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1.
Artigo em Inglês | MEDLINE | ID: mdl-33284039

RESUMO

Background - The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts. Methods - Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed. Results - Of 5,873 patients (3,788 genotyped), 2,226 (37.9%) were women. At baseline, women were older (49.0±19.9 vs. 42.9±18.4 years, p<0.001) and more likely to have pathogenic/likely-pathogenic sarcomeric variants (SARC+; 51% vs 43%, p<0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (p<0.02) except for patients with MYH7 variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 vs 33.3±16.8 years, p=0.39). Over 7.7 median years of follow up, NYHA III-IV heart failure (HF) was more common in women (HR 1.87, CI 1.48-2.36, p<0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, SARC+, age and hypertension. All-cause mortality was increased in women (HR 1.50, CI 1.13-1.99, p<0.01), but neither ICD utilization nor ventricular arrhythmia varied by sex. Conclusions - In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe HF symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.

4.
Lancet ; 396(10253): 759-769, 2020 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-32871100

RESUMO

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.


Assuntos
Benzilaminas/uso terapêutico , Miosinas Cardíacas/antagonistas & inibidores , Cardiomiopatia Hipertrófica/tratamento farmacológico , Uracila/análogos & derivados , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Benzilaminas/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Método Duplo-Cego , Tolerância ao Exercício/fisiologia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Avaliação de Resultados da Assistência ao Paciente , Uracila/efeitos adversos , Uracila/uso terapêutico
5.
Circ Genom Precis Med ; 13(5): 396-405, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32841044

RESUMO

BACKGROUND: Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations. METHODS: Patients with hypertrophic cardiomyopathy and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry. Variant types and locations were analyzed, morphological severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro. RESULTS: Among 4756 genotyped patients with hypertrophic cardiomyopathy in Sarcomeric Human Cardiomyopathy Registry, 1316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or nontruncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5'-3' quartiles or by founder variant subgroup). Nontruncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, P<0.001 versus Genome Aggregation Database common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ≈90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type. CONCLUSIONS: Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Nontruncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss of function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating versus nontruncating variants.

7.
Am Heart J ; 225: 108-119, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480058

RESUMO

INTRODUCTION: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. METHODS AND RESULTS: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13). CONCLUSION: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Heterozigoto , Mutação com Perda de Função , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Proteínas Quinases/genética , Anormalidades Múltiplas/genética , Adulto , Idade de Início , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 15/genética , Ecocardiografia , Eletrocardiografia , Humanos , Lactente , Fenótipo
8.
Circulation ; 141(23): 1872-1884, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32372669

RESUMO

BACKGROUND: Mutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series. METHODS: Clinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. RESULTS: DSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant). CONCLUSIONS: DSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.

9.
J Am Coll Cardiol ; 75(21): 2649-2660, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32466879

RESUMO

BACKGROUND: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. OBJECTIVES: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

10.
Heart Rhythm ; 17(10): 1704-1710, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32454220

RESUMO

BACKGROUND: Mutations in LMNA cause an arrhythmogenic cardiomyopathy (cardiolaminopathy) with high risk of ventricular tachycardia (VT). The natural history of VT among patients with cardiolaminopathy is incompletely understood. OBJECTIVE: The purpose of this study was to determine the longitudinal burden and progression of VT, including change in tachycardia cycle length (TCL), response to antitachycardia pacing (ATP), and prognostic significance of high-burden VT (>5 episodes of VT at any device interrogation) in cardiolaminopathy patients. METHODS: Patients with cardiolaminopathy and an implantable cardioverter-defibrillator (ICD) were identified from a single-center database. Serial device interrogations and medical records were used to collect data on VT burden, TCL, and response to ATP. RESULTS: Cardiolaminopathy patients with primary (n = 27) or secondary prevention (n = 16) ICDs were followed for 2 years (interquartile range [IQR] 1-5). VT burden was substantially higher in patients receiving secondary prevention ICDs (28 ± 40.9 vs 3.6 ± 7.3 episodes per 100 patient-years; P <.001). ATP was highly effective (94%) at terminating VT except for short TCL (<250 ms), for which ATP failed in 60%. Among patients with recurrent VT, TCL increased by 112 ± 93.6 ms during follow-up. Inappropriate shocks were rare (0.4% of all therapies). Median time to transplantation, ventricular assist device, or death was 18 months (IQR 0.7-27.1) in patients with high-burden VT. CONCLUSION: In patients with cardiolaminopathy, VT is recurrent and highly responsive to ATP, which supports the use of transvenous ICDs iteratively programmed to manage VT of various TCLs. Onset of high-burden VT indicates poor prognosis and should warrant referral to a heart failure specialist.

11.
Circulation ; 141(17): 1371-1383, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32228044

RESUMO

BACKGROUND: The term "end stage" has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (LVSD), defined as occurring when left ventricular ejection fraction is <50%. The prognosis of HCM-LVSD has reportedly been poor, but because of its relative rarity, the natural history remains incompletely characterized. METHODS: Data from 11 high-volume HCM specialty centers making up the international SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development. RESULTS: From a cohort of 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD. Overall, 75% of patients with HCM-LVSD experienced clinically relevant events, and 35% met the composite outcome (all-cause death [n=128], cardiac transplantation [n=55], or left ventricular assist device implantation [n=9]). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial individual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (hazard ratio [HR], 5.6 [95% CI, 2.3-13.5]), atrial fibrillation (HR, 2.6 [95% CI, 1.7-3.5]), and left ventricular ejection fraction <35% (HR, 2.0 [95% CI, 1.3-2.8]). The incidence of new HCM-LVSD was ≈7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater left ventricular cavity size (HR, 1.1 [95% CI, 1.0-1.3] and wall thickness (HR, 1.3 [95% CI, 1.1-1.4]), left ventricular ejection fraction of 50% to 60% (HR, 1.8 [95% CI, 1.2, 2.8]-2.8 [95% CI, 1.8-4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR, 2.3 [95% CI, 1.0-4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR, 1.5 [95% CI, 1.0-2.1] and 2.5 [95% CI, 1.2-5.1], respectively). CONCLUSIONS: HCM-LVSD affects ≈8% of patients with HCM. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death equivalent an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and the risk for incident development of HCM-LVSD (thin filament variants).

12.
Curr Cardiol Rep ; 22(2): 8, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980956

RESUMO

PURPOSE OF REVIEW: Genetic studies have identified an increasing number of culprit disease genes in patients with dilated cardiomyopathy (DCM). While these studies were originally conducted in patients with primary DCM, recent research has identified culprit mutations among patients who develop DCM in response to an environmental exposure. This review will summarize the genetic architecture of DCM secondary to alcohol, anthracyclines, and pregnancy, as well as the potential modifying role of exercise. RECENT FINDINGS: Mutations in DCM-associated genes are identified in 10-20% of patients categorized as having a secondary cardiomyopathy, a similar frequency to patients with primary DCM. The most commonly mutated gene is TTN, which encodes the sarcomere protein titin. Clinical outcomes differ among patients with or without an identifiable mutation. Genetic contributors should be sought in patients with presumed secondary cardiomyopathy. Future studies are necessary to determine the prospective management of previously unaffected patients known to have a DCM-associated mutation at the time of pregnancy or exposure to cardiotoxins.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Antraciclinas/efeitos adversos , Cardiomiopatias/genética , Cardiomiopatia Dilatada/genética , Conectina/genética , Mutação/genética , Cardiomiopatia Dilatada/metabolismo , Conectina/metabolismo , Exposição Ambiental , Exercício Físico , Feminino , Humanos , Gravidez , Estudos Prospectivos
13.
Clin Cardiol ; 43(1): 43-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31721249

RESUMO

BACKGROUND: In patients hospitalized with acute heart failure (AHF), low urine sodium concentration (UNa ) after diuretic treatment may identify patients at risk for longer length of stay (LOS) and adverse events. We investigated the prognostic significance of 24-hour cumulative postdiuretic urine sodium concentration in a multicenter clinical trial population. METHODS: The Renal Optimization Strategies Evaluation AHF (ROSE AHF) trial randomized 360 patients with AHF and renal dysfunction receiving intravenous diuretic to dopamine, nesiritide, or placebo. Sodium concentration was measured in cumulative urine sample collected during the first 24 hours after randomization in 298 patients. Based on prior studies, lower UNa was defined as ≤60 mmol/L. RESULTS: Lower UNa was present in 142 (48%) patients, who had longer LOS (7 days vs 5 days, P < .001) and less 72-hour weight loss (5.7 lb vs 9.0 lb, P < .001). These associations persisted after controlling for baseline estimated glomerular filtration rate and outpatient furosemide dose. Lower UNa did not modify the null effects of dopamine or nesiritide on clinical outcomes. Results were similar for spot rather than cumulative 24-hour UNa concentration. CONCLUSION: In patients hospitalized for AHF and renal dysfunction, UNa ≤ 60 mmol/L during the first 24 hours of diuresis identifies patients at risk for prolonged hospitalization but does not provide an indication for adjunctive dopamine or nesiritide.


Assuntos
Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/urina , Tempo de Internação/estatística & dados numéricos , Insuficiência Renal/tratamento farmacológico , Sódio/urina , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Diuréticos/uso terapêutico , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal/etiologia , Fatores de Risco , Estados Unidos/epidemiologia
14.
JAMA Cardiol ; 5(1): 83-91, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31799990

RESUMO

Importance: Racial differences are recognized in multiple cardiovascular parameters, including left ventricular hypertrophy and heart failure, which are 2 major manifestations of hypertrophic cardiomyopathy. The association of race with disease expression and outcomes among patients with hypertrophic cardiomyopathy is not well characterized. Objective: To assess the association between race, disease expression, care provision, and clinical outcomes among patients with hypertrophic cardiomyopathy. Design, Setting, and Participants: This retrospective cohort study included data on black and white patients with hypertrophic cardiomyopathy from the US-based sites of the Sarcomeric Human Cardiomyopathy Registry from 1989 through 2018. Exposures: Self-identified race. Main Outcomes and Measures: Baseline characteristics; genetic architecture; adverse outcomes, including cardiac arrest, cardiac transplantation or left ventricular assist device implantation, implantable cardioverter-defibrillator therapy, all-cause mortality, atrial fibrillation, stroke, and New York Heart Association (NYHA) functional class III or IV heart failure; and septal reduction therapies. The overall composite outcome consists of the first occurrence of any component of the ventricular arrhythmic composite end point, cardiac transplantation, left ventricular assist device implantation, NYHA class III or IV heart failure, atrial fibrillation, stroke, or all-cause mortality. Results: Of 2467 patients with hypertrophic cardiomyopathy at the time of analysis, 205 (8.3%) were black (130 male [63.4%]; mean [SD] age, 40.0 [18.6] years) and 2262 (91.7%) were white (1351 male [59.7%]; mean [SD] age, 45.5 [20.5] years). Compared with white patients, black patients were younger at the time of diagnosis (mean [SD], 36.5 [18.2] vs 41.9 [20.2] years; P < .001), had higher prevalence of NYHA class III or IV heart failure at presentation (36 of 205 [22.6%] vs 174 of 2262 [15.8%]; P = .001), had lower rates of genetic testing (111 [54.1%] vs 1404 [62.1%]; P = .03), and were less likely to have sarcomeric mutations identified by genetic testing (29 [26.1%] vs 569 [40.5%]; P = .006). Implantation of implantable cardioverter-defibrillators did not vary by race; however, invasive septal reduction was less common among black patients (30 [14.6%] vs 521 [23.0%]; P = .007). Black patients had less incident atrial fibrillation (35 [17.1%] vs 608 [26.9%]; P < .001). Black race was associated with increased development of NYHA class III or IV heart failure (hazard ratio, 1.45; 95% CI, 1.08-1.94) which persisted on multivariable Cox proportional hazards regression (hazard ratio, 1.97; 95% CI, 1.34-2.88). There were no differences in the associations of race with stroke, ventricular arrhythmias, all-cause mortality, or the overall composite outcome. Conclusions and Relevance: The findings suggest that black patients with hypertrophic cardiomyopathy are diagnosed at a younger age, are less likely to carry a sarcomere mutation, have a higher burden of functionally limited heart failure, and experience inequities in care with lower use of invasive septal reduction therapy and genetic testing compared with white patients. Further study is needed to assess whether higher rates of heart failure may be associated with underlying ancestry-based disease pathways, clinical management, or structural inequities.

15.
J Voice ; 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33388230

RESUMO

INTRODUCTION: Inducible laryngeal obstruction is a common and challenging cause of exertional dyspnea. We report a case of an unanticipated cardiac condition that presented with symptoms suggestive of inducible laryngeal obstruction. DISCUSSION: A 55-year-old man was evaluated for progressive exertional dyspnea and throat tightness, unexplained after multiple medical evaluations. Resting laryngeal examination was suspicious for laryngopharyngeal reflux and mild vocal fold adduction during quiet expiration. Given progressive and refractory symptoms, maximal cardiopulmonary exercise testing with intermittent laryngeal examination was performed. This study excluded laryngeal causes of exercise limitation and led to an unexpected diagnosis of persistent atrial flutter and hypertrophic cardiomyopathy. CONCLUSION: Cardiopulmonary exercise testing with laryngeal examination can identify unexpected and life-threatening mimics of inducible laryngeal obstruction that may be missed by unmonitored exercise challenges. Suspicion for inducible laryngeal obstruction at rest may not predict the true nature of exercise limitation on cardiopulmonary exercise testing.

16.
Clin Cardiol ; 42(12): 1181-1188, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571248

RESUMO

BACKGROUND: Patient limitations guide selection of heart failure therapies, for which indications often specify New York Heart Association Class. OBJECTIVES: To determine the extent of patient-reported limitations during daily activities and compare to New York Heart Association class assigned by providers during the same visit, and to left ventricular ejection fraction (LVEF) group. METHODS AND RESULTS: While waiting for their appointment, 948 patients on return visits to an ambulatory HF clinic completed a written questionnaire assessing specific activity limitations, which were compared to physician-assigned NYHA class during the same visit. Patient-reported limitation to perform daily activity ranged from 25% for bathing to 61% for yardwork or housework and 71% for jogging or hurrying. Most patients who did not report limitations to perform daily life activities were correctly classified as NYHA I by the physicians (76%), but 12% of the 376 patients classified as NYHA I reported limitations to showering or bathing and 73% reported limitations while doing yardwork or house work. Limitation to walking was reported by 172 patients (50%) classified as class II. Limitations to walking one block were most common in patients with LVEF ≥40% compared to patients with LVEF <40%, and least commonly, in HF with better EF (improved from 31 ± 13 to 52 ± 7). CONCLUSIONS: Activity limitations are commonly reported by ambulatory HF patients, but underestimated by physicians. It is not clear how this should guide therapy validated for NYHA class but focused activity questions may merit wider use to track limitations and improvement in ambulatory HF.


Assuntos
Atividades Cotidianas , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Volume Sistólico , Inquéritos e Questionários , Função Ventricular Esquerda
17.
Mol Genet Genomic Med ; 7(11): e940, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31482667

RESUMO

BACKGROUND: Individuals with hypertrophic cardiomyopathy (HCM), even when asymptomatic, are at-risk for sudden cardiac death and stroke from arrhythmias, making it imperative to identify individuals affected by this familial disorder. Consensus guidelines recommend that first-degree relatives (FDRs) of a person with HCM undergo serial cardiovascular evaluations. METHODS: We determined the uptake of family screening in patients with HCM and developed an online video intervention to facilitate family communication and screening. Family screening and genetic testing data were collected through a prospective quality improvement initiative, a standardized clinical assessment and management plan (SCAMP), utilized in an established cardiovascular genetics clinic. Patients were prescribed an online video if screening of their FDRs was incomplete and a pilot study on video utilization and family communication was conducted. RESULTS: Two-hundred and sixteen probands with HCM were enrolled in SCAMP Phase I and 190 were enrolled in SCAMP Phase II. In both phases, probands reported that 51% of FDRs had been screened (382/749 in Phase I, 258/504 in Phase II). Twenty patients participated in a pilot study on video utilization and family communication. Nine participants reported watching the video and six participants reported sharing the video with relatives; however only one participant reported sharing the video with relatives who were not yet aware of the diagnosis of HCM in the family. CONCLUSION: Despite care in a specialized cardiovascular genetics clinic, approximately one half of FDRs of patients with HCM remained unscreened. Online interventions and videos may serve as supplemental tools for patients communicating genetic risk information to relatives.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Predisposição Genética para Doença , Testes Genéticos/métodos , Educação em Saúde/métodos , Programas de Rastreamento/psicologia , Sistemas On-Line , Participação do Paciente/psicologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/psicologia , Família , Feminino , Seguimentos , Testes Genéticos/tendências , Comunicação em Saúde , Promoção da Saúde/métodos , Humanos , Masculino , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Participação do Paciente/estatística & dados numéricos , Projetos Piloto , Prognóstico , Estudos Prospectivos
19.
J Am Coll Cardiol ; 74(3): 346-358, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31319917

RESUMO

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a variably penetrant disease increasingly identified in young patients. OBJECTIVES: This study sought to describe the diverse phenotype, genotype, and outcomes in pediatric and adolescent patients. METHODS: Records from 1999 to 2016 were reviewed for individuals age <21 years with a consistent personal or family history. Patients were categorized by right ventricular (RV), left dominant (LD), or biventricular subtypes using 2010 Task Force Criteria or proposed features of LD disease, encompassing electrocardiographic, structural, histological, and arrhythmic characteristics. Genetic variants classified as pathogenic and/or likely pathogenic by 2015 American College of Medical Genetics and Genomics criteria in recognized disease-associated genes were included. RESULTS: Manifest disease was evident in 32 patients (age 15.1 ± 3.8 years), of whom 22 were probands, including 16 RV, 7 LD, and 9 biventricular ACM. Nondiagnostic features were seen in 5 of 15 family members. RV disease was associated with cardiac arrest and ventricular tachycardia (p = 0.02) and prevalence of PKP2 variants (p < 0.01), whereas biventricular disease was associated with a younger age of onset (p = 0.02). LD ACM was associated with variants in DSP and LMNA, and biventricular ACM with more a diverse etiology in desmosomal genes. Cardiac arrest was observed in 5 probands (age 15.3 ± 1.9 years) and ventricular tachycardia in 10 (age 16.6 ± 2.7 years), 6 probands, and 4 family members. Features suggestive of myocardial inflammation were seen in 6 patients, with ventricular tachycardia and/or cardiac arrest in 3 patients. Cardiac transplantation was performed in 10 patients. There were no deaths. In RV and biventricular disease, electrocardiographic preceded imaging features, whereas the reverse was seen in LD disease. CONCLUSIONS: ACM in the young has highly varied phenotypic expression incorporating life-threatening arrhythmia, heart failure, and myocardial inflammation. Increased awareness of early onset, aggressive disease has important implications for patient management and familial screening.


Assuntos
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Adolescente , Fatores Etários , Criança , Feminino , Humanos , Masculino , Fenótipo , Estudos Retrospectivos
20.
Circ Cardiovasc Imaging ; 12(6): e008975, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31177817

RESUMO

Background The diagnostic yield of cardiac sarcoidosis (CS) by endomyocardial biopsy is limited. Fluorodeoxyglucose (FDG) positron emission tomography (PET) and cardiac magnetic resonance imaging (MRI) may facilitate noninvasive diagnosis, but the accuracy of this approach is not well defined. We aimed to correlate findings from FDG PET and cardiac MRI with histological findings from explanted hearts of patients who underwent cardiac transplantation. Methods We analyzed the explanted heart histology for all patients who underwent cardiac transplant at our center from April 2008 to July 2018 and had pretransplant FDG PET (n=18) or cardiac MRI (n=31). The likelihood of CS based on FDG PET or cardiac MRI was categorized in a blinded fashion using a previously published method. RESULTS: Using a CS probable cutoff for FDG PET resulted in a sensitivity of 100.0% (95% CI, 54.1%-100.0%) and a specificity of 33.3% (95% CI, 9.9%-65.1%). Three of the 9 CS probable by FDG PET cases were found to be arrhythmogenic cardiomyopathy. The test characteristics of cardiac MRI are more challenging to comment on using our data as there was only one confirmed case of CS on post-transplant histological assessment. Of the 8 CS highly probable or probable cases by cardiac MRI, 3 were found to be dilated cardiomyopathy, and 2 were found to be end-stage hypertrophic cardiomyopathy. Conclusions FDG PET and cardiac MRI can help facilitate the diagnosis of CS in patients with advanced heart failure with a high degree of sensitivity but lower specificity.


Assuntos
Cardiomiopatias/diagnóstico por imagem , Fluordesoxiglucose F18 , Transplante de Coração , Imagem por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Sarcoidose/diagnóstico por imagem , Humanos , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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