Mechanisms and Models in Heart Failure

Abstract

Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm for heart failure has withstood the test of time. Whereas clinicians initially viewed heart failure as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the "cardiorenal model" 1 ), as physicians began to perform careful hemodynamic measurements, it also became apparent that heart failure was associated with a reduced cardiac output and excessive peripheral vasoconstriction. This latter realization led to the development of the "cardiocirculatory" or "hemodynamic" model for heart failure, 1 wherein heart failure was thought to arise largely as a result of abnormalities of the pumping capacity of the heart and excessive peripheral vasoconstriction. However, although both the cardiorenal and cardiocirculatory models for heart failure explained the excessive salt and water retention that heart failure patients experience, neither of these models explained the relentless "disease progression" that occurs in this syndrome. Thus, although the cardiorenal models provided the rational basis for the use of diuretics to control the volume status of patients with heart failure, and the cardiocirculatory model provided the rational basis for the use of inotropes and intravenous vasodilators to augment cardiac output, these therapeutic strategies have not prevented heart failure from progressing, nor have they led to prolonged life for patients with moderate to severe heart failure. 1,2 In the present review we will summarize recent advances in the field of heart failure, with a focus on the new therapeutic strategies that have been developed for treating systolic heart failure. For a complete discussion on recent advances in the diagnosis and treatment of diastolic heart failure, the interested reader is referred to several recent reviews on this topic. [3][4][5] To provide the proper framework for this discussion, we will review current and emerging therapies within the context of the extant conceptual biological models that clinician scientists have used for envisioning the syndrome of systolic heart failure. However, as discussed at the conclusion of this review, our current working models for heart failure are insufficient for explaining several of the new and emerging therapies for treating systolic heart failure. To this end, we suggest a simplified conceptual model for heart failure that both unites and extends several of the existing working models for heart failure.

Heart Rate Reduction With Ivabradine Protects Against Left Ventricular Remodeling by Attenuating Infarct Expansion and Preserving Remote‐Zone Contractile Function and Synchrony in a Mouse Model of Reperfused Myocardial Infarction

“…Recent studies suggest that post‐MI dyssynchrony may be linked to escalating mechanical dysfunction resulting from the changes in myocardial geometry and composition during the LV remodeling process, leading to a positive feedback between LV remodeling and cardiac dysfunction 11, 37. Not surprisingly, the finding is also consistent with recent findings demonstrating that remote zone LV dyssynchrony develops in concert with global LV remodeling 11.…”

Prediction of Short-Term Outcomes in Patients With Idiopathic Dilated Cardiomyopathy Referred for Transplantation Using Standard Echocardiography and Strain Imaging

“…The progression of HF is consistent in patients with different etiologies, as it is ultimately driven by very similar biologically active molecules, regardless of the inciting cause (18).…”

“…In order to reduce wall stress hypertrophy develops. To counteract the excessive vasoconstriction resulting from excessive activation of ANS and RAS, the family of vasodilatory molecules, including natriuretic peptides, prostaglandins (PGE2, PGEI2) and nitric oxide, is activated (18)(19)(20). Yet for a longer time all these compensatory mechanisms show adverse affects, such as altered gene expression, resulting in changes in cardiac myocytes, growth and remodelling and apoptosis.…”

“…Yet all the currently available assessments of myocyte apoptosis in failing hearts have been performed on explanted hearts from heart transplantation recipients, many of whom were receiving inotropic support. As catecholamines are also known to provoke apoptosis, it remains unclear whether apoptosis occurs only in end-stage HF or whether it contributes to progression of cardiac remodelling and systolic dysfunction (18).…”

Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: the critical role of ASK1 and VEGF

“…[1][2][3][4] Clinical evidence shows that reninangiotensin system blockers, such as AT1 receptor blockers or angiotensin-converting enzyme inhibitors, are effective treatments for both cardiac hypertrophy and decompensated cardiac hypertrophy or heart failure. 5,6 However, the precise mechanism underlying the protective effects of renin-angiotensin system blockers against decompensated cardiac hypertrophy is not entirely clear.…”