New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy Semsarian, Christopher, MBBS, PhD, MPH; Ingles, Jodie, GradDipGenCouns, PhD, MPH; Maron, Martin S., MD ...
Journal of the American College of Cardiology,
03/2015, Letnik:
65, Številka:
12
Journal Article
Recenzirano
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Abstract Hypertrophic cardiomyopathy (HCM) is an important genetic heart muscle disease for which prevalence in the general population has not been completely resolved. For the past 20 years, most ...data have supported the occurrence of HCM at about 1 in 500. However, the authors have interrogated a number of relevant advances in cardiovascular medicine, including widespread fee-for-service genetic testing, population genetic studies, and contemporary diagnostic imaging, as well as a greater index of suspicion and recognition for both the clinically expressed disease and the gene-positive–phenotype-negative subset (at risk for developing the disease). Accounting for the potential impact of these initiatives on disease occurrence, the authors have revisited the prevalence of HCM in the general population. They suggest that HCM is more common than previously estimated, which may enhance its recognition in the practicing cardiovascular community, allowing more timely diagnosis and the implementation of appropriate treatment options for many patients.
Hypertrophic cardiomyopathy Maron, Barry J, MD; Maron, Martin S, Dr
The Lancet (British edition),
01/2013, Letnik:
381, Številka:
9862
Journal Article
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Summary Hypertrophic cardiomyopathy is a common inherited cardiovascular disease present in one in 500 of the general population. It is caused by more than 1400 mutations in 11 or more genes encoding ...proteins of the cardiac sarcomere. Although hypertrophic cardiomyopathy is the most frequent cause of sudden death in young people (including trained athletes), and can lead to functional disability from heart failure and stroke, the majority of affected individuals probably remain undiagnosed and many do not experience greatly reduced life expectancy or substantial symptoms. Clinical diagnosis is based on otherwise unexplained left-ventricular hypertrophy identified by echocardiography or cardiovascular MRI. While presenting with a heterogeneous clinical profile and complex pathophysiology, effective treatment strategies are available, including implantable defibrillators to prevent sudden death, drugs and surgical myectomy (or, alternatively, alcohol septal ablation) for relief of outflow obstruction and symptoms of heart failure, and pharmacological strategies (and possibly radiofrequency ablation) to control atrial fibrillation and prevent embolic stroke. A subgroup of patients with genetic mutations but without left-ventricular hypertrophy has emerged, with unresolved natural history. Now, after more than 50 years, hypertrophic cardiomyopathy has been transformed from a rare and largely untreatable disorder to a common genetic disease with management strategies that permit realistic aspirations for restored quality of life and advanced longevity.
Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this hypothesis suggest that ...sarcomere mutations alone do not adequately explain all HCM clinical and pathobiological features. Disease-causing sarcomere mutations are absent in ∼70% of patients with established disease, and sarcomere gene carriers can live to advanced ages without developing HCM. Some features of HCM are also inconsistent with the single sarcomere gene hypothesis, such as regional left ventricular hypertrophy and myocardial fibrosis, as well as structurally abnormal elongated mitral valve leaflets and remodeled intramural coronary arterioles, which involve tissue types that do not express cardiomyocyte sarcomere proteins. It is timely to expand the HCM research focus beyond a single molecular event toward more inclusive models to explain this disease in its entirety. The authors chart paths forward addressing this knowledge gap using novel analytical approaches, particularly network medicine, to unravel the pathobiological complexity of HCM.
Hypertrophic cardiomyopathy (HCM) is the most common familial heart disease with vast genetic heterogeneity, demonstrated over the past 20 years. Mutations in 11 or more genes encoding proteins of ...the cardiac sarcomere (>1,400 variants) are responsible for (or associated with) HCM. Explosive progress achieved in understanding the rapidly evolving science underlying HCM genomics has resulted in fee-for-service testing, making genetic information widely available. The power of HCM mutational analysis, albeit a more limited role than initially envisioned, lies most prominently in screening family members at risk for developing disease and excluding unaffected relatives, which is information not achievable otherwise. Genetic testing also allows expansion of the broad HCM disease spectrum and diagnosis of HCM phenocopies with different natural history and treatment options, but is not a reliable strategy for predicting prognosis. Interfacing a heterogeneous disease such as HCM with the vast genetic variability of the human genome, and high frequency of novel mutations, has created unforeseen difficulties in translating complex science (and language) into the clinical arena. Indeed, proband diagnostic testing is often expressed on a probabilistic scale, which is frequently incompatible with clinical decision making. Major challenges rest with making reliable distinctions between pathogenic mutations and benign variants, and those judged to be of uncertain significance. Genotyping in HCM can be a powerful tool for family screening and diagnosis. However, wider adoption and future success of genetic testing in the practicing cardiovascular community depends on a standardized approach to mutation interpretation, and bridging the communication gap between basic scientists and clinicians.
Risk stratification for sudden death (SD) is an essential component of hypertrophic cardiomyopathy (HC) management, given the proven effectiveness of implantable cardioverter-defibrillators (ICD) for ...preventing SD. Although highly effective in identifying high-risk patients, current stratification algorithms remain incomplete and novel strategies are encouraged. In this regard, reliability of the statistical model to predict SD risk in HC, as recommended by the recent European Society of Cardiology (ESC) guidelines, was retrospectively tested in an independent cohort of 1,629 consecutive patients with HC aged ≥16 years. Of the 1,629 patients, 35 incurred SD events, but only 4 of these (11%) had high predictive risk scores >6%/5 years consistent with an ICD recommendation, and most (60%; n = 21) had scores <4%/5 years that would not justify ICDs. Of 46 high-risk patients with appropriate ICD interventions for ventricular fibrillation/tachycardia, 27 (59%) had low SD risk scores of <4%/5 years, regarded by ESC as insufficient to recommend ICDs, and only 12 (26%) had scores >6%/5 years, considered an ICD indication; 11 of these 12 had already met conventional criteria warranting implantation with 2 to 3 risk markers. Of 414 patients with ICDs but without appropriate interventions, 258 (62%) had low risk scores (<4%/5 years) that would argue against implant. In conclusion, primary risk stratification using the ESC prognostic score applied retrospectively to a large independent HC cohort proved unreliable for prediction of future SD events. Most patients with HC with SD or appropriate ICD interventions were misclassified with low risk scores and therefore would have remained unprotected from arrhythmic SD without ICDs.
Abstract Background Left ventricular outflow tract gradients are absent in an important proportion of patients with hypertrophic cardiomyopathy (HCM). However, the natural course of this important ...patient subgroup remains largely unresolved. Objectives The authors systematically employed exercise (stress) echocardiography to define those patients without obstruction to left ventricular outflow at rest and/or under physiological exercise and to examine their natural history and clinical course to create a more robust understanding of this complex disease. Methods We prospectively studied 573 consecutive HCM patients in 3 centers (44 ± 17 years; 66% male) with New York Heart Association functional class I/II symptoms at study entry, including 249 in whom left ventricular outflow tract obstruction was absent both at rest and following physiological exercise (<30 mm Hg; nonobstructive HCM) and retrospectively assembled clinical follow-up data. Results Over a median follow-up of 6.5 years, 225 of 249 nonobstructive patients (90%) remained in classes I/II, whereas 24 (10%) developed progressive heart failure to New York Heart Association functional classes III/IV. Nonobstructive HCM patients were less likely to experience advanced limiting class III/IV symptoms than the 324 patients with outflow obstruction (1.6%/year vs. 7.4%/year rest obstruction vs. 3.2%/year provocable obstruction; p < 0.001). However, 7 nonobstructive patients (2.8%) did require heart transplantation for progression to end stage versus none of the obstructive patients. HCM-related mortality among nonobstructive patients was low (n = 8; 0.5%/year), with 5- and 10-year survival rates of 99% and 97%, respectively, which is not different from expected all-cause mortality in an age- and sex-matched U.S. population (p = 0.15). Conclusions HCM patients with nonobstructive disease appear to experience a relatively benign clinical course, associated with a low risk for advanced heart failure symptoms, other disease complications, and HCM-related mortality, and largely without the requirement for major treatment interventions. A small minority of nonobstructive HCM patients progress to heart transplant.
Objectives This study was designed to define more completely the clinical spectrum and consequences of stress cardiomyopathy (SC) beyond the acute event. Background Stress cardiomyopathy is a ...recently recognized condition characterized by transient cardiac dysfunction with ventricular ballooning. Methods Clinical profile and outcome were prospectively assessed in 136 consecutive SC patients. Results Patients were predominantly women (n = 130; 96%), but 6 were men (4%). Ages were 32 to 94 years (mean age 68 ± 13 years); 13 (10%) were ≤50 years of age. In 121 patients (89%), SC was precipitated by intensely stressful emotional (n = 64) or physical (n = 57) events, including 22 associated with sympathomimetic drugs or medical/surgical procedures; 15 other patients (11%) had no evident stress trigger. Twenty-five patients (18%) were taking beta-blockers at the time of SC events. Three diverse ventricular contraction patterns were defined by cardiovascular magnetic resonance (CMR) imaging, usually with rapid return to normal systolic function, although delayed >2 months in 5%. Right and/or left ventricular thrombi were identified in 5 patients (predominantly by CMR imaging), including 2 with embolic events. Three patients (2%) died in-hospital and 116 (85%) have survived, including 5% with nonfatal recurrent SC events. All-cause mortality during follow-up exceeded a matched general population (p = 0.016) with most deaths occurring in the first year. Conclusions In this large SC cohort, the clinical spectrum was heterogeneous with about one-third either male, ≤50 years of age, without a stress trigger, or with in-hospital death, nonfatal recurrence, embolic stroke, or delayed normalization of ejection fraction. Beta-blocking drugs were not absolutely protective and SC was a marker for increased noncardiac mortality. These data support expanded management and surveillance strategies including CMR imaging and consideration for anticoagulation.
Atrial fibrillation (AF), the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM), is capable of producing symptoms that impact quality of life and is associated with risk for ...embolic stroke. However, the influence of AF on clinical course and outcome in HCM remains incompletely resolved.
Records of 1558 consecutive patients followed at the Tufts Medical Center Hypertrophic Cardiomyopathy Institute for 4.8±3.4 years (from 2004 to 2014) were accessed.
Of the 1558 patients with HCM, 304 (20%) had episodes of AF, of which 226 (74%) were confined to symptomatic paroxysmal AF (average, 5±5; range, 1 to >20), whereas 78 (26%) developed permanent AF, preceded by 7±6 paroxysmal AF episodes. At last evaluation, 277 patients (91%) are alive at 62±13 years of age, including 89% in New York Heart Association class I or II. No difference was found in outcome measures for patients with AF and age- and sex-matched patients with HCM without AF. Four percent of patients with AF died of HCM-related causes (n=11), with annual mortality 0.7%; mortality directly attributable to AF (thromboembolism without prophylactic anticoagulation) was 0.1% per year (n=2 patients). Patients were treated with antiarrhythmic drugs (most commonly amiodarone n=103 or sotalol n=78) and AF catheter ablation (n=49) or the Maze procedure at surgical myectomy (n=72). Freedom from AF recurrence at 1 year was 44% for ablation patients and 75% with the Maze procedure (
<0.001). Embolic events were less common with anticoagulation prophylaxis (4/233, 2%) than without (9/66, 14%) (
<0.001).
Transient symptomatic episodes of AF, often responsible for impaired quality of life, are unpredictable in frequency and timing, but amenable to effective contemporary treatments, and infrequently progress to permanent AF. AF is not a major contributor to heart failure morbidity or a cause of arrhythmic sudden death; when treated, it is associated with low disease-related mortality, no different than for patients without AF. AF is an uncommon primary cause of death in HCM virtually limited to embolic stroke, supporting a low threshold for initiating anticoagulation therapy.
Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, ...myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine.
Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with diverse phenotypic and genetic expression, clinical presentation, and natural history. HCM has been recognized for 55 years, ...but recently substantial advances in diagnosis and treatment options have evolved, as well as increased recognition of the disease in clinical practice. Nevertheless, most genetically and clinically affected individuals probably remain undiagnosed, largely free from disease-related complications, although HCM may progress along 1 or more of its major disease pathways (i.e., arrhythmic sudden death risk; progressive heart failure HF due to dynamic left ventricular LV outflow obstruction or due to systolic dysfunction in the absence of obstruction; or atrial fibrillation with risk of stroke). Effective treatments are available for each adverse HCM complication, including implantable cardioverter-defibrillators (ICDs) for sudden death prevention, heart transplantation for end-stage failure, surgical myectomy (or selectively, alcohol septal ablation) to alleviate HF symptoms by abolishing outflow obstruction, and catheter-based procedures to control atrial fibrillation. These and other strategies have now resulted in a low disease-related mortality rate of <1%/year. Therefore, HCM has emerged from an era of misunderstanding, stigma, and pessimism, experiencing vast changes in its clinical profile, and acquiring an effective and diverse management armamentarium. These advances have changed its natural history, with prevention of sudden death and reversal of HF, thereby restoring quality of life with extended (if not normal) longevity for most patients, and transforming HCM into a contemporary treatable cardiovascular disease.
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