail, with a prevalence of frailty higher in the older age groups. Frail patients had higher rates of 30-day mortality than those who were not frail, across all but the ≥85 years age group; at 30 days, 626 patients (1.6%) patients died, of whom 174 (27.8%) were frail. Moreover, at 4 years, there were lower probabilities of survival in patients who were frail at the time of surgery [68]. Frailty has a strong positive relationship with the risk of major adverse cardiac and cerebrovascular events in patients undergoing cardiac surgery; in patients undergoing traditional procedures, such as CABG and/or valve procedures, frailty was associated with an increased OR of mortality, ranging from 1.10 to 2.63 [69].

A PCI is associated with better outcomes in octogenarians compared to young adults, in a higher or at least equal measure. An increased quality of life is one such outcome, but the risks and benefits of the PCI must be considered [70]. However, the efficacy of a PCI is limited by the late addressability of the senior patient, as often they already have complications [60].

A metanalysis which included 2658 seniors identified that the prevalence of frailty ranged from 12.5 to 27.8%. Frailty was associated with increased in-hospital mortality (OR 3.59, 95% CI 2.01–6.42), short-term mortality (OR 6.61, 95% CI 2.89–15.16), as well as long-term mortality (HR 3.24, 95% CI 2.04–5.14) in patients undergoing a PCI. Moreover, prefrailty was a predictor of all-cause mortality in senior patients undergoing a PCI [71]. Frailty also has a negative impact not only on mortality in old patients undergoing a PCI but also in hospital stay and time interval from admission to the PCI. A prospective study including 745 patients undergoing a PCI observed that the time interval from admission to the PCI was longer for frail patients (2.9 ± 5.6 vs. 1.7 ± 3.1 days, *p* < 0.001). After the PCI, frail patients remained in hospital substantially longer than non-frail patients (14.1 ± 26.7 vs. 3.5 ± 8.8 days, *p* < 0.001), and frail patients were nearly five times more likely to die within 30 days after the PCI, compared with non-frail patients (HR 4.8, 95% CI 1.4 to 16.3, *p* = 0.01) [72].

There are scarce data regarding a comparison of an OMT, PCI and CABG in frail old patients. The few data are for old patients with coronary chronic total occlusion, regardless of their frailty status. In these patients, a complete revascularization is more frequently achieved with CABG rather than a PCI, quality of life could be elevated by CABG and the 30-day mortality and 1-year survival were similar between CABG and PCI. However, the authors stated that when patients have a higher surgical risk such as frailty, serious comorbidity or dementia, a PCI seems to be more appropriate [73]. The European Society of Cardiology recommends to adopt a conservative, a noninvasive or a less invasive strategy in frail old patients [72,74].

#### *6.4. Monitoring and Rehabilitation Programs*

A relationship of interdependence and mutual potentiation has been established between frailty and cardiovascular impairment. Therefore, it is plausible that some rehabilitation measures to reduce frailty, including resistance training or nutritional approach, which involve an increased intake of protein and amino acids, may benefit seniors with CVD and frailty [61].

Although there is much data regarding cardiac rehabilitation and its role in restoring functional capacity and the quality of life in the frail old aged, there are few data assessing the role of cardiac rehabilitation, by improving frailty, in improving the prognosis in patients with CVD, including CCSs. We also interpret this aspect based on the fact that resistance training is not advised in most patients with CVD, due to the fact that it raises the post-cardiac load [61,75].

Most frail old patients eligible for cardiac rehabilitation programs have limitations in accessing them: there is a need for resources in the use of mobile technologies and in the correct performance of physical therapy exercises. However, it is certain that these interventions, and especially those requiring high-intensity training, have not been fully explored in the senior population.

Telemedicine has also been shown to be an additional tool for frail seniors who are unable to participate in cardiovascular rehabilitation exercises in hospitals. New data and reviews have recently showed the advantages of hybrid programs, which use remote monitoring and telerehabilitation platforms. In old patients with HF, the improvement in distance after following these rehabilitation programs for 12 weeks was statistically significant [1,76,77].

Although no significant differences were identified in terms of increased quality of life, mortality and improved functional capacity between conventional and hybrid cardiac rehabilitation programs, greater compliance was shown with those who joined the latter.

Frail seniors with ACSs or CCSs are often excluded from multidisciplinary cardiac rehabilitation measures or programs based on exercise. Future studies will focus on identifying the best frailty assessment tool for developing individualized care models. Cardiac rehabilitation programs at home and telerehabilitation models imagined specifically for frail seniors are enthusiastically advised [1].

Cognitive-behavioral and psychological interventions, exercise-based cardiac rehabilitation, annual influenza vaccination and the holistic assessment of senior patients are the levers of an individualized therapeutic approach, with the chance to reduce disabilities, increase quality of life and increase life expectancy.

**Author Contributions:** Conceptualization, I.D.A. and A.C.I.; methodology A.C.I. and S.M.T.; validation: R.S. and A.I.P., investigation C.A.S.; resources, S.M.T., I.A.S. and A.-M.T.; data curation, I.D.A.; writing—original draft preparation, S.M.T.; writing—review and editing, A.C.I.; visualization, A.C.I. and R.S.; supervision, I.D.A. 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.

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

#### **References**