Association of Titin Variations With Late-Onset Dilated Cardiomyopathy.

IMPORTANCE: Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM). OBJECTIVE: To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM. DESIGN, SETTING, AND PARTICIPANTS: A population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. MAIN OUTCOMES AND MEASURES: The study outcome was all-cause mortality. RESULTS: A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67 [6] years; mean [SD] left ventricular ejection fraction, 32% [10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers of P/LP variants, while 6 patients (5.1%) were genotype-negative. CONCLUSIONS AND RELEVANCE: Late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients.

Clinical Implications of the Amyloidogenic V122I Transthyretin Variant in the General Population.

BACKGROUND: The V122I variant in transthyretin (TTR) is the most common amyloidogenic mutation worldwide. The aim of this study is to describe the cardiac phenotype and risk for adverse cardiovascular outcomes of young V122I TTR carriers in the general population. METHODS AND RESULTS: TTR genotypes were extracted from whole-exome sequence data in participants of the Dallas Heart Study. Participants with African ancestry, available V122I TTR genotypes (N = 1818) and either cardiac magnetic resonance imaging (n = 1364) or long-term follow-up (n = 1532) were included. The prevalence of V122I TTR carriers (45 ± 10 years) was 3.2% (n/N = 59/1818). The V122I TTR carriers had higher baseline left ventricular wall thickness (8.52 ± 1.82 vs 8.21 ± 1.62 mm, adjusted P = .038) than noncarriers, but no differences in other cardiac magnetic resonance imaging measures (P > .05 for all). Although carrier status was not associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline (P = .79), V122I TTR carriers had a greater increase in NT-proBNP on follow-up than noncarriers (median 28.5 pg/mL, interquartile range 11.4-104.1 pg/mL vs median 15.9 pg/mL, interquartile range 0.0-43.0 pg/mL, adjusted P = .018). V122I TTR carriers were at a higher adjusted risk of heart failure (hazard ratio 3.82, 95% confidence interval 1.80-8.13, P < .001), cardiovascular death (hazard ratio 2.65, 95% confidence interval 1.14-6.15, P = .023), and all-cause mortality (hazard ratio 1.95, 95% confidence interval 1.08-3.51, P = .026) in comparison with noncarriers. CONCLUSIONS: V122I TTR carrier status was associated with a greater increase in NT-proBNP, slightly greater left ventricular wall thickness, and a higher risk for heart failure, cardiovascular death, and all-cause mortality. These findings suggest the need to develop amyloidosis screening strategies for V122I TTR carriers.

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study.

BACKGROUND: Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. METHODS: We conducted a double-blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2 ) and minute ventilation/carbon dioxide production (VE/VCO2 ) slope (co-primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2 , ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12-week follow-up. RESULTS: The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM-1 min-1 , P = .036), VAT (+1.5 mL kg-1 min-1 , P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg-1 min-1 , P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (-12.1, P = .018). CONCLUSIONS: In this small and short-term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2 , VAT and quality of life.

Inhalant-Abuse Myocarditis Diagnosed by Cardiac Magnetic Resonance.

Multiple reports of toxic myocarditis from inhalant abuse have been reported. We now report the case of a 23-year-old man found to have toxic myocarditis from inhalation of a hydrocarbon. The diagnosis was made by means of cardiac magnetic resonance imaging with delayed enhancement. The use of cardiac magnetic resonance to diagnose myocarditis has become increasingly common in clinical medicine, although there is not a universally accepted criterion for diagnosis. We appear to be the first to document a case of toxic myocarditis diagnosed by cardiac magnetic resonance. In patients with a history of drug abuse who present with clinical findings that suggest myocarditis or pericarditis, cardiac magnetic resonance can be considered to support the diagnosis.

Use of aldosterone antagonists at discharge after myocardial infarction: results from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry-Get with the Guidelines (GWTG).

BACKGROUND: Aldosterone antagonists (AldA) improve survival after myocardial infarction (MI) in patients with left ventricular systolic dysfunction (ejection fraction [EF] <40%) concomitant with either clinical heart failure (HF) or diabetes mellitus (DM). Although current American College of Cardiology/American Heart Association guidelines provide a class I recommendation for AldA therapy in such patients, how US practice reflects these recommendations is unclear. METHODS: Using data from the National Cardiovascular Data Registry ACTION Registry-GWTG, we describe contemporary discharge AldA prescription patterns among 202,213 patients discharged after acute MI from 526 US sites participating in ACTION Registry-GWTG between January 2007 and March 2011. RESULTS: Overall, 10.0% of patients were eligible for AldA without documented contraindication, with only 14.5% of eligible patients receiving AldA at discharge. Among the subset of AldA-eligible patients discharged on otherwise optimal medical therapy (68.9%), AldAs were prescribed to 16.1%. Aldosterone antagonist use was higher in patients with EF <40% and clinical HF with or without DM (17.7% and 16.6%, respectively), compared with patients with EF <40% and DM without clinical HF (7.8%, P < .001 for each). Fewer than 2% of participating centers used AldA in ≥50% of eligible patients. CONCLUSIONS: Despite clinical outcome evidence and class I guideline recommendations, AldAs are underused in the United States, with only 1 in 7 eligible patients prescribed AldA at discharge after MI. This contrasts with high use of other evidence-based post-MI medications and identifies a specific gap in translation of evidence into clinical practice.

The natural history of new-onset heart failure with a severely depressed left ventricular ejection fraction: implications for timing of implantable cardioverter-defibrillator implantation.

BACKGROUND: Guidelines recommend that patients with new-onset systolic heart failure (HF) receive a trial of medical therapy before an implantable cardiac defibrillator (ICD). This strategy allows for improvement of left ventricular ejection fraction (LVEF), thereby avoiding an ICD, but exposes patients to risk of potentially preventable sudden cardiac death during the trial of medical therapy. METHODS: We reviewed a consecutive series of patients with HF of <6 months duration with a severely depressed LVEF (<30%) evaluated in a HF clinic (N = 224). The ICD implantation was delayed with plans to reassess LVEF approximately 6 months after optimization of ß-blockers. Mortality was ascertained by the National Death Index. RESULTS: Follow-up echocardiograms were performed in 115 of the 224 subjects. Of these, 50 (43%) had mildly depressed or normal LVEF at follow-up ("LVEF recovery") such that an ICD was no longer indicated. In a conservative sensitivity analysis (using the entire study cohort, whether or not a follow-up echocardiogram was obtained, as the denominator), 22% of subjects had LVEF recovery. Mortality at 6, 12, and 18 months in the entire cohort was 2.3%, 4.5%, and 6.8%, respectively. Of 87 patients who tolerated target doses of ß-blockers, only 1 (1.1%) died during the first 18 months. CONCLUSION: Patients with new-onset systolic HF have both a good chance of LVEF recovery and low 6-month mortality. Achievement of target ß-blocker dose identifies a very low-risk population. These data support delaying ICD implantation for a trial of medical therapy.