Background-The clinical course of patients with hypertrophic cardiomyopathy and advanced heart failure (HF) subtended by progressive left ventricular dysfunction has received limited attention. Our aim was to assess the outcome of HF and impact of treatment options including the implantable cardioverter-defibrillator and heart transplantation (HT) in patients with hypertrophic cardiomyopathy evaluated at 2 Italian referral centers >3 decades. Methods and Results-All-cause mortality and a combined end point including death, HT, or appropriate implantable cardioverter-defibrillator shock were assessed in 71 consecutive patients with HF not related to outflow obstruction (7% of the entire hypertrophic cardiomyopathy cohort) followed up for 6.1±6.9 years after development of New York Heart Association class III to IV symptoms. At enrollment, left ventricular ejection fraction was <50% in 55 patients and >50% in 16; all had restrictive left ventricular filling. During follow-up, 35 patients died (49%%; 5-year rate, 49%) and 53 met the combined end point (75%; 5-year rate, 62%). Most events occurred in the 3 years after HF onset (17% per year compared with only 3% per year subsequently). Appropriate implantable cardioverter-defibrillator shocks occurred in 11 of 34 implanted patients. Of 37 patients evaluated for HT, 14 were transplanted, 10 listed, and 13 excluded; 2 early post-HT deaths occurred in patients with elevated pulmonary vascular resistance. Eleven of the 14 HT patients were alive at 10±8 years. Conclusions-In hypertrophic cardiomyopathy, advanced HF not associated with outflow obstruction portends a severely unfavorable prognosis, particularly in the first 3 years after onset of symptoms, despite frequently preserved systolic function in about one quarter of the patients. Outcome of HT is favorable but requires early consideration, as the window of opportunity may be short. (Circ Heart

twitter: @dr_pavia // @fernidom Tweet: "Natural history study of PRKAG2 syndrome reveals high rates of AF, conduction disease, advanced HF and life-threatening arrhythmias." ABSTRACT Background: PRKAG2 gene variants cause a syndrome characterised by cardiomyopathy, conduction disease and ventricular preexcitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. Objectives: To describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. Methods: We retrospectively studied clinical, electrocardiographic and echocardiographic data from 90 individuals with PRKAG2 variants (53% males, median 33 years (IQR: 15-50) recruited from 27 centers. Results: At first evaluation, 93% of patients were in NYHA functional class I or II. Maximum left ventricular (LV) wall thickness was 18±8 mm and LV ejection fraction was 61±12%. LV hypertrophy (LVH) was present in 60 (67%) subjects at baseline. Thirty patients (33%) had ventricular preexcitation or had undergone an accessory pathway ablation; 17 (19%) had a pacemaker (median age at implantation 36 years (IQR: 27-46)) and 16 (18%) had atrial fibrillation (AF) (median age 43 years (IQR: 31-54)). After a median follow-up of 6 years (IQR:2.3-13.9), 71% of individuals had LVH, 29% had AF, 21% a de novo pacemaker (median age at implantation 37 years (IQR: 29-48)), 14% required admission for heart failure (HF), 8% experienced sudden cardiac death or equivalent, 4% required a heart transplant and 13% died. Conclusions: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of AF, conduction disease, advanced HF and life-threatening arrhythmias. Classical features of preexcitation and severe LVH are not uniformly present and diagnosis should be considered in patients with LVH who develop AF or require a PPM at a young age.

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Background: Although disopyramide has been widely used to reduce left ventricular outflow obstruction (LVOTO) and to improve symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM), its use in real world as well as patient characteristics associated with a positive treatment response are still unclear. Methods: From 1980 to 2021, 1527 patients with HCM were evaluated and 372 (23%) had a LVOTO with active follow-up. The efficacy and safety of disopyramide were assessed systematically during 12 months (2-, 6-, and 12-month visits). Responders were patients with a final NYHA = I and a LVOTO < 30 mmHg; incomplete responders were those patients with NYHA > I and a LVOTO < 30 mmHg; and non-responders were symptomatic patients with no change in functional class NYHA and a LVOT gradient > 30 mmHg. Results: Two-hundred-fifty-four (66%) patients were in functional class NYHA I/II and 118 (34%) in NYHA III/IV. A total of 118/372 (32%, 55 ± 16 years) underwent disopyramide therapy. Twenty-eight (24%) patients responded to therapy, 39 (33%) were incomplete responders, and 51 (43%) did not respond. Responder were mainly patients in functional NYHA class I/II (24/28, 86%), whereas incomplete responders and non-responders were more often in functional NYHA class III/IV (50/54 (93%)). An independent predictor of response to disopyramide treatment was the presence of NYHA I/II at the initiation of therapy (HR 1.5 (95% CI 1.1–4.5), p = 0.03). No major life-threatening arrhythmic events or syncope occurred, despite 19 (16%) patients showing reduced QTc from baseline, 19 (16%) having no difference, while 80 (69%) patients had prolonged QTc interval. Thirty-one (26%) patients experienced side effects, in particular, 29 of the anticholinergic type. Conclusions: Disopyramide was underused in oHCM but effective in reducing LVOTO gradients and symptoms in slightly symptomatic patients with less severe disease phenotype with a safe pro-arrhythmic profile.

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