|Year : 2003 | Volume
| Issue : 1 | Page : 4
The Management of Systolic Heart Failure
Niranjan Seshadri1, Roger M Mills1, Stanley Nattel2
1 Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
2 Montreal Heart Institute Research Center, 5000 Belanger, St. East Montreal, Quebec H1T 1C8, Canada
|Date of Web Publication||22-Jun-2010|
Roger M Mills
Department of Cardiovascular Medicine, Desk F15 The Cleveland Clinic Foundation, 9500 Euclid Avenue Cleveland, Ohio 44195
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Seshadri N, Mills RM, Nattel S. The Management of Systolic Heart Failure. Heart Views 2003;4:4
| Introduction|| |
Systolic heart failure is a syndrome characterized by a perturbation in the neurohormonal system resulting in clinical manifestations such as dyspnea, orthopnea or paroxysmal nocturnal dyspnea. In the United States, about 5 million people carry a diagnosis of heart failure. Furthermore, about 400, 000 to 700, 000 new cases of congestive heart failure are diagnosed each year in the U.S.  .
In recent years, the therapeutic armamentarium for the management of acute decompensation of heart failure has expanded considerably through the availability of several new agents, such as natriuretic peptides  . In the management of chronic congestive heart failure, there have been major advances in drug therapy such as the use of beta-blockers , . Several interventional approaches for the treatment of chronic congestive heart failure such as cardiac resynchronization by pacing the left ventricle ,,, , implantable-cardioverterdefibrillators  ,stem-cell transplantation  and left-ventricular assist devices as destination (i.e., not a bridge to transplantation)therapy  arealsonow available.
Recently, there have been changes in the organization of care such as the setting up of dedicated heart failure clinics and natriuretic peptide guided treatment  . Tailored outpatient therapy of heart failure using natriuretic peptide is emerging as a potentially new adjunct in the management of these patients.
This review will provide an overview of the currently available treatment options and the future management strategies for the care of patients with systolic heart failure.
| Etiology and Pathophysiology of Heart Failure|| |
The most common causes of heart failure in the developed world are coronary artery disease and hypertension  . The prevalence of coronary artery disease in patients with heart failure is 50-70%  . In the developing world, infectious agents such as Chagas disease and rheumatic valvular heart disease account for a majority of cases. Other etiologies include infections with human immunodeficiency virus. Potentially reversible factors contributing to heart failure include arrhythmias. Atrial fibrillation, particularly if untreated for a prolonged duration, may result in tachycardia-induced cardiomyopathy. Other reversible factors such as heavy alcohol consumption,obesity,anemia,thyroid abnormalities may also result in heart failure and should be borne in mind when managing patients with this condition  .
Regardless of the etiology, the common denominator in the pathogenesis of the heart failure syndrome is left ventricular dysfunction. Injury to the cardiac myocyte or abnormalities in the myocardial reparative processes results in decreased ability of the heart to maintain normal function at a given loading condition. Several compensatory mechanisms may help to maintain myocardial performance early in the course of disease. The initial adaptation to ventricular dysfunction is an increased chamber size, which helps maintain an adequate stroke volume by increasing preload, based on the Frank-Starling mechanism. Following this, further remodeling of the heart occurs. The heart becomes more spherical, and this process results in a decrease in left ventricular ejection fraction. Ultimately, it leads to a dilated and thinned out left ventricle  .
Anotherinitially"adaptive"mechanism is activation of the neurohormonal cascade. This includes activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and release of a variety of neurohormonal agents including plasma norepinephrine, plasma renin and arginine vasopressin. However, these neurohormones ultimately perpetuate heart failure by altering cardiac loading conditions with increased peripheral resistance adding to afterload and fluid retention increasing preload. These loading changes also lead to a more spherical shape, worsening mitral regurgitation, and increased wall tension. Activation of the neurohormonal cascade may also cause structural changes such as fibrosis of the myocytes and the vasculature  .
In response to increased ventricular filling pressures, the heart releases natriuretic peptides. With the availability of a clinical assay for B-type brain natriuretic peptide (BNP), a polypeptide produced predominantly in the ventricles, it is now possible to assess the intensity of neurohormonal activation in patients with heart failure  . BNP correlates well with the left ventricular end-diastolic pressure. Since the fluid retention which elevates left ventricular end-diastolic pressure reflects renin-angiotensin-aldosterone system activity, BNP measurement may be used to diagnose and follow patients with congestive heart failure . In one small study, BNP-driven management was superior to clinical management  .
| Management of Acute Episodes of Heart Failure|| |
Besides atherosclerotic coronary artery disease, which is the most common cause of heart failure, a host of other entities such as valvular abnormalities, hypertension, cardiac arrhythmias, pericardial diseases, acute myocarditis and inadequate pharmacological management may result in acute decompensation.The management of acute heart failure consists of rapid recognition and early institution of treatment. Therapeutic options include vasodilators such as nitroglycerin, nitroprusside or nesiritide; positive inotropic therapy, either dobutamine or milrinone; diuretics; and endothelin antagonists  .
Vasodilators are effective in the immediate managementofacuteheartfailure decompensation. The mechanism whereby vasodilators benefit patients with heart failure is either afterload reduction (mainly sodium nitroprusside) or decreased preload (nitroglycerin and nesiritide) See [Table 1] and [Figure 1]. The hemodynamics of the vasodilator response is shown in [Table 2]. There is evidence that afterload reduction therapy can significantly improve precapillary pulmonary hypertension ,, . With the institution of vasodilator therapy, left and right atrial pressures decline, which is accompanied by an increase in forward cardiac output with little or no change in stroke volume. The mechanism for this response is redistribution of mitral regurgitant flow in response to systemic vasodilation , .
Nitroglycerin is an immediate acting venodilator that can be used to rapidly decrease pulmonary congestion. It reduces filling pressures manifested by a lower pulmonary capillary wedge pressure. Prolonged infusions may be associated with tachyphylaxis, necessitating higher doses to achieve the desired hemodynamic goals. Sodium nitroprusside is a potent direct acting vasodilator. It is used in conjunction with invasive hemodynamic monitoring to rapidly lower filling pressures. Cyanide toxicity, although reported to occur with prolonged administration, is rarely seen. The most common side effect is hypotension  .
Nesiritide, a recently approved drug, is a recombinant form of naturally occurring B-type natriuretic peptide , . It acts mainly as a vasodilator and is used in conjunction with a diuretic. It is an arterial and venous vasodilator that reduces preload and afterload without significant inotropic effects. Moreover it is a relatively safe drug with no proarrhythmic effects  . It may be used with or without invasive hemodynamic monitoring in intensive care units, stepdown units or even in the emergency room , . In the Vasodilator in the Management of Acute Congestive Heart Failure (VMAC) trial, a randomized control trial of 489 inpatients with decompensated congestive heart failure, use of nesiritide was associated with improved hemodynamics compared to nitroglycerin or placebo  .
Positive inotropic agents such as dobutamine and milrinone are useful for patients presenting with pulmonary congestion and a systemic low-output state. Their use is associated with a higher risk of tachyarrhythmias , . Hypotension from time to time occurs with the use of milrinone  ; in these cases, dobutamine may be a preferred agent. However, the use of dobutamine in the treatment of decompensated heart failure may be associated with a higher incidence of sustained ventricular arrhythmias, and dobutamine is not useful in beta-blocked patients  . New information suggests that routine use of inotropes such as milrinone to treat exacerbations of heart failure may, in fact, be detrimental  . The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic heart Failure (OPTIME-CHF) trial, evaluated the short-term use of milrinone in patients hospitalized with NYHA class III-IV heart failure  . Although the end point of death or readmission within 60 days was similar in the groups receiving either milrinone or placebo, the milrinone group had a higher incidence of sustained hypotension and new atrial arrhythmias  .
The current ACC/AHA heart failure guidelines discourage routine use of positive inotropic agents in acute decompensation or for chronic management of heart failure  However, these agents may be used for palliation of refractory heart failure and as a bridge to more definitive treatment options, such as bypass surgery or heart transplantation.
Diuretics may be used as primary or adjunctive therapy for acute decompensation. Careful studies of patients receiving diuretics as primary therapy all confirm that diuretics alone decrease cardiac output and increase renin  . We feel that diuretic treatment should be adjunctive, tailored to needs, and doses reduced as early as possible. Previous studies have shown an increased mortality with the use of diuretics  .
The endothelin system consists of peptides that have very potent vasoconstrictor properties. Plasma levels of endothelin-1 are increased in heart failure and are a predictor of worse outcomes , . Several endothelin receptor antagonists have been studied in experimental models of heart failure and in clinical settings. These include bosentan, an orally active, non-selective endothelin receptor antagonist that has been shown to be useful in pulmonary hypertension  . In the Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure (ENABLE) study, 1,613 patients with severe heart failure were randomized to receive either bosentan (125 mg twice a day) or placebo. Bosentan use, however, was associated with an increased risk of heart failure requiring hospitalization, mainly related to excess fluid retention  .
Other studies using endothelin receptor antagonists have not shown positive results. In the Randomized Intravenous Tezosentan (RITZ) I trial, 669 patients hospitalized with heart failure were randomized to either tezosentan (a parenteral endothelin receptor ETA/ ETB antagonist) or placebo (26). In this study, tezosentan was not effective in improving symptoms compared to placebo. Moreover, the study medication caused hypotension  . In another study using a nonselective endothelin receptor antagonist, enrasentan, there was worse outcome in the group of patients receiving enrasentan compared to placebo  . Further studies using more selective endothelin receptor antagonists are underway in experimental settings.
| Indications for Invasive Hemodynamic Monitoring|| |
Invasive hemodynamic monitoring of left ventricular filling pressures is essential in patients who do not improve quickly with treatment. The goal of acute management of heart failure is relief of symptoms, which requires reduction of elevated left ventricular filling pressures, reflected by the pulmonary capillary wedge pressure. Apart from improvement in symptoms, there is evidence that lowering filling pressures is associated with a decrease in neurohormonal activation. Pulmonary capillary wedge pressure is a good surrogate end-point for outcomes in patients with heart failure  .
| Chronic Out-Patient Management of Heart Failure|| |
In recent years, the major breakthrough in the drug-treatment of chronic heart failure has been the use of beta-blockers for heart failure , . Despite the availability of other medical treatment options including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aldosterone antagonists, diuretics and digoxin, there is still a dearth of effective medical therapy leading to sustained clinical improvement in most patients. On the other hand, there have been several advances in the non-pharmacological arena, resulting in the availability of a plethora of devices, including bi-ventricular pacers and left ventricular assist devices among others  .
Beta-blocker therapy reduces morbidity and mortality in patients with congestive heart failure , . The use of beta-blockers has been studied in randomized controlled trials involving over 10,000 patients with congestive heart failure varying in severity from mild to severe , . The beneficial effect of this class of medications is thought to be due to its effects in blunting the activation of the sympathetic nervous system that occurs as a compensatory mechanism in patients with congestive heart failure. Long-term activation of the adrenergic nervous system leads to cardiac remodeling and ultimately cardiac fibrosis and necrosis. Beta-blockers reverse this process of remodeling and may also have a beneficial effect in decreasing cardiac arrhythmias  . The beta-blockers shown to have a beneficial effect on mortality include metoprolol ,,, , bisoprolol , , carvedilol  and bucindolol  .
Metoprolol was studied in the Metoprolol in Dilated Cardiomyopathy (MDC) , and the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) , studies. The MDC trial enrolled 383 subjects with mild to moderate heart failure and an ejection fraction of < 40%. There was a 34% decrease in endpoint of death and cardiac transplantation in patients receiving metoprolol , . The MERIT-HF trial was a larger trial (3991 patients), which showed an equally impressive benefit of metoprolol in patients with NYHA class II to IV heart failure. There was a 34% decrease in all-cause mortality and a 38% decrease in cardiovascular mortality , .
The Cardiac Insufficiency Bisoprolol Studies (CIBIS I and II) showed that use of bisoprolol in the treatment of heart failure was associated with an improvement of functional class and a decrease in hospitalizations and mortality , . Recently, carvedilol, a non-selective beta-blocker that blocks both the beta-1, beta-2 and alpha-1 receptors, was shown to decrease mortality in patients with mild, moderate or severe heart failure and an ejection fraction of < 35%  . In the Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS), use of carvedilol was associated with a 35% decrease in all-cause mortality in patients with NYHA class III-IV heart failure  . The CAPRICORN study evaluated carvedilol in post-myocardial infarction patients with left ventricular dysfunction  . In this study, there was a decrease in all-cause mortality in patients receiving carvedilol  . Based on these studies, beta-blockers have now become the standard of care in the treatment of patients with heart failure.
In contrast to beta-blocker therapy, digoxin has not been shown to reduce mortality  . The DIG trial did not show a mortality benefit, however, there was a modest reduction in hospitalization overall and for heart failure in patients receiving digoxin  . More recently, digoxin use was shown to increase mortality in women and in men with serum levels of digoxin > 0.8 ng/ml  .
In the management of chronic congestive heart failure, several interventional techniques are currently being employed. These include implantable cardioverter-defibrillators, bi-ventricular pacemakers and left ventricular assist devices.
Sudden cardiac death due to ventricular arrhythmias remains a major contributor to the increased mortality in patients with a depressed left ventricular ejection fraction. Earlier studies have shown that implantable cardioverter-defibrillators confer a significant survival advantage in patients with a low ejection fraction and spontaneous or inducible ventricular arrhythmias. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT), patients with an ejection fraction 35%, documented asymptomatic nonsustained ventricular tachycardia, and inducible ventricular arrhythmias at electrophysiological study were randomized to receive either a defibrillator or conventional medical therapy. In this study, patients who received prophylactic defibrillator implantation had improved survival compared with medical therapy  . Similar results in favor of implantable defibrillators were noted in other studies such as the Antiarrhythmics Versus Implantable Defibrillators (AVID)  .
More recently, similar results were found the MADIT-II trial, in which 1,232 patients with a history of a prior myocardial infarction and an ejection fraction 30% were randomized to either a prophylactic defibrillator or conventional medical therapy  . Invasive electrophysiological testing was not required. This trial was stopped prematurely due to a significant survival benefit in the defibrillator arm  . In patients requiring a defibrillator, a single chamber device is probably sufficient. In the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial, patients requiring a defibrillator and no indication for antibradycardia pacing were randomized to receive either back-up ventricular pacing or dual-chamber pacing  . The 1-year survival rate was higher in patients who were randomized to back-up ventricular pacing  . Other trials of defibrillators are currently underway in patients with heart failure. These include the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), which is comparing defibrillator therapy versus amiodarone in patients with NYHA class II-III heart failure, and an ejection fraction of 35% , .
Cardiac resynchronization therapy with bi- ventricular pacing
QRS prolongation (>120 ms) on the surface electrocardiogram provides a clue to ventricular dyssynchrony in many patients with heart failure. Re-establishing ventricular synchrony by biventricular pacing may lead to better atrioventricular synchrony and improve ventricular performance  . Recent trials have shown that biventricular pacing may improve symptoms and increase exercise tolerance.
In the Multicenter InSync Randomized Clinical Evaluation (MIRACLE), biventricular pacing was associated with an improvement in the 6-minute walking distance, patients had an improvement in the NYHA class and the left ventricular ejection fraction improved by almost 5%  . Similarly in the MUltisite STImulation in Cardiomyopathy (MUSTIC) study, there was improvement in exercise tolerance and symptoms with cardiac resynchronization therapy  . More recently, the InSync ICD trial (not published) also showed improvement in quality of life and NYHA heart failure class in patients who met criteria for a defibrillator and also had a prolonged QRS complex on the surface electrocardiogram . Other long-term mortality and morbidity trials are currently underway. These include the Comparison Of Medical therapy and Pacing ANd DefibrillatION in Chronic Heart Failure (COMPANION) and the CArdiac REsynchronization in Heart Failure (CARE-HF) trials  .
Implantable hemodynamic monitors
Continuous invasive hemodynamic monitoring in ambulatory patients is now possible with implantable hemodynamic monitors. This device is similar to a single right ventricular lead permanent pacemaker. In a recent study, long-term ambulatory hemodynamic measurements with an implantable monitor was shown to be helpful in day-today management of patients with congestive heart failure  .
Left-ventricular assist devices
Patients with end-stage heart failure have a very limited prognosis with drug therapy. Currently, heart transplantation is the only long-term treatmentoptionforthesepatients. Transplantation, however, cannot impact the huge numbers of patients with end-stage heart failure. Efforts are underway to explore and develop other definitive therapeutic options such as left ventricular assist devices for this subgroup of heart failure patients , . Until recently, left ventricular assist devices were used only as a short term bridge to heart transplantation.
The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study evaluated the use of left ventricular assist devices as long term "destination" therapy in patients with NYHA class IV heart failure ineligible for heart transplantation  . In this study, 129 patients were randomized to receive either a left ventricular assist device (n=68) or conventional medical therapy (n=61). At the end of 2 years, 25% of patients who received left ventricular assist devices were alive compared to only 8% in the group receiving conventional medical therapy. However, the device group had a higher incidence of serious complications such as infection, bleeding and device malfunction. Overall, the quality of life indicators were better in the device group , . With the availability of newer, more sophisticated assist devices than the one used in the REMATCH study, LVAD support may potentially be an acceptable long-term option for end-stage heart failure , .
| Experimental Approaches|| |
Gene therapy for heart failure is currently experimental. Preliminary data holds promise for this new novel, therapeutic approach. The major components for the success of this approach include an appropriate vector system for gene delivery, effectively getting the vector to the area of interest and finally selection and identification of a gene to be expressed. An ideal vector system is one that is highly efficient in enabling transgene expression in cardiac myocytes. Recombinant adenovirus, adeno-associated virus and lentivirus are some of the currently available vectors that can achieve this. Once an appropriate vector is identified, there are several options for delivery to the cardiac tissues. These include catheter-based techniques such as intracoronary injection, direct intramyocardial injection by epicardial approach and inoculation of the pericardial space.
Another recent technique that has shown promise in animal models is a catheter based delivery system through the apex of the left ventricle while cross clamping the aorta and the pulmonary artery. This technique enables transduction of myocytes throughout the heart in a homogenous fashion. Further investigation is mandated before this technique is even considered for human investigation , .
Investigations on gene therapy for heart failure target several candidate molecular pathways in the myocytes of failing hearts. These include: 1) the calcium ATPase pump within the sarcoplasmic reticulum which enhances the process of excitation-contraction coupling and is involved in calcium homeostasis; 2) the beta-adrenergic signaling pathways; and 3) the pathways involved in programmed cell death or apoptosis , .
Gene therapy for heart failure is a promising new area, albeit still in the experimental stage. Preliminary animal work will need to be further refined and the safety and efficacy of clinically applicable vectors and systems of delivery needs further study.
| Changes in Health Care Delivery|| |
Recently, the availability of assays for B-type brain natriuretic peptide (BNP) has provided an opportunity for diagnosing and following patients with heart failure with a simple blood test  . BNP is predominantly produced in the ventricles in response to elevated left ventricular end-diastolic pressure. BNP can now be used as a point of care assay in emergency rooms for the diagnosis of congestive heart failure  .
BNP levels may help titrating medical therapy in the outpatient setting. BNP-guided treatment may reduce incidence of cardiovascular death and hospital readmission for new episodes of congestive heart failure compared to symptom guided therapy  . A study using BNP-guided titration of beta-blockers demonstrated that BNP levels predicted success or failure of the use of carvedilol  . In another outpatient study, BNP-assisted titration of ACE-inhibitors resulted in better inhibition of the rennin-angiotensin-aldosterone system  . The FUSION trial (Follow-Up Serial Infusions Of Natrecor) will evaluate the utility of short, intermittent infusions of two doses of nesiritide in outpatients who are at high risk for being readmitted for congestive heart failure.
| Summary|| |
In the last 2 decades, we have seen dramatic improvements in the approach to the treatment of both acute and chronic congestive heart failure. Advances in drug therapy include beta-blockers and nesiritide. New device therapies for heart failure include defibrillators, biventricular pacemakers, and left ventricular assist devices. Diagnostic insights from BNP measurements have also changed the approach to the treatment of heart failure. The challenge facing health care providers who care for patients with congestive heart failure is to bring these new therapies to their patients. The dedicated heart failure clinic, integrating the best of technology, patient education, and clinical care offers the best hope we have for effectively managing our patients ,  .
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[Table 1], [Table 2]