Hypertrophic cardiomyopathy - phenotypic variations beyond wall thickness.

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of another causal disease. Several morphologic and histologic changes have been described. Given the morbidity and mortality associated with HCM, understanding these anatomic variations is key to interpreting imaging. This is especially important since many patients exhibit these associated findings in the absence of LVH and prompt early detection of these variations may lead to early diagnosis and treatment. This article describes the appearance of morphologic variations seen in HCM beyond myocardial thickening including: papillary muscle and mitral valve variants, myocardial crypts, left ventricular myocardial bands, and dystrophic calcification related to increased wall tension.

Comorbidity Burden and Adverse Outcomes After Transcatheter Aortic Valve Replacement.

Background Transcatheter aortic valve replacement (TAVR) has become the preferred treatment for symptomatic patients with aortic stenosis and elevated procedural risk. Many deaths following TAVR are because of noncardiac causes and comorbid disease burden may be a major determinant of postprocedure outcomes. The prevalence of comorbid conditions and associations with outcomes after TAVR has not been studied. Methods and Results This was a retrospective single-center study of patients treated with TAVR from January 2015 to October 2018. The association between 21 chronic conditions and short- and medium-term outcomes was assessed. A total of 341 patients underwent TAVR and had 1-year follow-up. The mean age was 81.4 (SD 8.0) years with a mean Society of Thoracic Surgeons predicted risk of mortality score of 6.7% (SD 4.8). Two hundred twenty (65%) patients had ≥4 chronic conditions present at the time of TAVR. There was modest correlation between Society of Thoracic Surgeons predicted risk of mortality and comorbid disease burden (r=0.32, P<0.001). After adjusting for Society of Thoracic Surgeons predicted risk of mortality, age, and vascular access, each additional comorbid condition was associated with increased rates of 30-day rehospitalizations (odds ratio, 1.21; 95% CI, 1.02-1.44), a composite of 30-day rehospitalization and 30-day mortality (odds ratio, 1.20; 95% CI, 1.02-1.42), and 1-year mortality (odds ratio, 1.29; 95% CI, 1.05-1.59). Conclusions Comorbid disease burden is associated with worse clinical outcomes in high-risk patients treated with TAVR. The risks associated with comorbid disease burden are not adequately captured by standard risk assessment. A systematic assessment of comorbid conditions may improve risk stratification efforts.

Enhanced American College of Cardiology/American Heart Association Strategy for Prevention of Sudden Cardiac Death in High-Risk Patients With Hypertrophic Cardiomyopathy.

Importance: Strategies for reliable selection of high-risk patients with hypertrophic cardiomyopathy (HCM) for prevention of sudden cardiac death (SCD) with implantable cardioverter/defibrillators (ICDs) are incompletely resolved. Objective: To assess the reliability of SCD prediction methods leading to prophylactic ICD recommendations to reduce the number of SCDs occurring in patients with HCM. Design, Setting, and Participants: In this observational longitudinal study, 2094 predominantly adult patients with HCM consecutively evaluated over 17 years in a large HCM clinical center were studied. All patients underwent prospective ICD decision making relying on individual major risk markers derived from the HCM literature and an enhanced American College of Cardiology/American Heart Association (ACC/AHA) guidelines-based risk factor algorithm with complete clinical outcome follow-up. Data were collected from June 2017 to February 2018, and data were analyzed from February to July 2018. Main Outcomes and Measures: Arrhythmic SCD or appropriate ICD intervention for ventricular tachycardia or ventricular fibrillation. Results: Of the 2094 study patients, 1313 (62.7%) were male, and the mean (SD) age was 51 (17) years. Of 527 patients with primary prevention ICDs implanted based on 1 or more major risk markers, 82 (15.6%) experienced device therapy-terminated ventricular tachycardia or ventricular fibrillation episodes, which exceeded the 5 HCM-related SCDs occurring among 1567 patients without ICDs (0.3%), including 2 who declined device therapy, by 49-fold (95% CI, 20-119; P = .001). Cumulative 5-year probability of an appropriate ICD intervention was 10.5% (95% CI, 8.0-13.5). The enhanced ACC/AHA clinical risk factor strategy was highly sensitive for predicting SCD events (range, 87%-95%) but less specific for identifying patients without SCD events (78%). The C statistic calculated for enhanced ACC/AHA guidelines was 0.81 (95% CI, 0.77-0.85), demonstrating good discrimination between patients who did or did not experience an SCD event. Compared with enhanced ACC/AHA risk factors, the European Society of Cardiology risk score retrospectively applied to the study patients was much less sensitive than the ACC/AHA criteria (34% [95% CI, 22-44] vs 95% [95% CI, 89-99]), consistent with recognizing fewer high-risk patients. Conclusions and Relevance: A systematic enhanced ACC/AHA guideline and practice-based risk factor strategy prospectively predicted SCD events in nearly all at-risk patients with HCM, resulting in prophylactically implanted ICDs that prevented many catastrophic arrhythmic events in this at-risk population.

Impact of Effective Management Strategies on Patients With the Most Extreme Phenotypic Expression of Hypertrophic Cardiomyopathy.

Advances in treatment options for hypertrophic cardiomyopathy (HC) have proven effective in many patients for promoting favorable long-term outcomes. Whether this expectation is similar for patients with the most extreme expression of massive left ventricular (LV) hypertrophy, a particularly aggressive form of the disease is unresolved. Of 1,766 consecutive HC patients presenting to Tufts HC Institute (2004 to 2015), 92 were identified with extreme LV wall thickness (30 to 48 mm), and compared with 1,674 HC patients with less marked hypertrophy (13 to 29 mm). Follow-up assessment was over 5.3 ± 3.4 years. Patients with massive LV hypertrophy (n = 92) had higher sudden death event rates (3.0%/year) than did patients with lesser hypertrophy (0.8%/year; p <0.001). In 16 of the 92 patients (17%), potentially lethal ventricular tachyarrhythmia were successfully aborted by primary prevention implantable cardioverter defibrillator (ICD) therapy at 30 ± 13 years (n = 11), or by resuscitated cardiac arrest with external defibrillation (n = 5) and later by secondary prevention interventions (n = 3); no patient experienced arrhythmic sudden death. Aborted sudden death events (3.0%/year) exceeded HC-related mortality by 7-fold (n = 2; 0.4%/year; p <0.001). European Society of Cardiology risk score would have failed to identify 60% of patients with arrhythmic sudden death events, leaving them exposed to sudden death without ICDs. In addition, 35 patients required surgical myectomy for progressive heart failure due to LV outflow obstruction (improved to NYHA I/II in 30). Eighty-eight (96%) of the 92 patients have survived to age 38 ± 14 years (23% ≥ 50 years). All-cause mortality did not differ from an age and gender-matched general population (p = 0.62). In conclusion, in this referral-based population, patients with the most extreme expression of HC are at increased arrhythmic sudden death risk reliably prevented with prophylactic ICDs. Progressive heart failure secondary to outflow obstruction was reversible with surgical myectomy. Despite extreme phenotypic expression, with contemporary treatment interventions young HC patients have an opportunity to achieve extended survival with good quality of life.

Epoxyeicosatrienoic Acid as Therapy for Diabetic and Ischemic Cardiomyopathy.

Cardiovascular disease remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves epoxyeicosatrienoic acid (EET) and soluble epoxide hydroxylase (sEH) inhibition. sEH is the enzyme that converts EET to its less potent metabolite; therefore, EET is upregulated by its inhibitor. EET has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin sensitivity. Recent reports indicate that EET agonists and sEH inhibitors are capable of not only reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, which is a hallmark of cardiomyopathy and the metabolic syndrome. EET agonists and sEH inhibitors are in development as potential therapies, and at least one drug is already in clinical trials. This review examines the activity of EET in biological systems, proposes a series of pathways to explain its mechanism of action, and discusses how these might be exploited for potential therapeutic use.

Multicomponent synthesis of substituted and fused-ring imidazoles via phospha-münchnone cycloaddition.

A new, one-pot synthesis of imidazoles from imines, acid chlorides, and N-nosyl imines or tethered nitriles is reported. The reaction is mediated by the phosphonite PPh(catechyl) and proceeds via regioselective cycloaddition with an in situ-generated phospha-münchnone 1,3-dipole. This provides an efficient route to construct both highly substituted and polycyclic imidazoles directly from available substrates, without metal catalysts, and with access to product diversity.