Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These “sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy.

Differentiation between primary dilated cardiomyopathy and ischemic cardiomyopathy has an important clinical significance. Contrast-enhanced cardiovascular magnetic resonance can play a role in this task, identifying myocardial scarring or fibrosis as presence of delayed enhancement. The aim of the present study was to evaluate the diagnostic potential of contrast-enhanced cardiovascular magnetic resonance in differentiating dilated cardiomyopathy from ischemic cardiomyopathy. Contrast-enhanced cardiovascular magnetic resonance was performed in 100 patients with left ventricular dilatation and reduced systolic function: 24 had normal coronary arteries (dilated cardiomyopathy group) and 76 had significant coronary artery disease (ischemic cardiomyopathy group), with or without previous myocardial infarction. In the dilated cardiomyopathy group, only seven (29%) patients showed delayed enhancement and its pattern was characterized by mid-wall, patchy or diffuse location. All patients with ischemic cardiomyopathy and prior myocardial infarction (54 subjects) showed delayed enhancement with subendocardial (n = 4) or transmural (n = 50) extension. Among the 22 patients with ischemic cardiomyopathy but without previous myocardial infarction, 13 (59%) showed either subendocardial (n = 4) or transmural (n = 9) delayed enhancement. Patterns of delayed enhancement are different in dilated cardiomyopathy and ischemic cardiomyopathy, reflecting the presence of scarring or various degrees of fibrosis in left ventricular myocardium. The presence of subendocardial or transmural delayed enhancement at contrast-enhanced cardiovascular magnetic resonance allowed distinction between dilated cardiomyopathy and ischemic cardiomyopathy with high sensitivity (88%) and specificity (100%). Integration of cardiovascular magnetic resonance results with angiographic information can be useful in the identification of pathogenic mechanisms underlying left ventricular dysfunction.

The discovery of hypertrophic cardiomyopathy (HCM) dates back to 1958, when the pathologist Donald Teare of the St. George’s Hospital in London performed autopsies in eight cases with asymmetric hypertrophy of the ventricular septum and bizarre disorganization (disarray) at histology, first interpreted as hamartoma. Seven had died suddenly. The cardiac specimens were cut along the long axis, similar to the 2D echo. In the same year, at the National Institute of Health U.S.A., Eugene Braunwald, a hemodynamist, and Andrew Glenn Morrow, a cardiac surgeon, clinically faced a patient with an apparently similar morbid entity, with a systolic murmur and subaortic valve gradient. “Discrete” subaortic stenosis was postulated. However, at surgery, Dr. Morrow observed only hypertrophy and performed myectomy to relieve the obstruction. This first Braunwald–Morrow patient underwent a successful cardiac transplant later at the disease end stage. The same Dr. Morrow was found to be affected by the familial HCM and died suddenly in 1992. The term “functional subaortic stenosis” was used in 1959 and “idiopathic hypertrophic subaortic stenosis” in 1960. Years before, in 1957, Lord Brock, a cardiac surgeon at the Guy’s Hospital in London, during alleged aortic valve surgery in extracorporeal circulation, did not find any valvular or discrete subaortic stenoses. In 1980, John F. Goodwin of the Westminster Hospital in London, the head of an international WHO committee, put forward the first classification of heart muscle diseases, introducing the term cardiomyopathy (dilated, hypertrophic, and endomyocardial restrictive). In 1995, the WHO classification was revisited, with the addition of two new entities, namely arrhythmogenic and purely myocardial restrictive, the latter a paradox of a small heart accounting for severe congestive heart failure by ventricular diastolic impairment. A familial occurrence was noticed earlier in HCM and published by Teare and Goodwin in 1960. In 1989–1990, the same family underwent molecular genetics investigation by the Seidman team in Boston, and a missense mutation of the β-cardiac myosin heavy chain in chromosome 14 was found. Thus, 21 years elapsed from HCM gross discovery to molecular discoveries. The same original family was the source of both the gross and genetic explanations of HCM, which is now named sarcomere disease. Restrictive cardiomyopathy, characterized grossly without hypertrophy and histologically by myocardial disarray, was found to also have a sarcomeric genetic mutation, labeled “HCM without hypertrophy”. Sarcomere missense mutations have also been reported in dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy. Moreover, sarcomeric gene defects have been detected in some DNA non-coding regions of HCM patients. The same mutation in the family may express different phenotypes (HCM, DCM, and RCM). Large ischemic scars have been reported by pathologists and are nowadays easily detectable in vivo by cardiac magnetic resonance with gadolinium. The ischemic arrhythmic substrate enhances the risk of sudden death.

Since its first pathological description over 65 years ago, hypertrophic cardiomyopathy (HCM), with a worldwide prevalence of 1:500, has emerged as the most common genetically determined cardiac disease. Diagnostic work-up has dramatically improved over the last decades, from clinical suspicion and abnormal electrocardiographic findings to hemodynamic studies, echocardiography, contrast-enhanced cardiac magnetic resonance, and genetic testing. The implementation of screening programs and the use of implantable cardioverter defibrillators (ICDs) for high-risk individuals have notably reduced arrhythmic sudden deaths, altering the disease’s mortality profile. Therapeutic breakthroughs, including surgical myectomy, alcohol septal ablation, and the novel introduction of “myosin inhibitors”, have revolutionized symptom management and reduced progression to advanced heart failure (HF) and death. Despite this progress, refractory HF—both with preserved and reduced systolic function—has become the predominant cause of HCM-related mortality. While most patients with HCM experience a favorable clinical course with low morbidity and mortality, timely identification and targeted treatment of high-risk subgroups progressing toward progressive HF remain a pressing challenge, even for expert clinicians.

Hypertrophic cardiomyopathy (HCM) is a genetically and phenotypically heterogeneous disease in which management requires integration of clinical assessment, cardiovascular physiology, multimodality imaging, functional evaluation, and arrhythmic risk. This review examines contemporary evaluation, risk stratification, and treatment of sarcomeric HCM across obstructive and non-obstructive phenotypes. In obstructive HCM, conventional negative inotropic therapy and septal reduction therapy remain established treatments, while cardiac myosin inhibitors have introduced a mechanism-based approach that improves left ventricular outflow tract obstruction, symptoms, and exercise capacity. Their role relative to septal reduction therapy should be individualized according to anatomy, hemodynamics, treatment burden, durability, and patient preference. In non-obstructive HCM, treatment remains largely symptom-directed, although recent trials of myosin inhibition have yielded divergent results, emphasizing the importance of appropriate patient selection. Emerging strategies targeting myocardial energetics and earlier disease stages may further expand treatment options. Gene-based therapies, including first-in-human MYBPC3 replacement, offer the possibility of targeting the underlying molecular defect but require careful evaluation of safety, durability, and timing. Overall, HCM remains a paradigmatic disease for physiology-driven, phenotype- and stage-specific care, increasingly complemented by molecularly targeted therapies.