Heart failure, also known as congestive heart failure or CHF, is an inability of the heart to pump sufficient blood around the body.
Pathogenesis of Heart Failure
Heart failure typically occurs secondary to an existing pathology that alters cardiac function. Examples of syndromes that can precede heart failure include myocardial infarction, arrhythmia or infection. These can also cause dilated cardiomyopathy, a condition which accounts for approximately one third of all cases of heart failure.
The pathogenesis of heart failure is cyclical and progressive; endogenous mechanisms, which are activated during heart failure in an attempt to counteract the symptoms, actually worsen cardiac function. Cardiac dysfunction, either systolic or diastolic, triggers a decrease in stroke volume and a resultant increase in cardiac output. In healthy individuals the body responds to decreases in cardiac output by initiating the renin-angiotensin-aldosterone system (RAAS) to promote fluid retention, and also by activating the sympathetic nervous system to cause peripheral vasoconstriction. Under normal circumstances this counteracts the imbalance in stroke volume, restoring cardiac output to normal levels.
In patients with heart failure the increase in blood volume, together with the heightened peripheral resistance and elevated levels of circulating catecholamines, causes an increased load on the already weakened ventricles with each contraction, and the stroke volume does not return to normal levels. Repeated cycles of this process further weaken the ventricle walls, prompting ventricular hypertrophy and a decreased force of contraction.
Treatment of Heart Failure
The two most common therapeutic strategies for heart failure are to increase intracellular calcium concentration within myocytes by activating second messenger signaling pathways, and also to block or counteract the neurohormonal compensatory reflexes through the inhibition of the RAAS. Pharmacological agents which trigger a rise in intracellular calcium include positive inotropes, α adrenergic receptor agonists, and phosphodiesteraseinhibitors.
However, indirectly targeting the signaling pathways involved in cardiac contractility also induces mechanism-related adverse effects. More recent therapy using small molecule drugs looks to be a promising and more effective strategy for improving contractility in patients with heart failure. Additionally, blocking the neurohormonal reflexes in the failing heart is a more efficacious therapeutic strategy for heart failure compared to increasing contractility, and can be achieved using angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). The administration of diuretics reduces symptoms associated with heart failure, such as peripheral edema, but it does not reverse or halt the disease pathology.
In addition to the existing compounds, future therapeutic targets include the matrix metalloproteinase enzymes MMP-2 and MMP-9. The expression of these collagenases is increased in heart failure whilst the expression of their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), has been shown to be downregulated in the same tissue. In support of this, experimental inhibition of MMP-9 reduces ventricular dilatation in a model of heart failure.
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An irreversible inhibitor of carnitine palmitoyltransferase-1 (CPT-1) that inhibits fatty acid β-oxidation in rat liver with IC50 of 5-20 nM; affects ketogenesis, cholesterol synthesis, and gluconeogenesis both in vitro and in vivo; decreases viability in LNCaP, VCaP, and patient-derived benign and prostate cancer cells, associated with decreased AR expression, decreased mTOR signaling, and increased caspase-3 activation; decreases xenograft growth in mice.
Finerenone (BAY 94-8862) is a potent, selective, orally available mineralocorticoid receptor (MR) antagonist with IC50 of 18 nM; displays excellent selectivity (>500-fold) versus GR, AR, and PR, also shows no L type Ca2+ channel activity; elicits a significant and dose-dependent increase in the urinary sodium/potassium ratio in vivo, with a MED of 0.3 mg kg1 p.o.; exhibits three- to tenfold greater potency and higher efficacy in acute rat natriuresis model compared with eplerenone, demonstrates potential for the treatment of chronic heart failure (CHF).
Cimlanod is a second-generation nitroxyl (HNO) donor.
Gemopatrilat is a potent, orally available, dual ACE-neutral endopeptidase (vasopeptidase) inhibitor with IC50 of 12 and 63 nM, respectively; causes prolonged inhibition of circulating and renal ACE and renal NEP after a single oral dose in atherogenic diet rabbits.
A novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio); causes dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provides sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats; orally active.
FPL64176 (ARC-64176) is a potent L-type Ca++ channel activator with EC50 of 16 nM; prolongs action potential duration and enhances contractility in guinea pig papillary muscle, induces contractile response with EC50 of 0.2 uM; produces biexponential tail current decays at -50 mV with fast and slow time constants of 4.30 +/- 0.30 and 44.52 +/- 4.56 msec, respectively; produces large increases in cardiac contractile force and diastolic blood pressure in anesthetized dogs (100 mg/kg, i.v.).
NKH 477 HCl
NKH 477 hydrochloride (Colforsin dapropate) is a water-soluble analog of Forskolin and a potent activator of adenylyl cyclase, shows some selectivity for cardiac (type V) adenylyl cyclase; increases cAMP accumulation in HEK293 cells stably overexpressing type V more than forskolin; A PKA activator.
Sarpogrelate hydrochloride is a potent, specific 5HT2 receptor antagonist with Ki of 8.39 nM for 5-HT2A; also shows binding affinity for 5-HT2B; displays selectivity over 5-HT1-like, 5-HT3, beta, H1, H2 and M3; blocks serotonin-induced platelet aggregation.
Ruboxistaurin hydrochloride is a potent, selective, ATP-competitive, orally available PKC beta (PKCβ) inhibitor with IC50 of 4.7 and 5.9 nM for PKCβ I and PKCβ II, respectively; displays >60-fold selectivity over PKCα, and other ATP dependent kinases (PKA, Calcium calmodulin, Caesin kinase and Src); ameliorates the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats.
Rolofylline (KW-3902;KW3902) is a potent, selective and orally active adenosine A1 receptor antagonist with Ki of 1.3 nM; displays 290-fold selectivity over A2AR; antagonizes NECA-induced bradycardic response in anesthetized rats (0.1-1mg/kg), causes significant increases of urine volume and sodium excretion with little change of potassium excretion in saline-loaded normal rats (0.001-1 mg/kg).
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