heart function fails when the organ is unable to pump blood at a rate proportional to the body s need for oxygen or when this function leads to elevated cardiac chamber filling pressures ( cardiogenic pulmonary edema ) . despite our sophisticated knowledge of heart failure , even the so - called ejection fraction 
up 175% over the past 25 years  and costs of nearly $ 15.4 billion dollars , acute heart failure is a critically important health concern . furthermore , half of the patients discharged from the hospital are readmitted within half - a - year .
in - hospital mortality remains high between 4% and 7%.1,2 heart failure is a significant problem as the population ages .
the prevalence is 2.5% of the us population or 5 million patients ( from the national health and nutrition education survey).2
common etiological mechanisms of heart failure include coronary ischemia , valvular disease , hypertension , and diastolic dysfunction .
yet , other causes include : postpartum cardiomyopathy ; postinfectious , chronic tachycardia ; metabolic dysregulation ; adverse medication side effects ( particularly adriamycin chemotherapy ) ; orphan disease duchenne s muscular dystrophy ; infiltrative diseases ( such as amyloidosis ) ; and inflammatory / connective tissue diseases ( such as systemic lupus erythematosus ) . when known causes of heart failure
less often studied versus chronic heart failure , acute decompensated heart failure is associated with abrupt - onset symptoms associated with hospitalization .
nearly half of the admitted patients with heart failure have preserved ejection fraction.2,3 in order to appreciate the physiology of heart failure , a review of fundamental principles is on order .
the frank  starling law states that the stroke volume of the heart increases in response to an increase in the volume of blood filling the heart ( the end diastolic volume ) when all other factors remain constant .
the increased volume of blood stretches the ventricular wall , causing cardiac muscle to contract more forcefully ( the so - called frank  starling mechanism ) .
the stroke volume may also increase as a result of greater contractility of the cardiac muscle during exercise , independent of the end - diastolic volume .
the frank  starling mechanism appears to make its greatest contribution to increasing stroke volume at lower work rates , and contractility has its greatest influence at higher work rates.4 while the frank  starling mechanism may contribute at lower work rates , cardiac injury at lower work rates may activate additional mechanisms .
cardiac injury in heart failure leads to not only reduced left ventricular ( lv ) dysfunction but also activation of the renin angiotensin system and sympathetic nervous system , ultimately causing lv thickening , remodeling , vasoconstriction ( with pulmonary hypertension and cell dysregulation ) , and , possibly , apoptosis or programmed cell death .
severity is graded by the new york heart association class , with increasing severity of classes i to iv .
another grading system is the american heart association staging system with stage c , classified as the symptomatic stage .
this stage c is a result of known structural heart diseases and is associated with shortness of breath , fatigue , and reduced exercise tolerance .
the obvious goal is to prevent progressive lv dysfunction to end - stage d , resulting in lv assist device implantation , cardiac transplant , or palliative care.5
medication management of acute heart failure often entails diuretics to reduce preload , vasodilators to reduce preload and/or afterload , and inotropes to augment contractility .
angiotensin - converting enzyme ( ace ) inhibitors and angiotensin receptor blockers ( arbs ) and aldosterone antagonists also aim to reduce preload and afterload.6 one adverse side effect ( usually nonallergic antibody , non - ige  mediated ) of ace inhibitors is angioedema ( risk up to 15.5% ) .
, this angioedema results from increased bradykinin production , which can occur at any time while taking these medications due to interruption of the conversion of angiotensin i to angiotensin ii .
angioedema from ace inhibitors and arbs may lead to life - threatening swelling of the throat , requiring critical interventions , ie , intubation or tracheostomy . for arbs ,
the mechanism of action of angioedema is not due to direct production of bradykinin and is unclear .
some evidence suggests that treatment with a bradykinin b2 receptor blocker ( icatibant ) may attenuate angioedema attacks early.79 patients with hereditary angioedema ( deficiency of c1 esterase inhibitor ) and spontaneous attacks of swelling should not take ace inhibitors .
clearly , it would be prudent to design a heart failure drug that does not incur risk of angioedema .
other medications used for heart failure include inotropes  such as dopamine and dobutamine . while inotropes increase cardiac output , they often do so at the expense of increasing myocardial oxygen demand , predisposition to arrhythmias , and neurohormonal activation
there is 50% survival at 6 months and nearly 100% mortality at 1 year for those heart failure patients who are dependent on inotropes.10 long - term survival among heart failure patients may be improved with -blockers,11 ace inhibitors,12 aldosterone antagonists,13 electrophysiology devices such as automatic implantable cardiovascular defibrillators , and vasodilators .
another aspect of heart failure is diastolic dysfunction with preserved lv ejection fraction , accounting for half of the hospitalizations .
pathophysiologically , there is concentric remodeling and increased lv end diastolic pressure from a stiff left ventricle , thereby preventing relaxation .
medications for diastolic dysfunction are similar to systolic dysfunction : ace inhibitors , arbs , diuretics , and -blockers.14
in august of 2014 , the first new drug for heart failure in many years , called lcz696 , was shown to prevent deaths and hospitalizations in heart failure patients 
better than the gold standard enalipril , which is an ace inhibitor . in the paradign - hf study ,
lcz696 , which is comprised of two drugs  an arb and a neprilysin inhibitor called sacubitril  reduced the risk of cardiovascular - related death to 13.3% , versus the ace inhibitor cohort rate of 16.5% .
this use of sacubitril is an example of utilizing new or different pathways to treat heart failure.15 sacubitril is a prodrug that is activated to lbq657 by de - ethylation via esterases.16 lbq657 inhibits the enzyme neprilysin,17 which is responsible for the degradation of atrial and brain natriuretic peptide , two blood pressure  lowering peptides that work mainly by reducing blood volume . as a result of reduced degradation of helpful peptides , these heart failure patients on sacubitril have less circulating blood volume and have done well in terms of prevention of deaths and hospitalizations ( supra vide ) .
on april 15 , 2015 , the food and drug administration approved corlanor ( ivabradine ) to reduce hospitalizations from worsening heart failure .
the indications for ivabradine are specific : symptoms of heart failure that are stable and a normal heartbeat with a resting heart rate of at least 70 beats per minute and patients must already be taking -blockers at the highest dose they can tolerate .
ivabradine is thought to work by decreasing heart rate and represents the first approved product in this drug class .
it works via the if ( funny channel ) and does not affect other cardiac ionic currents ( not beta receptor mediated ) .
ventricular contractility is preserved.18 in clinical trials of 6,505 participants , hospitalizations for heart failure were reduced compared to placebo .
the most notable side effects were bradycardia , hypertension , atrial fibrillation , and temporary visual disturbance entailing seeing flashes of light
. the bradycardia may be severe.19 other novel therapeutic agents for heart failure may consequently have plausible efficacy on the heels of sacubitril and ivabradine .
for example , vasoactive intestinal peptide ( vip ) , discovered by drs sami i. said and victor mutt in the 1970s , is a 28amino acid peptide found in nerve terminals and in mast cells.20 vip increases cyclic adenosine monophosphate ( camp ) intracellularly to cause cardiac contraction in an analogous fashion to glucagon.21 vip also is a smooth muscle relaxant , which may be beneficial in pulmonary hypertension associated with heart failure22 and vip inhibits the proliferation of smooth muscle cells , attenuating vascular remodeling.23 inasmuch as sometimes vascular remodeling is a compensatory mechanism for dysfunction in heart failure , vip has promise to treat this deleterious component .
enhanced peripheral vascular tone is a major factor in determining deterioration of clinical heart failure .
nakamura has reviewed peripheral circulatory failure in heart failure and notes that it is caused  not only by simple arterial muscle constriction , but also by structural and functional changes , including receptor and post - receptor levels in the vasculature . 
thus , vascular remodeling potentially may be an important mechanism underlying vasodilatory failure in both limb conduit and intraskeletal muscle vessels , contributing significantly to lv dysfunction and exercise intolerance in patients with heart failure.24 what is compelling about vip as a novel therapeutic agent for heart failure is evident in mice lacking the gene for vip .
gene programs are overexpressed in vip knockout mice.25 so , the plausibility of vip as both a treatment for heart failure in patients and a modifier of one s biology in a pharmacogenomic fashion may have traction .
four categories of genes triggering heart failure are increased in mice without heart - protective vip : ( 1 ) force generation and propagation ; ( 2 ) energy production and regulation ; ( 3 ) ca cycling ; and ( 4 ) transcriptional regulators .
force generation gene mutations encoding proteins of the muscle sarcomere have been associated with both hypertrophic and dilated cardiomyopathy .
overexpression of sarcomere protein expression in the setting of a dilated cardiomyopathy26 may suggest a compensatory mechanism .
upregulated expression of other force generation genes such as sarcoglycan and caveolin27 in vip knockout mice supports the concept of increased force to the extracellular matrix , with ventricular hypertrophy , for apparent release of protein products of these genes in heart failure . regarding energy production and regulation genes
, it has been increasingly recognized that nuclear - encoded metabolic gene mutations are key regulators of hypertrophic cardiac remodeling and heart failure .
for example , mutations in genes encoding the lysosome - associated membrane protein are associated with heart failure in patients.28 in the absence of vip in vip knockout ( ko ) mice , upregulation of prkag2 , for example,29 would support a compensatory response to thinning of the cardiac wall .
ca cycling  is critically important , since protein and rna levels of key calcium modulators are altered in acquired and inherited forms of heart failure .
overexpression of fkbp30 in mice supports the concept that these mice would have aberrant excessive release of calcium during the relaxation / diastolic phase of the cardiac cycle , enhancing the opportunity to generate hypertrophy .
cardiac hypertrophy is attenuated in murine models with overexpression of caveolin-3 , a potent upstream inhibitor of t - type ca current,18 and rats treated with calhex231 , an inhibitor of calcium - sensing receptor.31 similarly , deleterious lv hypertrophy may therefore plausibly be suppressed with exogenous vip administration .
mechanisms which activate or repress cardiac gene transcription may induce key molecules , which directly or indirectly lead to cardiac remodeling .
lack of vip in vip ko mice with the phenotype of biventricular dilated cardiomyopathy and primary pulmonary hypertension is concurrent with strong overexpression of cardiac muscle genes , supporting the concept of vip in vivo as a maestro conductor maintaining homeostasis of the heart.26 table 1 shows on the next page multiple heart failure gene programs which are overexpressed in vip ko mice .
these physiological abnormalities are associated with premature death compared to the wild type ( fig .
3 ) . compensatory and pathogenic gene programs are displayed in figure 4 , with overexpression of leptin as a compensatory reaction for cardiac cachexia and low body weight along with proinflammatory interleukin-6 ( il-6 ) and il-1 .
vip increases intracellular camp and acts via protein kinase a to activate transcriptional promoters.32,33 vip upregulates il-10 , which is anti - inflammatory.34 kupari et al found that vip levels in serum from healthy subjects and patients with aortic stenosis and heart failure were released into the coronary sinus .
these authors concluded that , although vip was marginally elevated systemically in heart failure , it is the major neuroendocrine contributor to heart failure.35 smitherman infused vip into the left coronary artery of four other men at four levels .
the maximum decline in coronary vascular resistance was 46% and was not associated with an increase in myocardial oxygen uptake .
he concluded that  1 ) intravenous administration of low to intermediate doses of vip in humans is associated with substantial coronary vasodilation , 2 ) the coronary bed appears to be at least as responsive as other vascular beds , 3 ) the coronary vasodilation is due to both direct and indirect effects , and 4 ) the coronary vasodilation does not appear to be mediated by prostaglandins.36,37 so , the potential of an exogenous , sustainable vip drug would be to help relax coronary arteries .
lucia et al also found that vip plasma levels were higher in heart failure patients with dilated cardiomyopathy compared to healthy subjects and was higher in older subjects .
heart failure patients with higher new york heart association severity had lower levels of vip .
these data also suggest that heart failure patients with worse disease have an inability to produce vip .
the capacity of the elderly to produce vip is heartening , so that low levels are not due to aging itself.38 phasebio corporation recently conducted a phase 1 , single ascending dose ( sad ) study in patients with essential hypertension .
pb1046 was administered subcutaneously and was found to be well - tolerated and demonstrated a prolonged , dose - dependent effect on blood pressure , which was used as a biomarker for activity in this study .
( see http://clinicaltrials.gov/ct2/show/nct01523067 for further details . ) with this demonstration of safety and tolerability at efficacious doses , phasebio conducted a second phase 1 sad study in patients with essential hypertension , with the product administered intravenously to support the use of pb1046 in an acute setting ( http://clinicaltrials.gov/show/nct01873885 ) .
subsequent phase 2 clinical studies will examine the efficacy of multiple ascending doses of pb1046 in patients with pulmonary arterial hypertension and heart failure .
in august of 2014 , the first new drug for heart failure in many years , called lcz696 , was shown to prevent deaths and hospitalizations in heart failure patients 
better than the gold standard enalipril , which is an ace inhibitor . in the paradign - hf study ,
lcz696 , which is comprised of two drugs  an arb and a neprilysin inhibitor called sacubitril  reduced the risk of cardiovascular - related death to 13.3% , versus the ace inhibitor cohort rate of 16.5% .
this use of sacubitril is an example of utilizing new or different pathways to treat heart failure.15 sacubitril is a prodrug that is activated to lbq657 by de - ethylation via esterases.16 lbq657 inhibits the enzyme neprilysin,17 which is responsible for the degradation of atrial and brain natriuretic peptide , two blood pressure  lowering peptides that work mainly by reducing blood volume . as a result of reduced degradation of helpful peptides , these heart failure patients on sacubitril have less circulating blood volume and have done well in terms of prevention of deaths and hospitalizations ( supra vide ) .
on april 15 , 2015 , the food and drug administration approved corlanor ( ivabradine ) to reduce hospitalizations from worsening heart failure .
the indications for ivabradine are specific : symptoms of heart failure that are stable and a normal heartbeat with a resting heart rate of at least 70 beats per minute and patients must already be taking -blockers at the highest dose they can tolerate .
ivabradine is thought to work by decreasing heart rate and represents the first approved product in this drug class .
it works via the if ( funny channel ) and does not affect other cardiac ionic currents ( not beta receptor mediated ) .
ventricular contractility is preserved.18 in clinical trials of 6,505 participants , hospitalizations for heart failure were reduced compared to placebo .
the most notable side effects were bradycardia , hypertension , atrial fibrillation , and temporary visual disturbance entailing seeing flashes of light
other novel therapeutic agents for heart failure may consequently have plausible efficacy on the heels of sacubitril and ivabradine .
for example , vasoactive intestinal peptide ( vip ) , discovered by drs sami i. said and victor mutt in the 1970s , is a 28amino acid peptide found in nerve terminals and in mast cells.20 vip increases cyclic adenosine monophosphate ( camp ) intracellularly to cause cardiac contraction in an analogous fashion to glucagon.21 vip also is a smooth muscle relaxant , which may be beneficial in pulmonary hypertension associated with heart failure22 and vip inhibits the proliferation of smooth muscle cells , attenuating vascular remodeling.23 inasmuch as sometimes vascular remodeling is a compensatory mechanism for dysfunction in heart failure , vip has promise to treat this deleterious component
. enhanced peripheral vascular tone is a major factor in determining deterioration of clinical heart failure .
nakamura has reviewed peripheral circulatory failure in heart failure and notes that it is caused  not only by simple arterial muscle constriction , but also by structural and functional changes , including receptor and post - receptor levels in the vasculature . 
thus , vascular remodeling potentially may be an important mechanism underlying vasodilatory failure in both limb conduit and intraskeletal muscle vessels , contributing significantly to lv dysfunction and exercise intolerance in patients with heart failure.24 what is compelling about vip as a novel therapeutic agent for heart failure is evident in mice lacking the gene for vip .
human heart failure gene programs are overexpressed in vip knockout mice.25 so , the plausibility of vip as both a treatment for heart failure in patients and a modifier of one s biology in a pharmacogenomic fashion may have traction .
four categories of genes triggering heart failure are increased in mice without heart - protective vip : ( 1 ) force generation and propagation ; ( 2 ) energy production and regulation ; ( 3 ) ca cycling ; and ( 4 ) transcriptional regulators .
force generation gene mutations encoding proteins of the muscle sarcomere have been associated with both hypertrophic and dilated cardiomyopathy .
overexpression of sarcomere protein expression in the setting of a dilated cardiomyopathy26 may suggest a compensatory mechanism .
upregulated expression of other force generation genes such as sarcoglycan and caveolin27 in vip knockout mice supports the concept of increased force to the extracellular matrix , with ventricular hypertrophy , for apparent release of protein products of these genes in heart failure . regarding energy production and regulation genes
, it has been increasingly recognized that nuclear - encoded metabolic gene mutations are key regulators of hypertrophic cardiac remodeling and heart failure .
for example , mutations in genes encoding the lysosome - associated membrane protein are associated with heart failure in patients.28 in the absence of vip in vip knockout ( ko ) mice , upregulation of prkag2 , for example,29 would support a compensatory response to thinning of the cardiac wall .
ca cycling  is critically important , since protein and rna levels of key calcium modulators are altered in acquired and inherited forms of heart failure .
overexpression of fkbp30 in mice supports the concept that these mice would have aberrant excessive release of calcium during the relaxation / diastolic phase of the cardiac cycle , enhancing the opportunity to generate hypertrophy .
cardiac hypertrophy is attenuated in murine models with overexpression of caveolin-3 , a potent upstream inhibitor of t - type ca current,18 and rats treated with calhex231 , an inhibitor of calcium - sensing receptor.31 similarly , deleterious lv hypertrophy may therefore plausibly be suppressed with exogenous vip administration .
mechanisms which activate or repress cardiac gene transcription may induce key molecules , which directly or indirectly lead to cardiac remodeling .
lack of vip in vip ko mice with the phenotype of biventricular dilated cardiomyopathy and primary pulmonary hypertension is concurrent with strong overexpression of cardiac muscle genes , supporting the concept of vip in vivo as a maestro conductor maintaining homeostasis of the heart.26 table 1 shows on the next page multiple heart failure gene programs which are overexpressed in vip ko mice .
these physiological abnormalities are associated with premature death compared to the wild type ( fig .
3 ) . compensatory and pathogenic gene programs are displayed in figure 4 , with overexpression of leptin as a compensatory reaction for cardiac cachexia and low body weight along with proinflammatory interleukin-6 ( il-6 ) and il-1 .
vip increases intracellular camp and acts via protein kinase a to activate transcriptional promoters.32,33 vip upregulates il-10 , which is anti - inflammatory.34 kupari et al found that vip levels in serum from healthy subjects and patients with aortic stenosis and heart failure were released into the coronary sinus .
these authors concluded that , although vip was marginally elevated systemically in heart failure , it is the major neuroendocrine contributor to heart failure.35 smitherman infused vip into the left coronary artery of four other men at four levels .
the maximum decline in coronary vascular resistance was 46% and was not associated with an increase in myocardial oxygen uptake .
he concluded that  1 ) intravenous administration of low to intermediate doses of vip in humans is associated with substantial coronary vasodilation , 2 ) the coronary bed appears to be at least as responsive as other vascular beds , 3 ) the coronary vasodilation is due to both direct and indirect effects , and 4 ) the coronary vasodilation does not appear to be mediated by prostaglandins.36,37 so , the potential of an exogenous , sustainable vip drug would be to help relax coronary arteries .
lucia et al also found that vip plasma levels were higher in heart failure patients with dilated cardiomyopathy compared to healthy subjects and was higher in older subjects .
heart failure patients with higher new york heart association severity had lower levels of vip .
these data also suggest that heart failure patients with worse disease have an inability to produce vip . the capacity of the elderly to produce vip is heartening , so that low levels are not due to aging itself.38 phasebio corporation recently conducted a phase 1 , single ascending dose ( sad ) study in patients with essential hypertension .
pb1046 was administered subcutaneously and was found to be well - tolerated and demonstrated a prolonged , dose - dependent effect on blood pressure , which was used as a biomarker for activity in this study .
( see http://clinicaltrials.gov/ct2/show/nct01523067 for further details . ) with this demonstration of safety and tolerability at efficacious doses , phasebio conducted a second phase 1 sad study in patients with essential hypertension , with the product administered intravenously to support the use of pb1046 in an acute setting ( http://clinicaltrials.gov/show/nct01873885 ) .
subsequent phase 2 clinical studies will examine the efficacy of multiple ascending doses of pb1046 in patients with pulmonary arterial hypertension and heart failure .
current therapies do not control progression of heart failure well and must often be used in combinations to optimize results .
lcz696 utilizes a novel pathway to treat heart failure and improves mortality in comparison to the current standard of care , enalipril .
it is important to remember that as a combination therapy utilizing an arb , it carries a risk of inducing life - threatening angioedema .
ivabradine reduces rates of heart failure  related hospitalization , but the indications for use are strict and this medication carries undesirable side effects that potentiate etiologic mechanisms of heart failure .
vip , an endogenous peptide , shows widespread cardiovascular benefits as a vasodilator , an attenuator of smooth muscle proliferation , and a homeostatic regulator of heart failure gene programs thereby preventing hypertrophy of cardiac myocytes .
endogenous levels of vip have been shown to be elevated in certain stages of heart failure . however , later stages of the disease show significantly diminished levels .
administration of exogenous vip in early and late stages of heart failure may provide the most benefit for patients .
use of an elastin polymer to protect and stabilize vip as a therapeutic agent shows the interface between engineering and medicine , and it bodes well for the influence of technology on society , particularly since heart failure will continue to grow as a prevalent problem as the population ages .
vip may therefore have a chance to satisfy the unmet need as a treatment for acute heart failure , thus fulfilling discoverer dr sami i. said s dream to promote human health .
 heart function fails when the organ is unable to pump blood at a rate proportional to the body s need for oxygen or when this function leads to elevated cardiac chamber filling pressures ( cardiogenic pulmonary edema ) . despite our sophisticated knowledge of heart failure , 
 even so - called ejection fraction - preserved heart failure has high rates of mortality and morbidity . 
 so , novel therapies are sorely needed . 
 this review discusses current standard therapies for heart failure and launches an exploration into emerging novel treatments on the heels of recently - approved sacubitril and ivbradine . 
 for example , vasoactive intestinal peptide ( vip ) is protective of the heart , so in the absence of vip , vip knockout mice have dysregulation in key heart failure genes : 1 ) force generation and propagation ; 2 ) energy production and regulation ; 3 ) ca+2 cycling ; 4 ) transcriptional regulators . 
 vip administration leads to coronary dilation in human subjects . in heart failure patients , 
 vip levels are elevated as a plausible endogenous protective effect . with the development of elastin polymers to stabilize vip and prevent its degradation 
 , vip may therefore have a chance to satisfy the unmet need as a potential treatment for acute heart failure . 
Introduction
Current Standard Therapies
Emerging Novel Therapies
LCZ696
Ivabradine
Vasoactive intestinal peptide
Conclusion