Olivotto, Iacopo

With stress echo (SE) 2020 study, a new standard of practice in stress imaging was developed and disseminated: the ABCDE protocol for functional testing within and beyond CAD. ABCDE protocol was the fruit of SE 2020, and is the seed of SE 2030, which is articulated in 12 projects: 1-SE in coronary artery disease (SECAD); 2-SE in diastolic heart failure (SEDIA); 3-SE in hypertrophic cardiomyopathy (SEHCA); 4-SE post-chest radiotherapy and chemotherapy (SERA); 5-Artificial intelligence SE evaluation (AI-SEE); 6-Environmental stress echocardiography and air pollution (ESTER); 7-SE in repaired Tetralogy of Fallot (SETOF); 8-SE in post-COVID-19 (SECOV); 9: Recovery by stress echo of conventionally unfit donor good hearts (RESURGE); 10-SE for mitral ischemic regurgitation (SEMIR); 11-SE in valvular heart disease (SEVA); 12-SE for coronary vasospasm (SESPASM). The study aims to recruit in the next 5 years (2021–2025) ≥10,000 patients followed for ≥5 years (up to 2030) from ≥20 quality-controlled laboratories from ≥10 countries. In this COVID-19 era of sustainable health care delivery, SE2030 will provide the evidence to finally recommend SE as the optimal and versatile imaging modality for functional testing anywhere, any time, and in any patient.

Coronary microvascular dysfunction (CMD) is an important primary feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and ventricular remodelling, and is predictive of adverse outcome. Whether there is any association between presence/severity of CMD and HCM’s pathogenic substrate remains to be determined. To address this issue, we used positron emission tomography (PET) to assess CMD in an HCM cohort that received comprehensive genetic testing for sarcomeric/myofilament-HCM. We measured maximum (intravenous dipyridamole, 0.56 mg/kg) myocardial blood flow (Dip-MBF), using 13 N-labeled ammonia and PET in 46 HCM patients (age 38±14 years, 32 male). Genetic testing was performed by denaturing high performance liquid chromatography and automatic DNA sequencing of nine myofilament-encoding genes including both thick filament proteins (myosin binding protein C, beta-myosin heavy chain, regulatory and essential light chains); and thin filament proteins (troponin-T, troponin-I, troponin-C, alpha-tropomyosin and alpha-actin). Results . Thirty-four mutations were identified in 30/46 patients (myofilament-HCM; 65%), including 29 with thick filament and 6 with thin filament mutations, as well as 4 with complex genotype. Despite similar age and clinical features, patients with myofilament-HCM showed lower Dip-MBF values than the patients with a negative genetic test (1.6±0.7 versus 2.2±0.9 ml/min/g, respectively; p=0.03). Specifically, 13/30 (43%) patients with myofilament-HCM had a Dip-MBF below the lower tertile for the study group (≤1.38 ml/min/g), compared to 2/16 (12%) patients with a negative genetic test (p=0.034). No difference in Dip-MBF was evident with respect to the particular sarcomeric gene involved (ANOVA p=0.63). HCM due to sarcomere gene mutations is characterized by more severe impairment in microvascular function compared to myofilament negative disease, irrespective of the involved contractile protein. These findings suggest that sarcomeric mutations might be implicated in adverse remodelling of the microcirculation in patients with HCM, and account for the greater prevalence of ventricular dysfunction and failure in this subset.

Introduction: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by dynamic LV outflow tract (LVOT) obstruction resulting from ventricular hypertrophy and mitral valve systolic anterior motion (SAM), and by elevated left ventricular (LV) filling pressures, all of which result in a significant morbidity despite medical therapy. Mavacamten (Mava) is a novel inhibitor of cardiac myosin that significantly reduces LVOT gradients in oHCM, noted initially in the phase 2 PIONEER and more recently in the phase 3 EXPLORER-HCM studies. Additional echocardiographic analyses were performed to investigate the effect of Mava on focused measures of cardiac structure and function in oHCM. Methods: EXPLORER-HCM (NCT03470545) was a multicenter, double-blind, placebo-controlled, phase 3 study that randomized symptomatic oHCM patients (LV ejection fraction ≥55% and resting and/or provoked LVOT gradient ≥50 mmHg) 1:1 to Mava vs placebo for 30 weeks. Echocardiograms were performed serially every 2-4 weeks over 30 weeks. Results: In total, 251 patients with oHCM were enrolled and 244 patients completed the study (mean age 58.5; 40.6% female). Compared to placebo, 30-week treatment with Mava led to significant reductions in LA volume index (-7.5 ml/m 2 , p<0.0001), lateral E/e’ (-3.8, p<0.0001), septal E/e’ (-3.4, p<0.0001), and LV mass index (-15.5 g/m 2 , p<0.0001) ( Table ). Significantly more Mava-treated patients achieved resolution of mitral valve SAM compared to placebo (80.9% vs 34.0% of patients; difference of 46.8%; p<0.0001) and mitral regurgitation (MR) (9.0% vs 0.0% of patients; difference of 9.0%; p=0.0006). Conclusions: Treatment with Mava for 30 weeks led to improvement in LV hypertrophy and markers of left-sided filling pressures (LA volume and E/e’). Furthermore, Mava treatment was associated with reduction of SAM and MR. These findings suggest that Mava has beneficial effects on several adverse pathophysiologic processes that are hallmarks of oHCM.

Background: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. Methods: EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. Conclusions: EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03470545.

AbstractHypertrophic cardiomyopathy (HCM) is a common inherited monogenic disease with a prevalence of 1/500 in the general population, representing an important cause of arrhythmic sudden cardiac death (SCD), heart failure, and atrial fibrillation in the young. HCM is a global condition, diagnosed in &gt;50 countries and in all continents. HCM affects people of both sexes and various ethnic and racial origins, with similar clinical course and phenotypic expression. The most unpredictable and devastating consequence of HCM is represented by arrhythmic SCD, most commonly caused by sustained ventricular tachycardia or ventricular fibrillation. Indeed, HCM represents one of the main causes of arrhythmic SCD in the young, with a marked preference for children and adults &lt;30 years. SCD is most prevalent in patients with paediatric onset of HCM but may occur at any age. However, risk is substantially lower after 60 years, suggesting that the potential for ventricular tachyarrhythmias is mitigated by ageing. SCD had been linked originally to sports and vigorous activity in HCM patients. However, it is increasingly clear that the majority of events occurs at rest or during routine daily occupations, suggesting that triggers are far from consistent. In general, the pathophysiology of SCD in HCM remains unresolved. While the pathologic and physiologic substrates abound and have been described in detail, specific factors precipitating ventricular tachyarrhythmias are still unknown. SCD is a rare phenomenon in HCM cohorts (&lt;1%/year) and attempts to identify patients at risk, while generating clinically useful algorithms for primary prevention, remain very inaccurate on an individual basis. One of the reasons for our limited understanding of these phenomena is that limited translational research exists in the field, while most efforts have focused on clinical markers of risk derived from pathology, instrumental patient evaluation, and imaging. Specifically, few studies conducted in animal models and human samples have focused on targeting the cellular mechanisms of arrhythmogenesis in HCM, despite potential implications for therapeutic innovation and SCD prevention. These studies found that altered intracellular Ca2+ homoeostasis and increased late Na+ current, leading to an increased likelihood of early and delayed after-depolarizations, contribute to generate arrhythmic events in diseased cardiomyocytes. As an array of novel experimental opportunities have emerged to investigate these mechanisms, including novel ‘disease-in-the-dish’ cellular models with patient-specific induced pluripotent stem cell-derived cardiomyocytes, important gaps in knowledge remain. Accordingly, the aim of the present review is to provide a contemporary reappraisal of the cellular basis of SCD-predisposing arrhythmias in patients with HCM and discuss the implications for risk stratification and management.

Background Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or ‘modifier genes’. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins. Methods We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy. Results Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy. Conclusions Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.

Background: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. Methods: This was an observational, retrospective, longitudinal cohort study. Results: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9–3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93–1.12), C-index of 0.70 (95% CI, 0.68–0.72), and D-statistic of 1.17 (95% CI, 1.05–1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8–2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96–13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. Conclusions: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.