When the Failing, End-Stage Heart Is Not End-Stage
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《新英格兰医药杂志》
Heart failure is increasing in incidence and prevalence, is expensive to treat, and is associated with substantial morbidity and mortality.1 In the nomenclature of the guidelines of the American Heart Association and the American College of Cardiology, the majority of patients with heart failure are classified as having stage C heart failure, characterized by structural heart disease that is or has been symptomatic.2 Numerous drugs (e.g., angiotensin converting–enzyme inhibitors or angiotensin-receptor blockers, beta-blockers, and aldosterone blockers) and electrophysiological devices may temporarily halt, slow, or even reverse the pathophysiological processes in patients with stage C heart failure. Reversion of the heart toward more normal shape and function is called reverse remodeling.
Yet the course of heart failure in many patients is generally an inexorable downward spiral (Figure 1). The repetitive and iterative physiological derangements eventually result in refractory, end-stage disease (stage D heart failure). Life expectancy for patients with stage D heart failure is short, with a 1-to-2-year survival rate of less than 50 percent. Medications that previously were beneficial are no longer so well tolerated. Cardiac-resynchronization therapy in this setting is rarely, if ever, even palliative. End-of-life strategies, transplantation, or support with a left ventricular assist device — intended as permanent or "destination" therapy — is required.3 Spontaneous reversal of stage D heart failure is unusual.
Figure 1. Pathophysiological Mechanisms of and Treatment Options for End-Stage Heart Failure.
An insult such as a myocardial infarction or a viral infection initiates the progression toward symptomatic heart failure — that is, stage C (current or previous symptoms associated with structural heart disease) or stage D (refractory, end-stage heart failure). Progression toward end-stage heart failure occurs without additional insults because of repetitive and iterative pathophysiological derangements. The sequence of events progresses from myocardial insult to myocardial dysfunction to neurohormonal activation to altered gene expression and apoptosis to adverse remodeling to further myocardial dysfunction. With adverse remodeling, the geometry of the left ventricle changes, evolving from an ellipsoid to a sphere. Many patients with stage D heart failure have poor tolerance for drugs that were previously beneficial. End-of-life strategies, transplantation, or permanent support with a left ventricular assist device (LVAD) is required. In selected patients, the LVAD may serve as a platform for the administration of therapies that enable reverse remodeling that is sufficient to allow removal of the device. These may be pharmacologic, gene-based, or cell-based therapies. With such an approach, stage D heart failure may revert to stage C.
Nevertheless, some reports indicate that intervention can modify progression, suggesting that stage D heart failure does not always represent a point of no return. For instance, in one study of patients with severe heart failure in whom beta-blockers had adverse hemodynamic effects, the administration of a phosphodiesterase inhibitor (a positive inotropic agent) made possible the administration of appropriate doses of beta-blockers, with their known long-term myocardial and survival benefits.4 Half the patients had improvement of a sufficient magnitude that the phosphodiesterase inhibitor was no longer needed to maintain adequate cardiac output. Other investigators have reported that some patients requiring support with a left ventricular assist device had sufficient spontaneous left ventricular recovery to permit removal of the device.5 These and other anecdotal successes are not totally surprising, given the evidence that some mammalian cardiac myocytes may retain the ability to repair and regenerate themselves under the right circumstances and stimuli.6,7,8,9
In this issue of the Journal, Birks et al. report on the sustained reversal of severe heart failure in selected patients with the use of a left ventricular assist device as a platform from which to administer disease-altering pharmacologic regimens.10 After implantation of the left ventricular assist device, the authors applied two phases of medical therapies. In the first phase, patients received medications designed to enhance reverse remodeling, including ACE inhibitors, angiotensin-receptor blockers, nonselective beta-blockers, and aldosterone antagonists. In the second phase, in an attempt to prevent myocardial atrophy, a nonselective beta-blocker was replaced by a selective beta1-blocker coupled with the selective beta2-agonist, clenbuterol.
Twenty-seven patients with stage D heart failure received left ventricular assist devices. Three patients were excluded because they had coronary artery disease, four because they were in severe cardiogenic shock at the time of implantation, and five because they did not complete the pharmacologic regimen. After an average of 320 days of support, 11 of the remaining 15 patients recovered sufficiently to qualify for removal of the device. Of these, one died early after explantation, but the others survived for more than 2 years. The actuarial survival rate 1 year and 4 years after explantation was 90.9 percent and 81.8 percent, respectively. Freedom from recurrence of heart failure at 4 years for surviving members of the group that underwent explantation was 88.9 percent.
The study, however, leaves unresolved questions. How important were the individual agents used in the first phase to reverse remodeling? In the second phase, was the use of a selective beta2-agonist necessary to minimize the adverse effects of chronic unloading? This second phase may be critically important, since prolonged unloading by a left ventricular assist device prompts myocyte atrophy and increases collagen cross-linking and myocardial stiffness.11 Did the patients in the study really have stage D heart failure? The hemodynamic measurements indicate that they did, suggesting that the left ventricular recovery seen by Birks et al. was not the result of the early application of therapeutic interventions in patients with stage C heart failure. Rather, treatments administered while a patient had the support of a left ventricular assist device probably had important contributions to reverse remodeling of stage D heart failure.
Furthermore, it should be acknowledged that the population of patients was selected carefully, not all patients had a response, the exact role and doses of the medications have not been completely elucidated, the number of patients was small, there was no control group, and the measures used to qualify for progression from one phase to another were standardized but have not yet been corroborated. To use legal parlance, Birks et al. have achieved a "preponderance of evidence" but are not convincing "beyond a reasonable doubt" about the specifics in question.
Despite the acknowledged limitations of their study, Birks et al. have tantalizingly provided more than just a series of anecdotes regarding recovery from end-stage heart failure. Their report is reasonably convincing that support with a left ventricular assist device may serve as a platform from which to administer promising therapies. Sometimes, it seems, active intervention may modify the natural history of heart failure. Maybe, in some patients, the failing heart is not end-stage after all.
The treatment of stage D heart failure now includes more than end-of-life strategies, transplantation, and permanent implantation of left ventricular assist devices. Indeed, left ventricular assist devices may sustain therapies that enable reverse remodeling, improve myocardial energetics, and prepare the heart for removal of the device. Use of the left ventricular assist device as a platform for other therapies for reversing heart failure from stage D to stage C, such as gene- or cell-based therapies, could be attempted and might improve on the therapies described by Birks et al.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program (D.G.R., A.G.K.), the Division of Cardiology, LDS Hospital (D.G.R., A.G.K.), and the Division of Cardiology, University of Utah School of Medicine (D.G.R.) — all in Salt Lake City.
References
Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of heart failure): developed in collaboration with the International Society for Heart and Lung Transplantation: endorsed by the Heart Failure Society of America. Circulation 2001;104:2996-3007.
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult -- summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:1825-1852.
Rose EA, Gelijns AC, Moskowitz AJ, et al. Long term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001;345:1435-1443.
Shakar SF, Abraham WT, Gilbert EM, et al. Combined oral positive inotropic and beta-blocker therapy for treatment of refractory class IV heart failure. J Am Coll Cardiol 1998;31:1336-1340.
Dipla K, Mattiello JA, Jeevanandam V, Houser SR, Margulies KB. Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation 1998;97:2316-2322.
Anversa P, Kajstura J. Ventricular myocytes are not terminally differentiated in the adult mammalian heart. Circ Res 1998;83:1-14.
Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A 1998;95:8801-8805.
Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763-776.
Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodeling. Nature 2002;415:240-243.
Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006;355:1873-1884.
Klotz S, Foronjy RF, Dickstein ML, et al. Mechanical unloading during left ventricular assist device support increases left ventricular collagen cross-linking and myocardial stiffness. Circulation 2005;112:364-374.(Dale G. Renlund, M.D., an)
Yet the course of heart failure in many patients is generally an inexorable downward spiral (Figure 1). The repetitive and iterative physiological derangements eventually result in refractory, end-stage disease (stage D heart failure). Life expectancy for patients with stage D heart failure is short, with a 1-to-2-year survival rate of less than 50 percent. Medications that previously were beneficial are no longer so well tolerated. Cardiac-resynchronization therapy in this setting is rarely, if ever, even palliative. End-of-life strategies, transplantation, or support with a left ventricular assist device — intended as permanent or "destination" therapy — is required.3 Spontaneous reversal of stage D heart failure is unusual.
Figure 1. Pathophysiological Mechanisms of and Treatment Options for End-Stage Heart Failure.
An insult such as a myocardial infarction or a viral infection initiates the progression toward symptomatic heart failure — that is, stage C (current or previous symptoms associated with structural heart disease) or stage D (refractory, end-stage heart failure). Progression toward end-stage heart failure occurs without additional insults because of repetitive and iterative pathophysiological derangements. The sequence of events progresses from myocardial insult to myocardial dysfunction to neurohormonal activation to altered gene expression and apoptosis to adverse remodeling to further myocardial dysfunction. With adverse remodeling, the geometry of the left ventricle changes, evolving from an ellipsoid to a sphere. Many patients with stage D heart failure have poor tolerance for drugs that were previously beneficial. End-of-life strategies, transplantation, or permanent support with a left ventricular assist device (LVAD) is required. In selected patients, the LVAD may serve as a platform for the administration of therapies that enable reverse remodeling that is sufficient to allow removal of the device. These may be pharmacologic, gene-based, or cell-based therapies. With such an approach, stage D heart failure may revert to stage C.
Nevertheless, some reports indicate that intervention can modify progression, suggesting that stage D heart failure does not always represent a point of no return. For instance, in one study of patients with severe heart failure in whom beta-blockers had adverse hemodynamic effects, the administration of a phosphodiesterase inhibitor (a positive inotropic agent) made possible the administration of appropriate doses of beta-blockers, with their known long-term myocardial and survival benefits.4 Half the patients had improvement of a sufficient magnitude that the phosphodiesterase inhibitor was no longer needed to maintain adequate cardiac output. Other investigators have reported that some patients requiring support with a left ventricular assist device had sufficient spontaneous left ventricular recovery to permit removal of the device.5 These and other anecdotal successes are not totally surprising, given the evidence that some mammalian cardiac myocytes may retain the ability to repair and regenerate themselves under the right circumstances and stimuli.6,7,8,9
In this issue of the Journal, Birks et al. report on the sustained reversal of severe heart failure in selected patients with the use of a left ventricular assist device as a platform from which to administer disease-altering pharmacologic regimens.10 After implantation of the left ventricular assist device, the authors applied two phases of medical therapies. In the first phase, patients received medications designed to enhance reverse remodeling, including ACE inhibitors, angiotensin-receptor blockers, nonselective beta-blockers, and aldosterone antagonists. In the second phase, in an attempt to prevent myocardial atrophy, a nonselective beta-blocker was replaced by a selective beta1-blocker coupled with the selective beta2-agonist, clenbuterol.
Twenty-seven patients with stage D heart failure received left ventricular assist devices. Three patients were excluded because they had coronary artery disease, four because they were in severe cardiogenic shock at the time of implantation, and five because they did not complete the pharmacologic regimen. After an average of 320 days of support, 11 of the remaining 15 patients recovered sufficiently to qualify for removal of the device. Of these, one died early after explantation, but the others survived for more than 2 years. The actuarial survival rate 1 year and 4 years after explantation was 90.9 percent and 81.8 percent, respectively. Freedom from recurrence of heart failure at 4 years for surviving members of the group that underwent explantation was 88.9 percent.
The study, however, leaves unresolved questions. How important were the individual agents used in the first phase to reverse remodeling? In the second phase, was the use of a selective beta2-agonist necessary to minimize the adverse effects of chronic unloading? This second phase may be critically important, since prolonged unloading by a left ventricular assist device prompts myocyte atrophy and increases collagen cross-linking and myocardial stiffness.11 Did the patients in the study really have stage D heart failure? The hemodynamic measurements indicate that they did, suggesting that the left ventricular recovery seen by Birks et al. was not the result of the early application of therapeutic interventions in patients with stage C heart failure. Rather, treatments administered while a patient had the support of a left ventricular assist device probably had important contributions to reverse remodeling of stage D heart failure.
Furthermore, it should be acknowledged that the population of patients was selected carefully, not all patients had a response, the exact role and doses of the medications have not been completely elucidated, the number of patients was small, there was no control group, and the measures used to qualify for progression from one phase to another were standardized but have not yet been corroborated. To use legal parlance, Birks et al. have achieved a "preponderance of evidence" but are not convincing "beyond a reasonable doubt" about the specifics in question.
Despite the acknowledged limitations of their study, Birks et al. have tantalizingly provided more than just a series of anecdotes regarding recovery from end-stage heart failure. Their report is reasonably convincing that support with a left ventricular assist device may serve as a platform from which to administer promising therapies. Sometimes, it seems, active intervention may modify the natural history of heart failure. Maybe, in some patients, the failing heart is not end-stage after all.
The treatment of stage D heart failure now includes more than end-of-life strategies, transplantation, and permanent implantation of left ventricular assist devices. Indeed, left ventricular assist devices may sustain therapies that enable reverse remodeling, improve myocardial energetics, and prepare the heart for removal of the device. Use of the left ventricular assist device as a platform for other therapies for reversing heart failure from stage D to stage C, such as gene- or cell-based therapies, could be attempted and might improve on the therapies described by Birks et al.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program (D.G.R., A.G.K.), the Division of Cardiology, LDS Hospital (D.G.R., A.G.K.), and the Division of Cardiology, University of Utah School of Medicine (D.G.R.) — all in Salt Lake City.
References
Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of heart failure): developed in collaboration with the International Society for Heart and Lung Transplantation: endorsed by the Heart Failure Society of America. Circulation 2001;104:2996-3007.
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult -- summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:1825-1852.
Rose EA, Gelijns AC, Moskowitz AJ, et al. Long term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001;345:1435-1443.
Shakar SF, Abraham WT, Gilbert EM, et al. Combined oral positive inotropic and beta-blocker therapy for treatment of refractory class IV heart failure. J Am Coll Cardiol 1998;31:1336-1340.
Dipla K, Mattiello JA, Jeevanandam V, Houser SR, Margulies KB. Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation 1998;97:2316-2322.
Anversa P, Kajstura J. Ventricular myocytes are not terminally differentiated in the adult mammalian heart. Circ Res 1998;83:1-14.
Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A 1998;95:8801-8805.
Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763-776.
Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodeling. Nature 2002;415:240-243.
Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006;355:1873-1884.
Klotz S, Foronjy RF, Dickstein ML, et al. Mechanical unloading during left ventricular assist device support increases left ventricular collagen cross-linking and myocardial stiffness. Circulation 2005;112:364-374.(Dale G. Renlund, M.D., an)