Heart, failing

Higher vasopressin concentrations are linked to dilutional hyponatremia and a poor prognosis in HF. Vasopressin exerts its effects through vasopressin type la (Vla) and vasopressin type 2 (V2) receptors.5,7 Vasopressin type la stimulation leads to vasoconstriction, while actions on the V2 receptor cause free water retention through aquaporin channels in the collecting duct. Vasopressin increases preload, afterload, and myocardial oxygen demand in the failing heart. 

Inflammatory cytokines have been implicated in the pathophysiology of HF.9 Several proinflammatory (e.g., tumor necrosis factor-a [TNF-a], interleukin-1, interleukin-6, and interferon-y) and anti-inflammatory cytokines (e.g., interleukin-10) are overexpressed in the failing heart. The most is known about TNF-a, a pleiotrophic cytokine that acts as a negative inotrope, stimulates cardiac cell apoptosis, uncouples 3-adrenergic receptors from adenylyl cyclase, and is related to cardiac cachexia. The exact role of cytokines and inflammation in HF pathophysiology continues to be studied. 

It is this reduction in preload that, in some cases, is beneficial to patients experiencing heart failure or hypertension. Unlike a healthy heart, a failing heart is unable to pump all of the blood returned to it. Instead, the blood dams up and overfills the chambers of the heart. This results in congestion and increased pressures in the heart and venous system and the formation of peripheral edema. Because the failing heart is operating on the flat portion of a depressed cardiac function curve (see Figure 14.2), treatment with diuretics will relieve the congestion and edema, but have little effect on stroke volume and cardiac output. 

Marx SO, Reiken S, Hisamatsu Y et al 2000 PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor) defective regulation in failing hearts. Cell 101 365-376... 

In other work, C87-3754has been compared with SIN-1, the equivalent metabolite from molsidomine, and from the organic nitrate class, isosorbide-5-mononitrate (IS-5-MN) [146]. In this latter study, which involved long term oral administration in a dog model, IS-5-MN showed tolerance whilst the sydnonimines showed no self- or cross-tolerance. Elsewhere, tolerance studies in dogs by oral or continuous infusion of C87-3754 have shown benefits in the treatment of a failing heart, without tolerance [147] and with better results than those observed by nitroglycerin [148]. 

In patients with cardiac hypertrophy, this situation reverses to some extent. In the failing heart glucose oxidation increases, and p-oxidation falls. 

Leclercq C, Kass DA. Retiming the failing heart principles and current clinical status of cardiac resynchronization. [Review, 81 refs]. J. Am. Coll. Cardiol. 2002 39 194-201. 

Spragg DD, Leclercq C, Loghmani M, et al. Regional alterations in protein expression in the dyssynchronous failing heart. Circulation 2003 108 929-32. 

Despite efforts such as revascularization to halt the progression to ischemic heart failure, ventricular remodeling is still a growing danger. Efforts to treat severely failing hearts refractory to medical therapy have included heart transplantation and mechanical ventricular assistance [1]. Until recently, cardiologists believed that beyond revascularization and medical therapy, the process of ischemic heart failure was irreversible because the heart lacked the capacity to renew itself. 

Myocyte replication is the failing heart s attempt to compensate for a limited capacity for hypertrophy. When Urbanek et al. [37] used Ki-67 (a nuclear protein expressed during cell division) to assess the mitotic activity of myocytes, they observed significantly greater mitotic activity at infarct border zones than in distant myocardium or undiseased control hearts. The evidence that cardiac myocytes divide shortly after a myocardial infarction led investigators to search for the origin of the dividing myocytes [82]. This culminated in the description of resident CSCs [35-37]. 

De Mello WC Renin-angiotensin system and cell communication in the failing heart. Hypertension 1996 27 1267-1272. 

The pathogenesis of heart failure is characterized by depressed cardiac contractility, which is normally controlled by the rhythmic release and reuptake of Ca2+ from the SR. A reduction in SR Ca2+ content has consistently been described in various forms of heart failure. Several mechanisms have been proposed to explain the decrease in SR Ca2+ loading in failing hearts, including 1) increased diastolic SR Ca2+ release,... 

Marx, S. O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., and Marks, A. R. (2000). PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor) Defective Regulation in Failing Hearts. Cell 101(4) 365—76. 

In addition to its effects on cardiac contractility, digitalis has a direct inhibitory effect on sympathetic nervous system activity.37,60 This effect is beneficial because it decreases stress on the failing heart by decreasing excessive sympathetic stimulation of the heart and peripheral vasculature2. Therapeutic levels of digitalis likewise stabilize heart rate and slow impulse conduc-... 

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