Hypertrophic Cardiomyopathy in Adults and CV Mortality
Hypertrophic Cardiomyopathy in Adults and CV Mortality
Over the last 15 years, comprehensive HCM-related management strategies have evolved considerably, including an expanded risk stratification algorithm with greater appreciation for at-risk patients, leading to more reliable identification of those likely to achieve SD prevention with ICDs and in accordance with U.S. guidelines, HCM patients have also benefited from relief of heart failure symptoms and extended longevity due to advances in surgical septal myectomy technique (or alcohol ablation) and heart transplantation. Although the effectiveness of such treatments has been reported in selected high-risk subsets, ascertaining their true efficacy on clinical course, potential mortality, and longevity requires systematic assessment in established and consecutively assembled large adult HCM patient populations (such as the present one).
We recently recognized patient age as important in the natural history and clinical course of HCM, and decisions governing major treatment interventions, by demonstrating that advanced age (≥60 years) is associated with a low disease event rate. Thus, in the present study, we longitudinally tracked the impact of major treatment initiatives on the clinical course of adult patients between 30 and 59 years of age, with the rationale that the "midlife" age group is most often encountered for diagnosis or evaluation in clinical practice, as well as at-risk for adverse disease-related events, including SD and heart failure progression. We elected not to incorporate younger HCM patients in this report, who are encountered much less frequently in practice, and often with early onset aggressive disease expression.
Using our investigative strategy, we believe that the expectation for longevity is favorably altered for many HCM patients presenting in midlife, with a low mortality rate directly attributable to utilization of contemporary cardiovascular treatment options (Central Illustration). It was not possible, however, to assemble an untreated and rigidly matched control group to address the improved HCM mortality reported here. Nevertheless, it is a reasonable assertion that, in a cohort analysis such as ours, it is highly unlikely that patients would have survived to the present without treatment interventions known to preserve life, such as ICDs, surgical myectomy, heart transplantation, modern external defibrillation techniques (and therapeutic hypothermia), or prevention of embolic stroke death with prophylactic anticoagulant drugs.
For example, the HCM mortality rate among our 1,000 patients was just 0.5%/year, approximately 10-fold lower than the 3% to 6%/year reported from tertiary referral cohorts in a much earlier era, influenced by highly skewed patient referral patterns. Our HCM mortality rate documented here was also 3-fold less than the 1.5% annual HCM-related rate of death attached to this disease in the pre-ICD era. The older mortality estimates contributed to the characterization of HCM as an untreatable disease with a uniformly grim prognosis, a view that has unfortunately persisted, in part, to the present.
The relatively low HCM mortality rate of 0.5%/year reported here is largely attributable to aborted and nonfatal events, by virtue of utilizing the ICD for primary prevention of SD, as well as heart transplantation for prevention of heart failure-related death (Central Illustration). Indeed, when fatal and nonfatal HCM events were combined, the overall HCM event rate exceeded that in the general population, underscoring the survival advantage provided by major and contemporary therapeutic interventions translated to HCM here. Furthermore, our HCM mortality did not differ significantly from that expected in the general population, or that previously reported in HCM patients presenting ≥60 years of age. This revised perception of HCM-related mortality can serve as a measure of reassurance to many HCM patients, and evidence of what is possible in this disease with contemporary treatment.
Close inspection of clinical profiles in patients with HCM-related death showed that many of the SDs that occurred would be potentially preventable by current practice standards. For example, several patients declined the ICD, even after receiving a standard formal recommendation for prophylactic device therapy. Other patients were first evaluated in the 1990s, an era preceding penetration of ICDs into clinical practice for HCM and the availability of data supporting the efficacy of device therapy in this disease, or the expanded risk stratification models currently in use. Should these patients be hypothetically considered as likely survivors (with ICDs), the HCM-related mortality rate would decrease to 0.4%/year.
Notably, 95% of our patients with appropriate ICD interventions for VT/VF have survived to date, with the vast majority experiencing favorable quality of life with no or mild symptoms. Also, at the most recent follow-up, 80% of heart transplant patients had survived, representing a significant extension in life expectancy.
Our data support the evidence-based risk stratification strategy currently in widespread practice by most HCM investigators and clinicians and in turn are supported by American College of Cardiology/American Heart Association consensus guidelines. Individual HCM patients can become ICD candidates on the basis of 1 or more major SD risk factors in their clinical profile. This strategy has proved effective in identifying most high-risk HCM patients for prophylactic ICD implantation and SD prevention, although different from that used in coronary artery disease or the complex statistical/mathematical formula recently advanced in HCM by O'Mahony et al. for the European Society of Cardiology Guidelines. However, the fact that some patients in our cohort study experienced SD without conventional risk factors suggests the need for additional markers in HCM, such as extensive LGE with quantitative contrast CMR, which creates additional candidates for ICDs and potentially results in even lower HCM-related mortality.
In this study, 37 patients prospectively identified as high-risk ultimately experienced potentially lethal ventricular tachyarrhythmias that were terminated by the ICD, dispelling the myth that risk markers in HCM are relatively poor predictors. Nevertheless, the number of ICDs required to generate 1 implant that eventually intervened appropriately was approximately 9:1, similar to that in randomized trials of high-risk and clinically compromised patients with coronary artery disease or nonischemic cardiomyopathy. However, because the arrhythmogenic substrate in HCM has proven unpredictable and many at-risk patients are identified at young ages, the present cross-sectional study design does not exclude the possibility that additional appropriate ICD interventions will continue to occur in this cohort over time.
A substantial proportion of our patients died of advanced heart failure or underwent heart transplantation, suggesting that the epidemiology of HCM-related mortality may be evolving to a new paradigm in which end-stage heart failure (and its treatment) is a more major component of the disease spectrum than previously considered. It is even possible that progressive advanced heart failure could soon replace arrhythmic SD as the predominant cause of demise in HCM. This shift may be explained, in part, by SD prevention with ICDs or greater recognition of severe heart failure in HCM and its implications.
Over 5 decades, severe limiting drug-refractory symptoms and progressive heart failure due to LV outflow obstruction have been treated effectively by surgical septal myectomy, resulting in reversal of heart failure and greatly improved quality of life, long-term survival equivalent to the general U.S. population, and possible reduction in SD risk. Performed with low operative risk, 90% of patients undergoing myectomy have survived to end of follow-up (HCM-related death in <5%), with improved quality of life attributable to abolition of the outflow gradients responsible for heart failure symptoms. Taken together, these observations underscore the range of therapies effective in extending longevity (and improving quality of life) now available to HCM patients.
A large, well-defined study cohort, as presented here, permits detailed assessment of the impact of major treatment interventions on the clinical course of individual HCM patients. However, assessing changes in mortality rates over time with controlled comparisons between treated and untreated patient groups in a heterogeneous and relatively uncommon disease, such as HCM is an impractical aspiration. Finally, by demonstrating in principle what can be achieved optimally in a focused HCM environment, our data (although assembled from tertiary referral centers) are relevant to more general and less highly selected HCM patient populations.
Discussion
Over the last 15 years, comprehensive HCM-related management strategies have evolved considerably, including an expanded risk stratification algorithm with greater appreciation for at-risk patients, leading to more reliable identification of those likely to achieve SD prevention with ICDs and in accordance with U.S. guidelines, HCM patients have also benefited from relief of heart failure symptoms and extended longevity due to advances in surgical septal myectomy technique (or alcohol ablation) and heart transplantation. Although the effectiveness of such treatments has been reported in selected high-risk subsets, ascertaining their true efficacy on clinical course, potential mortality, and longevity requires systematic assessment in established and consecutively assembled large adult HCM patient populations (such as the present one).
We recently recognized patient age as important in the natural history and clinical course of HCM, and decisions governing major treatment interventions, by demonstrating that advanced age (≥60 years) is associated with a low disease event rate. Thus, in the present study, we longitudinally tracked the impact of major treatment initiatives on the clinical course of adult patients between 30 and 59 years of age, with the rationale that the "midlife" age group is most often encountered for diagnosis or evaluation in clinical practice, as well as at-risk for adverse disease-related events, including SD and heart failure progression. We elected not to incorporate younger HCM patients in this report, who are encountered much less frequently in practice, and often with early onset aggressive disease expression.
Using our investigative strategy, we believe that the expectation for longevity is favorably altered for many HCM patients presenting in midlife, with a low mortality rate directly attributable to utilization of contemporary cardiovascular treatment options (Central Illustration). It was not possible, however, to assemble an untreated and rigidly matched control group to address the improved HCM mortality reported here. Nevertheless, it is a reasonable assertion that, in a cohort analysis such as ours, it is highly unlikely that patients would have survived to the present without treatment interventions known to preserve life, such as ICDs, surgical myectomy, heart transplantation, modern external defibrillation techniques (and therapeutic hypothermia), or prevention of embolic stroke death with prophylactic anticoagulant drugs.
For example, the HCM mortality rate among our 1,000 patients was just 0.5%/year, approximately 10-fold lower than the 3% to 6%/year reported from tertiary referral cohorts in a much earlier era, influenced by highly skewed patient referral patterns. Our HCM mortality rate documented here was also 3-fold less than the 1.5% annual HCM-related rate of death attached to this disease in the pre-ICD era. The older mortality estimates contributed to the characterization of HCM as an untreatable disease with a uniformly grim prognosis, a view that has unfortunately persisted, in part, to the present.
The relatively low HCM mortality rate of 0.5%/year reported here is largely attributable to aborted and nonfatal events, by virtue of utilizing the ICD for primary prevention of SD, as well as heart transplantation for prevention of heart failure-related death (Central Illustration). Indeed, when fatal and nonfatal HCM events were combined, the overall HCM event rate exceeded that in the general population, underscoring the survival advantage provided by major and contemporary therapeutic interventions translated to HCM here. Furthermore, our HCM mortality did not differ significantly from that expected in the general population, or that previously reported in HCM patients presenting ≥60 years of age. This revised perception of HCM-related mortality can serve as a measure of reassurance to many HCM patients, and evidence of what is possible in this disease with contemporary treatment.
Close inspection of clinical profiles in patients with HCM-related death showed that many of the SDs that occurred would be potentially preventable by current practice standards. For example, several patients declined the ICD, even after receiving a standard formal recommendation for prophylactic device therapy. Other patients were first evaluated in the 1990s, an era preceding penetration of ICDs into clinical practice for HCM and the availability of data supporting the efficacy of device therapy in this disease, or the expanded risk stratification models currently in use. Should these patients be hypothetically considered as likely survivors (with ICDs), the HCM-related mortality rate would decrease to 0.4%/year.
Notably, 95% of our patients with appropriate ICD interventions for VT/VF have survived to date, with the vast majority experiencing favorable quality of life with no or mild symptoms. Also, at the most recent follow-up, 80% of heart transplant patients had survived, representing a significant extension in life expectancy.
Our data support the evidence-based risk stratification strategy currently in widespread practice by most HCM investigators and clinicians and in turn are supported by American College of Cardiology/American Heart Association consensus guidelines. Individual HCM patients can become ICD candidates on the basis of 1 or more major SD risk factors in their clinical profile. This strategy has proved effective in identifying most high-risk HCM patients for prophylactic ICD implantation and SD prevention, although different from that used in coronary artery disease or the complex statistical/mathematical formula recently advanced in HCM by O'Mahony et al. for the European Society of Cardiology Guidelines. However, the fact that some patients in our cohort study experienced SD without conventional risk factors suggests the need for additional markers in HCM, such as extensive LGE with quantitative contrast CMR, which creates additional candidates for ICDs and potentially results in even lower HCM-related mortality.
In this study, 37 patients prospectively identified as high-risk ultimately experienced potentially lethal ventricular tachyarrhythmias that were terminated by the ICD, dispelling the myth that risk markers in HCM are relatively poor predictors. Nevertheless, the number of ICDs required to generate 1 implant that eventually intervened appropriately was approximately 9:1, similar to that in randomized trials of high-risk and clinically compromised patients with coronary artery disease or nonischemic cardiomyopathy. However, because the arrhythmogenic substrate in HCM has proven unpredictable and many at-risk patients are identified at young ages, the present cross-sectional study design does not exclude the possibility that additional appropriate ICD interventions will continue to occur in this cohort over time.
A substantial proportion of our patients died of advanced heart failure or underwent heart transplantation, suggesting that the epidemiology of HCM-related mortality may be evolving to a new paradigm in which end-stage heart failure (and its treatment) is a more major component of the disease spectrum than previously considered. It is even possible that progressive advanced heart failure could soon replace arrhythmic SD as the predominant cause of demise in HCM. This shift may be explained, in part, by SD prevention with ICDs or greater recognition of severe heart failure in HCM and its implications.
Over 5 decades, severe limiting drug-refractory symptoms and progressive heart failure due to LV outflow obstruction have been treated effectively by surgical septal myectomy, resulting in reversal of heart failure and greatly improved quality of life, long-term survival equivalent to the general U.S. population, and possible reduction in SD risk. Performed with low operative risk, 90% of patients undergoing myectomy have survived to end of follow-up (HCM-related death in <5%), with improved quality of life attributable to abolition of the outflow gradients responsible for heart failure symptoms. Taken together, these observations underscore the range of therapies effective in extending longevity (and improving quality of life) now available to HCM patients.
Study Limitations
A large, well-defined study cohort, as presented here, permits detailed assessment of the impact of major treatment interventions on the clinical course of individual HCM patients. However, assessing changes in mortality rates over time with controlled comparisons between treated and untreated patient groups in a heterogeneous and relatively uncommon disease, such as HCM is an impractical aspiration. Finally, by demonstrating in principle what can be achieved optimally in a focused HCM environment, our data (although assembled from tertiary referral centers) are relevant to more general and less highly selected HCM patient populations.
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