Risk stratification and role of implantable defibrillators for prevention of sudden death in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young people, including trained athletes. It is now 30 years since the introduction of implantable cardioverter-defibrillators (ICDs) to clinical cardiovascular practice and coronary artery disease, and now device therapy represents the most significant therapeutic innovation and the only definitive strategy for prolonging the life of HCM patients. ICDs have proved effective in preventing SCD in young HCM patients with appropriate intervention rates of 11% for secondary and 4% for primary prevention, despite massive left ventricular (LV) hypertrophy, LV outflow obstruction, diastolic dysfunction or microvascular ischemia. Targeting candidates for prophylactic ICD therapy can be complex, compounded by the unpredictability of the arrhythmogenic substrate, the absence of a dominant risk factor, and difficulty in assembling randomized trials. However, a single major risk factor is often sufficient to justify an ICD, although additional markers and other disease features can resolve ambiguous decision-making. Nevertheless, the absence of all risk factors does not convey absolute immunity to SCD. The current risk factor algorithm, when combined with a measure of individual physician judgment (and patient autonomy considerations), is an effective guide to identifying high-risk HCM patients. ICDs have altered the natural history of HCM for many patients and provided an opportunity to achieve many decades of productive life, and the potential for normal or near-normal longevity. Indeed, prevention of SCD has now become a new paradigm in the management of HCM.

Historical Perspectives in the Evolution of Hypertrophic Cardiomyopathy.

Since the first anatomic description of hypertrophic cardiomyopathy (HCM) in 1958, significant advancements have expanded the understanding of this condition. At the same time, new imaging tools and treatment modalities have contributed to an ever-changing armamentarium for the assessment and treatment of patients with HCM. The historical perspective of HCM discovery and the progress made in the last several decades shed light on the road still ahead, which is expected to lead to better forms of treatment and perhaps even prevention of this, at times, devastating disease.

The First Operation for Apical Hypertrophic Cardiomyopathy-Dr Dwight McGoon, 1972.

The first operation for apical hypertrophic cardiomyopathy (ApHCM) was performed on September 7, 1972 by Dr Dwight McGoon at Mayo Clinic on a 16-year-old boy who was thought to have a cardiac neoplasm.

The Remarkable 50 Years of Imaging in HCM and How it Has Changed Diagnosis and Management: From M-Mode Echocardiography to CMR.

The almost 50-year odyssey of cardiac imaging in hypertrophic cardiomyopathy (HCM), revisited and described here, has been remarkable, particularly when viewed in the timeline of advances that occurred during a single generation of investigators. At each step along the way, from M-mode to 2-dimensional echocardiography to Doppler imaging, and finally over the last 10 years with the emergence of high-resolution tomographic cardiac magnetic resonance (CMR), evolution of the images generated by each new technology constituted a paradigm change over what was previously available. Together, these advances have transformed the noninvasive diagnosis and management of HCM in a number of important clinical respects. These changes include a more complete definition of the phenotype, resulting in more reliable clinical identification of patients and family members, defining mechanisms (and magnitude) of left ventricular outflow obstruction, and novel myocardial tissue characterization (including in vivo detection of fibrosis/scarring); notably, these advances afford more precise recognition of at-risk patients who are potential candidates for life-saving primary prevention defibrillator therapy. This evolution in imaging as applied to HCM has indelibly changed cardiovascular practice for this morphologically and clinically complex genetic disease.

The challenge of cardiomyopathy.

The combined clinical and pathophysiologic characteristics and diagnostic features as well as current concepts of pathogenesis, therapy and prevention of the principal forms of cardiomyopathy are reviewed. These include hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy and specific cardiac muscle disease. Emphasis is placed on recent developments and unresolved questions requiring application of newer techniques of molecular biology and genetics and adult myocyte culturing.

Subaortic stenosis revisited: the importance of the dynamic pressure gradient.

Brachfeld and Gorlin's revised concept of subaortic stenosis derived from their recognition that the large magnitudes of the pressure gradients were incompatible with the relatively mild anatomic lesions found at surgery in 3 of their patients, and the rapidity of their arterial pulse upstroke. They proposed that a gradient caused by a superimposed systolic stenosis was responsible for the large pressure gradients and the overestimation of the severity of the discrete subaortic stenosis (DSAS). A fourth patient had no anatomic cause for the pressure gradient, and findings compatible with hypertrophic cardiomyopathy (HCM). All 4 patients had septal hypertrophy which they felt was instrumental in the brisk pulse contour and dynamic gradients across the outflow tract. In the ensuing decades, imaging techniques have been developed which permit detailed studies of ventricular ejection patterns in dynamic gradients associated with HCM and DSAS. These studies have been interpreted variously. The prevailing view is that there is a dynamic obstruction that increases progressively in severity during systole, as proposed by Brachfeld and Gorlin. An opposing view is that dynamic gradients can occur in the absence of any hindrance to ejection, and that these gradients instead result from rapid and complete emptying of the ventricle. Regardless of their cause, dynamic gradients are often superimposed upon gradients caused by DSAS and valvar aortic stenosis, leading to exaggerated estimates of severity. These dynamic gradients are uncovered when the anatomic cause of stenosis is removed, and seemingly increase the postoperative morbidity. A greater understanding of the significance of dynamic gradients and the mechanism(s) responsible for them should lead to more rational management of DSAS and HCM in the future.

Switzerland is small in size but big on cardiology.

Switzerland is a small country in the heart of Europe and well known worldwide for its Alps, foreign bank accounts, cheese, chocolate and watches. However, it also has made a significant contribution to cardiology, especially interventional cardiology. It was where balloon angioplasty and stenting of obstructed coronary arteries, two of the most stunning advances in cardiology in the last 30 years and the two most frequently performed interventional procedures in cardiology, originated. The author, who recently served as a visiting professor in the University of Geneva, University of Bern and University of Zurich, summarized his personal observations and impressions in this report.

Historical milestones and progress in the research on alcohol septal ablation for hypertrophic obstructive cardiomyopathy.

The first alcohol septal ablation was performed almost 20 years ago in 1994; since then it has become a widely used technique for the treatment of highly symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM). It has been shown that postprocedural basal septal shrinking as a result of myocardial scarring is followed by a decrease in left ventricular (LV) obstruction, regression of LV hypertrophy within the first postprocedural year, improvement of diastolic function, and reduction of the degree of mitral regurgitation. All these changes are accompanied by significant symptom relief. Although there is only limited evidence of postprocedural long-term survival, all the studies presented here are consistent in the low incidence of sudden death and similar prognoses with an age- and sex-matched general population. Conversely, we still have to be aware that a certain knowledge gap exists with regard to postprocedural long-term outcome. Therefore, careful selection of patients for alcohol septal ablation is needed, and all patients should be treated in centres offering all therapeutic options.

Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives.

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.

The 50-year history, controversy, and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy: from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy.

Dynamic obstruction to left ventricular (LV) outflow was recognized from the earliest (50 years ago) clinical descriptions of hypertrophic cardiomyopathy (HCM) and has proved to be a complex phenomenon unique in many respects, as well as arguably the most visible and well-known pathophysiologic component of this heterogeneous disease. Over the past 5 decades, the clinical significance attributable to dynamic LV outflow tract gradients in HCM has triggered a periodic and instructive debate. Nevertheless, only recently has evidence emerged from observational analyses in large patient cohorts that unequivocally supports subaortic pressure gradients (and obstruction) both as true impedance to LV outflow and independent determinants of disabling exertional symptoms and cardiovascular mortality. Furthermore, abolition of subaortic gradients by surgical myectomy (or percutaneous alcohol septal ablation) results in profound and consistent symptomatic benefit and restoration of quality of life, with myectomy providing a long-term survival similar to that observed in the general population. These findings resolve the long-festering controversy over the existence of obstruction in HCM and whether outflow gradients are clinically important elements of this complex disease. These data also underscore the important principle, particularly relevant to clinical practice, that heart failure due to LV outflow obstruction in HCM is mechanically reversible and amenable to invasive septal reduction therapy. Finally, the recent observation that the vast majority of patients with HCM have the propensity to develop outflow obstruction (either at rest or with exercise) underscores a return to the characterization of HCM in 1960 as a predominantly obstructive disease.