Pathophysiology and Treatment of Hypertrophic Cardiomyopathy: New Perspectives.

PURPOSE OF REVIEW: We provide a state of the art of therapeutic options in hypertrophic cardiomyopathy (HCM), focusing on recent advances in our understanding of the pathophysiology of sarcomeric disease. RECENT FINDINGS: A wealth of novel information regarding the molecular mechanisms associated with the clinical phenotype and natural history of HCM have been developed over the last two decades. Such advances have only recently led to a number of controlled randomized studies, often limited in size and fortune. Recently, however, the allosteric inhibitors of cardiac myosin adenosine triphosphatase, countering the main pathophysiological abnormality associated with HCM-causing mutations, i.e. hypercontractility, have opened new management perspectives. Mavacamten is the first drug specifically developed for HCM used in a successful phase 3 trial, with the promise to reach symptomatic obstructive patients in the near future. In addition, the fine characterization of cardiomyocyte electrophysiological remodelling has recently highlighted relevant therapeutic targets. Current therapies for HCM focus on late disease manifestations without addressing the intrinsic pathological mechanisms. However, novel evidence-based approaches have opened the way for agents targeting HCM molecular substrates. The impact of these targeted interventions will hopefully alter the natural history of the disease in the near future.

Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in the young, although not all patients eligible for sudden death prevention with an implantable cardioverter-defibrillator are identified. Contrast-enhanced cardiovascular magnetic resonance with late gadolinium enhancement (LGE) has emerged as an in vivo marker of myocardial fibrosis, although its role in stratifying sudden death risk in subgroups of HCM patients remains incompletely understood. METHODS AND RESULTS: We assessed the relation between LGE and cardiovascular outcomes in 1293 HCM patients referred for cardiovascular magnetic resonance and followed up for a median of 3.3 years. Sudden cardiac death (SCD) events (including appropriate defibrillator interventions) occurred in 37 patients (3%). A continuous relationship was evident between LGE by percent left ventricular mass and SCD event risk in HCM patients (P=0.001). Extent of LGE was associated with an increased risk of SCD events (adjusted hazard ratio, 1.46/10% increase in LGE; P=0.002), even after adjustment for other relevant disease variables. LGE of ≥15% of LV mass demonstrated a 2-fold increase in SCD event risk in those patients otherwise considered to be at lower risk, with an estimated likelihood for SCD events of 6% at 5 years. Performance of the SCD event risk model was enhanced by LGE (net reclassification index, 12.9%; 95% confidence interval, 0.3-38.3). Absence of LGE was associated with lower risk for SCD events (adjusted hazard ratio, 0.39; P=0.02). Extent of LGE also predicted the development of end-stage HCM with systolic dysfunction (adjusted hazard ratio, 1.80/10% increase in LGE; P<0.03). CONCLUSIONS: Extensive LGE measured by quantitative contrast enhanced CMR provides additional information for assessing SCD event risk among HCM patients, particularly patients otherwise judged to be at low risk.

Recurrent Intra-Stent Coronary Restenosis in a Carrier of Non-Disease-Specific Antinuclear Antibodies.

Intracoronary in-stent restenosis (ISR) is a phenomenon that generally occurs between 3 and 6 months after stent placement. With the introduction of drug-eluting stents (DES), the incidence of ISR has decreased but not disappeared. We report a case of reiterant in-stent restenosis of an 81-year-old female patient who underwent multiple percutaneous coronary intervention and two coronary artery bypass surgeries. ISR is possibly associated with extra-stent, stent-related and intra-stent factors. Here, we excluded the first two and focused on the intra-stent factors that seem more likely in our case. A challenging diagnostic workup led us to the hypothesis of a coronary vasculitis potentially triggered by some component of the stent in a predisposed patient carrier of non-disease-specific ANA, with an exaggerated immune response. No recurrence of ISR occurred after the introduction of steroids. Biological and intra-stent causes of ISR should be taken into careful consideration to aim for the early detection of the underlying mechanism of restenosis and to embrace the best therapeutic strategy. LEARNING POINTS: Intra-stent restenosis is possibly associated with extra-stent, stent-related and intra-stent factors.Coronary vasculitis is potentially triggered by some component of the stent in a predisposed patient.Immunosuppressive treatment should be taken into consideration in case of recurrent intra-stent restenosis.

Contrast-Induced Acute Kidney Injury in Patients with Heart Failure on Sodium-Glucose Cotransporter-2 Inhibitors Undergoing Radiocontrast Agent Invasive Procedures: A Propensity-Matched Analysis.

(1) Background: This single-center retrospective study aimed to evaluate whether sodium-glucose cotransporter-2 inhibitors (SGLT2-i) therapy may have a nephroprotective effect to prevent contrast-induced acute kidney injury (CI-AKI) in patients with heart failure (HF) undergoing iodinated contrast medium (ICM) invasive procedures. (2) Methods: The population was stratified into SGLT2-i users and SGLT2-i non-users according to the chronic treatment with gliflozins. The primary endpoint was CI-AKI incidence during hospitalization. Secondary endpoints were all-cause mortality and the need for continuous renal replacement therapy (CRRT). (3) Results: In total, 86 patients on SGLT2-i and 179 patients not on SGLT2-i were enrolled. The incidence of CI-AKI in the gliflozin group was lower than in the non-user group (9.3 vs. 27.3%, p < 0.001), and these results were confirmed after propensity matching analysis. Multivariable logistic regression showed that only SGLT2-i treatment was an independent preventive factor for CI-AKI (OR: 0.41, 95% CI: 0.16-0.90, p = 0.045). The need for CRRT was reported only in five patients in the non-SGLT2-i-user group compared to zero patients in the gliflozin group (p = 0.05). (4) Conclusions: SGLT2-i therapy was associated with a lower risk of CI-AKI in patients with HF undergoing ICM invasive procedures.

Lifetime Clinical Course of Hypertrophic Cardiomyopathy: Outcome of the Historical Florence Cohort Over 5 Decades.

Background: The current understanding of the clinical course and long-term outcome of patients with hypertrophic cardiomyopathy (HCM) has been extrapolated from cohorts with relatively short follow-up, usually <10 years. Extended assessments more closely reflecting HCM lifetime burden are not available. Objectives: The purpose of this study was to report the lifetime clinical course of HCM. Methods: We analyzed the clinical course of HCM patients diagnosed at our center from 1970 to 1992 and followed annually to the present. Cumulative incidence functions were used to estimate the incidence of HCM-related mortality (including heart failure [HF]/stroke related, sudden cardiac death [SCD]) and non-HCM related. Results: A total of 202 patients (age 41 ± 17 years; 63% male) were followed 27 ± 6 [range: 3-50] years. Overall, 97 (48%) survived and 105 (52%) died during the particularly long follow-up; 69 deaths were related to HCM, including 53 HF related, 11 fatal embolic strokes, and 16 SCDs. Annual overall HCM-related mortality was 1.3%/y, increasing from 0.7% during the first decade to 1.8% in the second/third decade (P < 0.01), mainly driven by increase in HF-/stroke-related events (from 0.6% to 1.3%). The SCD mortality rate was similar in the 2 periods (0.1% vs 0.44%, P = 0.10). Of the 69 HCM deaths, 29 (42%) occurred before the widespread availability of effective contemporary treatment strategies and are considered potentially preventable. Conclusions: In this unique HCM cohort followed for up to 50 years, often before contemporary therapies became widely implemented for HCM, HF frequently progressed over time, while arrhythmic SCD events were less common and remained constant over time. Despite spanning different management eras over 5 decades, HCM-related mortality remained relatively low (1.3%/y).

[Clinical relevance of genetic testing in hypertrophic cardiomyopathy]. / Rilevanza clinica del test genetico nella cardiomiopatia ipertrofica.

More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed, and become an important tool in clinical practice for diagnosis and prognosis overall in the Western countries. However its practical benefits are still understimated and clinicians often question about cost-effectiveness of genic testing in HCM patients and their families. This resistance is in contrast with considerable evidence supporting the role of genetics in tailoring management for HCM patients. Several current clinical uses of genetic testing in HCM, ranging from diagnosis in ambiguous situations, identification of disease phenocopies and HCM complex genotypes and confirmation of inherited disease in family members are reviewed. In the near future it is hoped that next generation sequencing will provide further diffusion of genetic testing in HCM and improvement in care.

Early Diagnosis and Outcome in Patients With Wild-Type Transthyretin Cardiac Amyloidosis.

Whether diagnostic timing in transthyretin (TTR) cardiac amyloidosis (CA) predisposes patients to worse outcomes is unresolved. We aimed to describe the long-term association of diagnostic timing (time from first onset of symptoms consistent with CA leading to medical contact to definitive diagnosis) with mortality in patients with wild-type TTR-CA (ATTRwt-CA). Overall, we reviewed the medical records of 160 patients seen at a tertiary care amyloidosis unit from January 1, 2016, to January 1, 2020 (median [interquartile range] follow-up, 21 [10 to 34] months), and compared them by survival. Median diagnostic timing was 4 (2 to 12) months and was longer in nonsurvivors (9 [3 to 15] vs 3 [1 to 7] months; P<.001). Patients diagnosed 6 or more months after symptom onset had higher mortality, with a median survival of 30 months (95% CI, 22 to 37 months). On Cox multivariable analysis, timing was independently associated with all-cause mortality (hazard ratio per month increase, 1.049 [95% CI, 1.017 to 1.083]) together with age at diagnosis, disease stage, New York Heart Association class, and coronary artery disease. In conclusion, diagnostic timing of ATTRwt-CA is associated with mortality. Timely diagnosis is warranted whenever "red flags" are present.

Comprehensive Risk Management in Arrhythmogenic Cardiomyopathy Associated With Autosomal Dominant Carvajal Syndrome: Protecting Families.

In a 37-year-old cardiac arrest survivor with autosomal dominant Carvajal syndrome and arrhythmogenic cardiomyopathy, a desmoplakin mutation was identified. Cascade screening identified 2 affected family members and 2 healthy children carrying the mutation. Strategies for primary and secondary risk prevention emphasize the role of genetic testing in rare cardiomyopathies. (Level of Difficulty: Advanced.).

Embolic risk stratification and prognostic impact of early surgery in left-sided infective endocarditis.

BACKGROUND: In patients with left-sided infective endocarditis (IE) and heart failure associated with large vegetations, early surgery prevents embolic events. However, optimal timing of surgery for other indications is still unresolved particularly when the presence of large vegetations represents the sole indication. METHODS: We retrospectively analyzed 308 consecutive patients admitted to our department with definite left-sided IE. Of these patients, 243 (79%) underwent cardiac surgery (complicated IE), 34 patients with uncomplicated IE received medical treatment, 24 were not operated due to prohibitive general conditions and 7 refused surgery. Long-term follow-up was obtained by structured telephone interviews. RESULTS: During the 6-year follow-up (average 121.8 weeks ± 76), patients not operated because of general conditions or refusal had the worst prognosis, while outcome in operated patients for complicated IE was comparable to that of uncomplicated IE treated medically. Early (<2 weeks from diagnosis) surgery was associated with better survival compared to delayed surgery (HR 0.58, p = 0.23). Embolic events were detected at admission in 38% of cases; Staphylococcus Aureus etiology and vegetation size were independently associated with embolism (OR 2.4, p = 0.01; OR 1, p=0.008 respectively). CONCLUSIONS: Compared to uncomplicated medically-treated patients, complicated IE showed comparable survival when managed aggressively by surgical intervention, whereas a conservative approach was associated with an adverse prognosis. Staphylococcus Aureus infection and vegetation size were independent predictors of systemic embolism. Our data support aggressive surgical management of complicated IE patients and highlight the importance of etiological characterization in clinical decision-making.

Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials.

BACKGROUND: Concerns have been raised on the risk of lower limb amputations with SGLT-2 inhibitors. Aim of the present metanalysis is the assessment of the effect of SGLT-2inhibitors on peripheral artery disease and lower limb amputations in randomized controlled trials performed in patients with type 2 diabetes. METHODS: A Medline and Embase search for "Canaglifozin" OR "Dapaglifozin" OR "Empaglifozin" OR "Ertuglifozin" OR "Ipraglifozin" OR Tofoglifozin" OR "Luseoglifozin" was performed, collecting randomized clinical trials (duration > 12 weeks) up to December 1st, 2018, comparing SGLT-2i at approved dose with placebo or other active comparators different from SGLT-2 inhibitors. Furthermore, unpublished studies were searched in the www.clinicaltrials.gov register. Separate analyses were performed for individual molecules of the class. In addition, a separate analysis was performed for placebo-controlled trials. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes defined above. RESULTS: A total of 27 trials fulfilling the inclusion criteria was identified. The overall incidence of peripheral artery disease was increased with SGLT-2 inhibitors (MH-OR: 1.26 [1.04, 1.52]). The increase of risk was statistically significant only with canagliflozin. MH-OR for amputation in the three cardiovascular safety trials with SGLT-2 inhibitors was 1.22 [0.59-2.52]. CONCLUSIONS: At present, there is no reason to believe that empagliflozin or dapagliflozin increase the risk of either peripheral artery disease of lower limb amputations. Canagliflozin could be associated with a specific risk, which needs to be further investigated.

Intravascular lithotripsy for calcific coronary and peripheral artery stenoses.

Heavily calcified lesions may be difficult to dilate adequately with conventional balloons and stents, which causes frequent periprocedural complications and higher rates of target lesion revascularisation (TLR). High-pressure non-compliant balloon angioplasty may be of insufficient force to modify calcium and, even when successful, may be limited in its ability to modify the entire calcified lesion. Scoring and cutting balloons hold theoretical value but data to support their efficacy are lacking and, because of their high lesion crossing profile, they often fail to reach the target lesion. Rotational and orbital atherectomy target superficial calcium; however, deep calcium, which may still impact on vessel expansion and luminal gain, is not affected. Intravascular lithotripsy (IVL), based on lithotripsy for renal calculi, is a new technology which uses sonic pressure waves to disrupt calcium with minimal impact to soft tissue. Energy is delivered via a balloon catheter, analogous to contemporary balloon catheters, with transmission through diluted ionic contrast in a semi-compliant balloon inflated at low pressure with sufficient diameter to achieve contact with the vessel wall. With coronary and peripheral balloons approved in Europe, peripheral balloons approved in the USA and multiple new trials beginning, we review the indications for these recently introduced devices, summarise the clinical outcomes of the available trials and describe the design of ongoing studies.

Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications.

: Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.

Comparison of long-term outcome in anthracycline-related versus idiopathic dilated cardiomyopathy: a single centre experience.

AIMS: Cardiac dysfunction is a severe complication of anthracycline-containing anticancer therapy. The outcome of anthracycline-induced cardiomyopathy (AICM) compared with other non-ischaemic causes of heart failure (HF), such as idiopathic dilated cardiomyopathy (IDCM), is unresolved. The aim of this study was to compare the survival of AICM patients with an IDCM cohort followed at our centre from 1990 to 2016. METHODS AND RESULTS: We included 67 patients (67% female, 50 ± 15 years) with AICM, defined as onset of otherwise unexplained left ventricular ejection fraction (LVEF) ≤50% following anthracycline therapy, and 488 IDCM patients (28% female, 55 ± 12 years). Patients were followed with constantly optimized HF therapy, for 7.6 ± 5.5 and 8.1 ± 5.5 years, respectively. In both cohorts, 25% of patients reached the combined endpoint of death/heart transplantation. Overall survival rates at 5 and 10 years were similar (AICM: 86% and 61%, IDCM: 88% and 75%; P = 0.61), and so was cardiovascular survival (AICM: 91% and 76%, IDCM: 91% and 80%; P = 0.373), also after 1:1 propensity matching (P = 0.27) and adjusting for age, LVEF and left ventricular size. A trend toward higher all-cause mortality was present in AICM patients [hazard ratio (HR) 1.67, 95% confidence interval (CI) 0.95-2.92, P = 0.076]. No differences were observed between AICM and IDCM with regard to pharmacological HF therapy, but AICM patients were less likely to receive devices (13% vs. 41.8% in IDCM, P < 0.001). CONCLUSION: Cardiovascular mortality in patients with AICM did not differ from that of a matched IDCM cohort, despite cancer-related morbidity and less prevalent use of devices. These data suggest that patients with AICM should be treated with appropriate guideline-directed medical therapies similar to other non-ischaemic dilated cardiomyopathies.

Timing of invasive septal reduction therapies and outcome of patients with obstructive hypertrophic cardiomyopathy.

BACKGROUND: Whether early vs. delayed referral to septal reduction therapies (SRT, alcohol septal ablation or surgical myectomy) bears prognostic relevance in hypertrophic obstructive cardiomyopathy (HOCM) is unresolved. We analyzed the impact of SRT timing on the outcome of HOCM patients. METHODS: We followed 126 patients for 5 ±â€¯4 years after SRT (mean age 53 ±â€¯15 years; 55 post-ASA and 71 post-SM). Based on time-to-treatment (TTT; from HOCM diagnosis to SRT), patients were divided into three groups: "<3" years, N = 50; "3-5" years, N = 25; ">5" years, N = 51. RESULTS: Patients with TTT > 5 years were younger at diagnosis and more often had atrial fibrillation (AF). Left ventricular outflow tract (LVOT) gradients were comparable in the 3 TTT groups. Two patients died peri-operatively, all with TTT > 5. Long-term, 8 patients died (3 suddenly and 5 due to heart failure). Mortality increased progressively with TTT (2% vs. 4% vs. 12% for TTT "<3", "3-5", and ">5" years, p for trend = 0.039). Independent predictors of disease progression (new-onset AF, worsening to NYHA III/IV symptoms, re-intervention or death) were TTT ("3-5" vs. "<3" years: HR: 4.988, 95%CI: 1.394-17.843; ">5" vs. "<3" years: HR: 3.420, 95%CI: 1.258-9.293, overall p-value = 0.025), AF at baseline (HR: 1.896, 95%CI: 1.002-3.589, p = 0.036) and LVOT gradient (HR per mm Hg increase: 1.022, 95%CI: 1.007-1.024, p = 0.023). CONCLUSIONS: Delay in SRT referral has significant impact on long-term outcome of patients with HOCM, particularly when >5 years from first detection of gradient, even when successful relief of symptoms and gradient is achieved. Earlier interventions are associated with lower complication rates and better prognosis, suggesting the importance of timely SRT to maximize treatment benefit and prevent late HOCM-related complications.

Efficacy of Ranolazine in Patients With Symptomatic Hypertrophic Cardiomyopathy: The RESTYLE-HCM Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: The late sodium current inhibitor ranolazine reverses the main electrophysiological and mechanical abnormalities of human hypertrophic cardiomyopathy (HCM) cardiomyocytes in vitro, suggesting potential clinical benefit. We aimed to assess the effect of ranolazine on functional capacity, symptomatic status, diastolic function, and arrhythmias in HCM. METHODS AND RESULTS: In this multicenter, double-blind, phase 2 study, 80 adult patients with nonobstructive HCM (age 53±14 years, 34 women) were randomly assigned to placebo (n=40) or ranolazine 1000 mg bid (n=40) for 5 months. The primary end point was change in peak VO2 compared with baseline using cardiopulmonary exercise test. Echocardiographic lateral and septal E/E' ratio, prohormone brain natriuretic peptide levels, 24-hour Holter arrhythmic profile, and quality of life were assessed. Ranolazine was safe and well tolerated. Overall, there was no significant difference in VO2 peak change at 5 months in the ranolazine versus placebo group (delta 0.15±3.96 versus -0.02±4.25 mL/kg per minute; P=0.832). Ranolazine treatment was associated with a reduction in 24-hour burden of premature ventricular complexes compared with placebo (>50% reduction versus baseline in 61% versus 31%, respectively; P=0.042). However, changes in prohormone brain natriuretic peptide levels did not differ in the ranolazine compared with the placebo group (geometric mean median [interquartile range], -3 pg/mL [-107, 142 pg/mL] versus 78 pg/mL [-71, 242 pg/mL]; P=0.251). Furthermore, E/E' ratio and quality of life scores showed no significant difference. CONCLUSIONS: In patients with nonobstructive HCM, ranolazine showed no overall effect on exercise performance, plasma prohormone brain natriuretic peptide levels, diastolic function, or quality of life. The drug showed an excellent safety profile and was associated with reduced premature ventricular complex burden. Late sodium current inhibition does not seem to improve functional capacity in HCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-004507-20.

Abrupt Onset of Refractory Heart Failure Associated With Light-Chain Amyloidosis in Hypertrophic Cardiomyopathy.

Importance: The natural history of hypertrophic cardiomyopathy (HCM) is complex and may include progressive heart failure and severe left ventricular dysfunction. When disease progression is abrupt, however, other coexisting diseases should be ruled out. This may be difficult in the case of amyloidosis, which classically mimics HCM. Results: We present an example of severe clinical deterioration in a patient with HCM due to superimposed amyloid light-chain amyloidosis. A man in his 70s with a longstanding history of genetically confirmed HCM presented with rapid development of congestive heart failure over 6 months, in sharp contrast to a previously stable, asymptomatic clinical course. He was diagnosed as having the illness in his late 40s after a resuscitated cardiac arrest and regularly followed up on a yearly basis. His most recent electrocardiogram was profoundly changed from previous tracings, with marked and diffuse voltage reduction (QS in V1-V3) and inferolateral T-wave inversion. The echocardiogram showed an abrupt increase in the severity of left ventricular (LV) hypertrophy, with a concentric rather than asymmetric appearance, granular sparkling of the myocardium, biatrial enlargement, thickening of the mitral valve leaflets, and interatrial septum and mild pericardial effusion. Severe LV dysfunction with a restrictive LV filling pattern was evident, which is associated with LV outflow tract obstruction loss and right ventricle systolic impairment. Following hospital admission, multiple myeloma was diagnosed and confirmed by bone marrow biopsy and aspiration. Furthermore, abdominal fat aspiration showed amyloid deposition and confirmed the diagnosis of amyloid light-chain amyloidosis. Electrocardiograms, echocardiographic images, and videos presented in this report describe the abrupt and marked evolution of a sarcomeric to infiltrative cardiomyopathy, leading to an ominous outcome in which the patient died despite specific treatment. Conclusions and Relevance: While progression to the end-stage phase occurs over several years for patients with HCM and can be detected at relatively early stages, the abrupt onset of congestive heart failure is uncommon and should raise suspicion of other, superimposed cardiac diseases.

Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (ß-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy.

BACKGROUND: The 2 most commonly affected genes in hypertrophic cardiomyopathy (HCM) are MYH7 (ß-myosin heavy chain) and MYBPC3 (ß-myosin-binding protein C). Phenotypic differences between patients with mutations in these 2 genes have been inconsistent. Scarce data exist on the genotype-phenotype association as assessed by tomographic imaging using cardiac magnetic resonance imaging. METHODS AND RESULTS: Cardiac magnetic resonance imaging was performed on 358 consecutive genotyped hypertrophic cardiomyopathy probands at 5 tertiary hypertrophic cardiomyopathy centers. Genetic testing revealed a pathogenic mutation in 159 patients (44.4%). The most common genes identified were MYH7 (n=53) and MYBPC3 (n=75); 33.1% and 47% of genopositive patients, respectively. Phenotypic characteristics by cardiac magnetic resonance imaging of these 2 groups were similar, including left ventricular volumes, mass, maximal wall thickness, morphology, left atrial volume, and mitral valve leaflet lengths (all P=non-significant). The presence of late gadolinium enhancement (65% versus 64%; P=0.99) and the proportion of total left ventricular mass (%late gadolinium enhancement; 10.4±13.2% versus 8.5±8.5%; P=0.44) were also similar. CONCLUSIONS: This multicenter multinational study shows lack of phenotypic differences between MYH7- and MYBPC3-associated hypertrophic cardiomyopathy when assessed by cardiac magnetic resonance imaging. Postmutational mechanisms appear more relevant to thick-filament disease expression and outcome than the disease-causing variant per se.

Contemporary Natural History and Management of Nonobstructive Hypertrophic Cardiomyopathy.

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.