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2.
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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33283874

RESUMO

Objective This longitudinal study aimed to measure precarious employment in the US using a multidimensional indicator. Methods We used data from the National Longitudinal Survey of Youth (1988-2016) and the Occupational Information Network database to create a longitudinal precarious employment score (PES) among 7568 employed individuals over 18 waves (N=101 290 observations). We identified 13 survey indicators to operationalize 7 dimensions of precarious employment, which we included in our PES (range: 0-7, with 7 indicating the most precarious): material rewards, working-time arrangements, stability, workers' rights, collective organization, interpersonal relations, and training. Using generalized estimating equations, we estimated the mean PES and change over time in the PES overall and by race/ethnicity, gender, education, income, and region. Results On average, the PES was 3.17 [standard deviation (SD) 1.19], and was higher among women (3.34, SD 1.20), people of color (Hispanics: 3.24, SD 1.23; non-Hispanic Blacks: 3.31, SD 1.23), those with less education (primary: 3.99, SD 1.07; high school: 3.43, SD 1.19), and with lower-incomes (3.84, SD 1.08), and those residing in the South (3.23, SD 1.17). From 1988 to 2016, the PES increased by 9% on average [0.29 points; 95% confidence interval (CI) 0.26-0.31]. While precarious employment increased over time across all subgroups, the increase was largest among males (0.35 points; 95% CI 0.33-0.39), higher-income (0.39 points; 95% CI 0.36-0.42) and college-educated (0.37 points; 95% CI 0.33-0.41) individuals. Conclusions Long-term decreases in employment quality are widespread in the US. Women and those from racialized and less-educated populations remain disproportionately precariously employed; however, we observed the largest increases among men, college graduates and higher-income individuals.

5.
West J Nurs Res ; : 193945920970229, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33158412

RESUMO

Recruiting participants with chronic medical conditions is time-consuming and expensive. Electronic medical record databases and patient portals may enable outreach to larger numbers of patients in comparison to face-to-face methods. We aimed to describe the yields, benefits, and limitations of recruitment strategies used for a randomized clinical trial of cognitive behavioral therapy for insomnia among patients with chronic stable heart failure (NCT02660385). We used multiple recruitment strategies including clinic-based recruitment, letters to patients identified from electronic databases, the patient portal, brochures and posters placed in clinics, presentations to heart failure support groups, and online advertising. We screened 10,291 medical records, enrolled 231 participants, and 195 participants completed baseline data collection. We enrolled 92 (23%) participants using clinic-based recruitment, 24 and 29 (6% and 10%) using letters to patients from two electronic databases, and 42 (55%) via the patient portal. Multiple recruitment strategies and flexibility are needed to achieve recruitment goals.

6.
Heart Fail Rev ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33215323

RESUMO

Psychological stress is common in patients with heart failure, due in part to the complexities of effective disease self-management and progressively worsening functional limitations, including frequent symptom exacerbations and hospitalizations. Emerging evidence suggests that heart failure patients who experience higher levels of stress may have a more burdensome disease course, with diminished quality of life and increased risk for adverse events, and that multiple behavioral and pathophysiological pathways are involved. Furthermore, the reduced quality of life associated with heart failure can serve as a life stressor for many patients. The purpose of this review is to summarize the current state of the science concerning psychological stress in patients with heart failure and to discuss potential pathways responsible for the observed effects. Key knowledge gaps are also outlined, including the need to understand patterns of exposure to various heart failure-related and daily life stressors and their associated effects on heart failure symptoms and pathophysiology, to identify patient subgroups at increased risk for stress exposure and disease-related consequences, and the effect of stress specifically for patients who have heart failure with preserved ejection fraction. Stress is a potentially modifiable factor, and addressing these gaps and advancing the science of stress in heart failure is likely to yield important insights about actionable pathways for improving patient quality of life and outcomes.

7.
ASAIO J ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33074860

RESUMO

Lymphopenia has been implicated in poor outcomes in the heart failure population. However, the prognostic implication of lymphopenia in left ventricular assist device (LVAD) patients is unknown. We examine the impact of lymphopenia on all-cause mortality in this population over a 24-month period post-implantation. A total of 170 patients between June 2011 and July 2018 receiving permanent durable LVAD at a single center formed the study population. Criteria for lymphopenia on admission, defined as an absolute lymphocyte count (ALC) <1500 cells/µl, was met in 99 patients. A total of 11 patients were excluded: two with ALC >4800/µl and nine with incomplete data. Survival across groups was compared with a Kaplan-Meier plot and log-rank statistics. The Cox proportional hazard model was used to examine the association between lymphopenia and 24-month all-cause mortality. In the lymphopenia group, mean ALC was 909.6 ± 331.9 versus 2073.6 ± 501.1 in the non-lymphopenic group. Twenty-four-month all-cause mortality was significantly higher in the lymphopenia group (p = 0.009). The lymphopenic patients had worse unadjusted (hazard ratio [HR] = 2.14, confidence interval [CI] = 1.19-3.82; p = 0.01) and adjusted survival (HR = 2.07, CI = 1.13-3.79; p = 0.02). Further clinical investigations are required to assess the utility of continued clinical monitoring of ALC levels beyond LVAD placement.

8.
Genet Med ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33046849

RESUMO

PURPOSE: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene-disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance. METHODS: We developed a disease-specific variant classifier, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias. We assessed CardioBoost's ability to discriminate known pathogenic from benign variants, prioritize disease-associated variants, and stratify patient outcomes. RESULTS: CardioBoost has high global discrimination accuracy (precision recall area under the curve [AUC] 0.91 for cardiomyopathies; 0.96 for arrhythmias), outperforming existing tools (4-24% improvement). CardioBoost obtains excellent accuracy (cardiomyopathies 90.2%; arrhythmias 91.9%) for variants classified with >90% confidence, and increases the proportion of variants classified with high confidence more than twofold compared with existing tools. Variants classified as disease-causing are associated with both disease status and clinical severity, including a 21% increased risk (95% confidence interval [CI] 11-29%) of severe adverse outcomes by age 60 in patients with hypertrophic cardiomyopathy. CONCLUSIONS: A disease-specific variant classifier outperforms state-of-the-art genome-wide tools for rare missense variants in inherited cardiac conditions ( https://www.cardiodb.org/cardioboost/ ), highlighting broad opportunities for improved pathogenicity prediction through disease specificity.

9.
Behav Sleep Med ; : 1-13, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33048589

RESUMO

OBJECTIVE: Examine the bidirectional relationships between within-person day-to-day fluctuations in physical activity (PA) and sleep characteristics among people with heart failure (HF) and insomnia. PARTICIPANTS: Ninety-seven community-dwelling adults [median age 61.9 (interquartile range 55.3,70.9) years, female 41%] with stable HF and insomnia (insomnia severity index >7). METHODS: This sub-study longitudinally analyzed 15 consecutive days and nights of wrist actigraphy recordings, that were collected for baseline data prior to participation in a randomized controlled trial of cognitive behavioral therapy for insomnia. We used two-level mixed models of within- (daily) and between-participants variation to predict daytime PA counts/minutes from sleep variables (total sleep time, sleep efficiency) and predict sleep variables from PA. RESULTS: PA counts/minutes were low compared to prior cohorts that did not have HF (209 (166,259)) and negatively associated with NYHA class (standardized coefficient ßs = -0.14, p < .01), age (ßs = -0.13, p = .01), comorbidities (ßs = -0.19, p < .01), and body mass index (ßs = -0.12, p = .04). After adjustment for all significant covariates, the within-participant association of total sleep time with next-day PA was estimated to be positive among participants with NYHA class II-IV HF (ßs = 0.09, p = .01), while the within-participant association of PA with same-night total sleep time was estimated to be positive among participants aged ≥60 years (ßs = 0.10, p = .03). CONCLUSIONS: Depending upon age and HF class, daytime PA was associated with longer same-night sleep and/or longer sleep was associated with greater next-day PA. Among those with more advanced HF, realistic sleep improvements were associated with clinically meaningful PA gains the next day.

10.
J Am Heart Assoc ; 9(18): e016038, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32867553

RESUMO

Background Outcomes data in patients with cardiac amyloidosis after implantable cardioverter-defibrillator (ICD) implantation are limited. We compared outcomes of patients with ICDs implanted for cardiac amyloidosis versus nonischemic cardiomyopathies (NICMs) and evaluated factors associated with mortality among patients with cardiac amyloidosis. Methods and Results Using National Cardiovascular Data Registry's ICD Registry data between April 1, 2010 and December 31, 2015, we created a 1:5 propensity-matched cohort of patients implanted with ICDs with cardiac amyloidosis and NICM. We compared mortality between those with cardiac amyloidosis and matched patients with NICM using Kaplan-Meier survival curves and Cox proportional hazards models. We also evaluated risk factors associated with 1-year mortality in patients with cardiac amyloidosis using multivariable Cox proportional hazards regression models. Among 472 patients with cardiac amyloidosis and 2360 patients with propensity-matched NICMs, 1-year mortality was significantly higher in patients with cardiac amyloidosis compared with patients with NICMs (26.9% versus 11.3%, P<0.001). After adjustment for covariates, cardiac amyloidosis was associated with a significantly higher risk of all-cause mortality (hazard ratio [HR], 1.80; 95% CI, 1.56-2.08). In a multivariable analysis of patients with cardiac amyloidosis, several factors were significantly associated with mortality: syncope (HR, 1.78; 95% CI, 1.22-2.59), ventricular tachycardia (HR, 1.65; 95% CI, 1.15-2.38), cerebrovascular disease (HR, 2.03; 95% CI, 1.28-3.23), diabetes mellitus (HR, 1.55; 95% CI, 1.05-2.27), creatinine = 1.6 to 2.5 g/dL (HR, 1.99; 95% CI, 1.32-3.02), and creatinine >2.5 (HR, 4.34; 95% CI, 2.72-6.93). Conclusions Mortality after ICD implantation is significantly higher in patients with cardiac amyloidosis than in patients with propensity-matched NICMs. Factors associated with death among patients with cardiac amyloidosis include prior syncope, ventricular tachycardia, cerebrovascular disease, diabetes mellitus, and impaired renal function.

11.
Circ Heart Fail ; 13(9): e007230, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32894986

RESUMO

BACKGROUND: Over the last 50 years, the epidemiology of hypertrophic cardiomyopathy (HCM) has changed because of increased awareness and availability of advanced diagnostic tools. We aim to describe the temporal trends in age, sex, and clinical characteristics at HCM diagnosis over >4 decades. METHODS: We retrospectively analyzed records from the ongoing multinational Sarcomeric Human Cardiomyopathy Registry. Overall, 7286 patients with HCM diagnosed at an age ≥18 years between 1961 and 2019 were included in the analysis and divided into 3 eras of diagnosis (<2000, 2000-2010, >2010). RESULTS: Age at diagnosis increased markedly over time (40±14 versus 47±15 versus 51±16 years, P<0.001), both in US and non-US sites, with a stable male-to-female ratio of about 3:2. Frequency of familial HCM declined over time (38.8% versus 34.3% versus 32.7%, P<0.001), as well as heart failure symptoms at presentation (New York Heart Association III/IV: 18.1% versus 15.8% versus 12.6%, P<0.001). Left ventricular hypertrophy became less marked over time (maximum wall thickness: 20±6 versus 18±5 versus 17±5 mm, P<0.001), while prevalence of obstructive HCM was greater in recent cohorts (peak gradient >30 mm Hg: 31.9% versus 39.3% versus 39.0%, P=0.001). Consistent with decreasing phenotypic severity, yield of pathogenic/likely pathogenic variants at genetic testing decreased over time (57.7% versus 45.6% versus 38.4%, P<0.001). CONCLUSIONS: Evolving HCM populations include progressively greater representation of older patients with sporadic disease, mild phenotypes, and genotype-negative status. Such trend suggests a prominent role of imaging over genetic testing in promoting HCM diagnoses and urges efforts to understand genotype-negative disease eluding the classic monogenic paradigm.

12.
JAMA Netw Open ; 3(9): e2017513, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32945877

RESUMO

Importance: Institution-level strategic changes may be associated with heart transplant volume and outcomes. Objective: To describe changes in practice that markedly increased heart transplant volume at a single center, as well as associated patient characteristics and outcomes. Design, Setting, and Participants: A pre-post cohort study was conducted of 107 patients who underwent heart transplant between September 1, 2014, and August 31, 2019, at Yale New Haven Hospital before (September 1, 2014, to August 31, 2018; prechange era) and after (September 1, 2018, to August 31, 2019; postchange era) a strategic change in patient selection by the heart transplant program. Exposure: Strategic change in donor and recipient selection at Yale New Haven Hospital that occurred in August 2018. Main Outcomes and Measures: Outcome measures were transplant case volume, donor and recipient characteristics, and 180-day survival. Results: A total of 49 patients (12.3 per year; 20 women [40.8%]; median age, 57 years [interquartile range {IQR}, 50-63 years]) received heart transplants in the 4 years of the prechange era and 58 patients (58 per year; 19 women [32.8%]; median age, 57 years [IQR, 52-64 years]) received heart transplants in the 1 year of the postchange era. Organ offers were more readily accepted in the postchange era, with an offer acceptance rate of 20.5% (58 of 283) compared with 6.4% (49 of 768) in the prechange era (P < .001). In the postchange era, donor hearts were accepted with a higher median number of prior refusals by other centers than in the prechange era (16.5 [IQR, 6-38] vs 3 [IQR, 1-6]; P < .001). Hearts accepted in the postchange era were from older donors than in the prechange era (median age, 40 years [IQR, 29-48 years] vs 30 years [IQR, 24-42 years]; P < .001). Recipients had a significantly shorter time on the waiting list in the postchange era compared with prechange era (median, 41 days [IQR, 12-289 days] vs 242 days [IQR, 135-428 days]; P < .001). More patients were supported on temporary circulatory assist devices preoperatively in the postchange era than the prechange era (14 [24.1%] vs 0; P < .001). Survival rates at 180 days were not significantly different (43 [87.8%] in the prechange era vs 52 [89.7%] in the postchange era). Mortality while on the waiting list was similar (2.8 deaths per year in the prechange era vs 3 deaths per year in the postchange era). During the comparable time period, 4 other regional centers had volume change ranging from -10% to 68%, while this center's volume increased by 374%. Conclusions and Relevance: This study suggests that strategic changes in donor heart and recipient selection may significantly increase the number of heart transplants while maintaining short-term outcomes comparable with more conservative patient selection. Such an approach may augment the allocation of currently unused donor hearts.

13.
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
14.
J Card Fail ; 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32750489

RESUMO

BACKGROUND: Sensitized patients awaiting heart transplantation spend a longer time on the waitlist and have higher mortality. We are now able to further characterize sensitization by discriminating antibodies against class I and II, but the differential impact of these has not been assessed systematically. METHODS AND RESULTS: Using United Network for Organ Sharing data (2004-2015), we analyzed 17,361 adult heart transplant patients whose class I and II panel reactive antibodies were reported. Patients were divided into 4 groups: class I and II ≤25% (group 1); class I ≤25% and class II ˃25% (group 2); class II ≤25% and class I >25% (group 3); and both class I and II >25% (group 4). Outcomes assessed were treated rejection at 1-year mortality, all-cause mortality, and rejection-related mortality. Compared with group 1, only group 4 was associated with a higher risk of treated rejection at 1 year (odds ratio 1.31, 95% confidence interval [CI] 1.05-1.64), all-cause mortality (hazard ratio 1.24, 95% CI 1.06-1.46), and mortality owing to rejection (subhazard ratio 1.84, 95% CI 1.18-2.85), whereas groups 2 and 3 were not (P > .05). CONCLUSIONS: Combined elevation in class I and II panel reactive antibodies seem to increase the risk of treated rejection and all-cause mortality, whereas risk with isolated elevation is unclear.

15.
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.

16.
Tex Heart Inst J ; 47(2): 152-154, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603465

RESUMO

Zinc, an essential micronutrient, affects the heart by modulating cardiomyocyte oxidative stress and maintaining myocardial structure, among other mechanisms. In cross-sectional studies, patients with heart failure have often had zinc deficiencies, suggesting effects on the ongoing pathogenesis of heart failure. Low plasma and myocardial zinc levels may cause reversible cardiomyopathy in patients who have nutritional deficiencies. We present the case of a 24-year-old woman with anorexia nervosa and new-onset heart failure whose depressed left ventricular systolic function improved after zinc supplementation. To our knowledge, this is the first report of low plasma zinc levels as the chief cause of cardiomyopathy that resolved after zinc supplementation.

17.
Circ Heart Fail ; 13(6): e006853, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32498620

RESUMO

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.


Assuntos
Benzilaminas/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Fármacos Cardiovasculares/uso terapêutico , Uracila/análogos & derivados , Benzilaminas/efeitos adversos , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Resultado do Tratamento , Uracila/efeitos adversos , Uracila/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
18.
Circulation ; 142(11): 1028-1039, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32410463

RESUMO

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations. METHODS: Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated. RESULTS: Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (P<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P=0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL [interquartile range, -536 to 153 mL] versus -14 mL [interquartile range, -282 to 335 mL]; P=0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL; P=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (P=0.02) and all other neurohormones were similar (P<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (P=0.20) or renal dysfunction (P>0.11 for all biomarkers), whereas both serum magnesium (P<0.001) and uric acid levels (P=0.008) improved. CONCLUSIONS: Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.

19.
Prev Med Rep ; 18: 101085, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32368435

RESUMO

Although statins are highly effective for reducing cardiovascular disease events, prior studies demonstrate their significant underuse in the US population, including among those with known atherosclerotic disease. It is unknown whether this finding applies to the subset of patients who present for outpatient surgery, as such patients would be expected to have recent exposures to healthcare providers during the preoperative referral period. The primary aim of this manuscript was to ascertain the prevalence of statin underuse and associated risk-factors for such underuse among ambulatory surgical patients with documented atherosclerotic cardiovascular disease. This was a retrospective observational study of a random sample of 600 patients ages 40-75 years presenting for ambulatory surgery within a 6-month period in 2016, at one of three ambulatory surgical centers affiliated with a large, tertiary care hospital. Compilation and analysis of data occurred in 2018-2019. Of the 600 subjects, 117 (19.5%) had documented atherosclerotic cardiovascular disease. Within this high-risk group, only 71 (60.7%) carried a prescription for any statin, and only 30 (25.6%) were prescribed a recommended high intensity statin dose for secondary prevention. In a multivariable logistic regression analysis, older age, male sex, and treatment for hypertension were positively associated with statin use. In conclusion, statin underuse among ambulatory surgical patients is common and mirrors what has been observed in non-surgical populations. Future trials are needed to investigate the possible role of surgical teams to promote guideline-based statin therapy, including the role of preoperative screening interventions to impact long term cardiovascular morbidity and mortality.

20.
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.

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