Levosimendan, a novel calcium sensitizer, improves myocardial contractility without causing an increase in myocardial oxygen demand. Its role in acute, decompensated heart failure is more established than in chronic heart failure, but it may reduce overall mortality and length of hospitalization. In the LIDO study, levosimendan improved survival and hemodynamic performance more effectively than dobutamine, in patients with severe, low-output heart failure. The superiority of levosimendan over dobutamine in improving central hemodynamics and left ventricular performance seems in part to be related to its anti-inflammatory and anti-apoptotic effects.
n-3 polyunsaturated fatty acids (n3-PUFA)
The GISSI-HF trial showed that the addition of n3-PUFA produced a small improvement in mortality and hospital admissions in patients with heart failure. However, a 2012 meta-analysis has shown insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease. Omega-3 PUFA supplementation is reasonable to use as adjunctive therapy in patients with New York Heart Association class II to IV symptoms and heart failure, unless contraindicated, to reduce mortality and cardiovascular hospitalizations.
Statins are not beneficial as adjunctive therapy when prescribed solely for treatment of heart failure in the absence of other indications for their use. Statin therapy has been broadly implicated in prevention of adverse cardiovascular events, including new-onset heart failure. Originally designed to lower cholesterol in patients with cardiovascular disease, statins are known to have beneficial effects on inflammation, oxidative stress, and vascular performance. To date, a sufficient body of evidence does not exist to support the primary prescribing of statins for the treatment of heart failure to improve clinical outcomes.
Nonspecific immunomodulation therapy
Inflammatory mediators are proposed to play a role in heart failure development and progression. In the ACCLAIM trial, nonspecific immunomodulation therapy reduced the risk of hospitalization or death, suggesting that this therapy may be of benefit in heart failure patients.
Recombinant human growth hormone
Preliminary studies suggest that recombinant human growth hormone may have beneficial effects in patients with left ventricular dysfunction, although it may produce an increased risk of arrhythmias. Further studies are required to determine the safety and efficacy of this treatment.
In a meta-analysis, trimetazidine, which shifts energy production from fatty acid oxidation to glucose oxidation, was shown to have no effect on mortality, but it improves left ventricular ejection fraction (LVEF) and functional class.
Some trials of stem-cell therapy in both ischemic and nonischemic heart failure have shown some potential benefit. A systematic review on the use of stem-cell therapy for chronic ischemic heart disease and congestive heart failure suggests that at both short- and long-term follow-up (≥12 months) the use of autologous bone marrow stem-cell treatment reduces all-cause mortality, although the quality of evidence is low.
An attractive strategy for treatment of heart failure is by gene therapy. In a small randomized study of patients (n=56) with heart failure and LVEF <40%, intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) increased the LVEF at 4 weeks, with no increase in exercise duration. In a larger double-blind placebo-controlled study (n=250), intracoronary infusion of 1 × 1013 DNase-resistant particle of adeno-associated virus 1 (AAV1)/sarcoplasmic endoplasmic reticulum Ca2 - ATPase (SERCA2a) did not improve the clinical course of patients with heart failure and reduced ejection fraction (ejection fraction ≤35%).
Supportive mechanical assist devices
The use of mechanical circulatory assist devices in end-stage heart failure is an area of intense investigation. In patients with severe heart failure, prolonged unloading of the myocardium with the use of a left ventricular assist device has been reported to lead to myocardial recovery in small numbers of patients for varying periods of time. Extracorporeal devices can be used for short-term circulatory support in patients who are expected to recover from a major cardiac insult (e.g., myocardial ischemia, postcardiotomy shock, or fulminant myocarditis). Left ventricular assist devices provide similar degrees of hemodynamic support; many are implantable and thus allow for long-term support, patient ambulation, and hospital discharge. Most clinical experience with these devices has been derived from their use as a "bridge-to-transplantation therapy." The REMATCH trial established the efficacy of device therapy as permanent or "destination" therapy in selected nontransplant-eligible patients. However, device-related adverse events are numerous including bleeding, infection, thromboembolic events, and device failure. The Food and Drug Administration issued an alert about serious adverse events associated with left ventricular assist devices. These adverse events include an increased rate of pump thrombosis (blood clots inside the pump) and a high rate of stroke. Improvements in newer generations of devices will hopefully permit even further prolongation of survival. Presently, destination device therapy is anticipated to benefit those patients predicted to have a 1-year survival of less than 50%, such as those not eligible for transplant, requiring continuous intravenous inotropic infusions. Some reports have suggested that prolonged mechanical decompression of the failing heart may occasionally be followed by sufficient recovery of myocardial function to allow explantation of the device. The use of continuous hemodynamic monitoring to guide care has also been investigated, but requires further evaluation.
There have been numerous reports of alternate surgical approaches for the treatment of end-stage heart failure. Mitral valve repair or replacement has been shown to improve clinical status in patients who have a clinically important degree of mitral regurgitation that is secondary to left ventricular dilation. However, no controlled studies have evaluated the effects of this procedure on ventricular function, rehospitalizations, or survival. One single-center study designed to assess the effects of mitral valve annuloplasty on mortality in patients with mitral regurgitation and left ventricular systolic dysfunction failed to demonstrate any clear survival benefit. A variant of the aneurysmectomy procedure is now being developed for the management of patients with ischemic cardiomyopathy, but its role in the management of heart failure remains to be defined. None of the current surgical reconstruction techniques offer "rescue therapy" to patients with critical hemodynamic compromise.
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