Radial dyssynchrony assessed by cardiovascular magnetic resonance in relation to left ventricular function, myocardial scarring and QRS duration in patients with heart failure

Radial dyssynchrony is almost universal in patients with heart failure. This vies against the notion that a lack of response to CRT is related to a lack of dyssynchrony

Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans

Supported by Medical Research Council program grant MRC G1001340 (to M Madhani, M Feelisch, and MP Frenneaux). We thank Lesley Cheyne for their contributions to the present study. The authors’ responsibilities were as follows—VSV, M Madhani, JDH, MF, DD, MPF: designed the research; MN, NEKP, KS, BLL, M Minnion, BOF, DV, DC-T, PGC: conducted the research; DV: provided essential materials; MN, NEKP, M Minnion, BOF, DC-T, MF, PGC: analyzed the data; MN, NEKP, PGC, MPF: wrote the paper; MPF: had primary responsibility for the final manuscript; and all authors: read and approved the final manuscript. None of the authors reported a conflict of interest related to the study.Peer reviewedPublisher PD

Genetic and Neuroimaging Approaches to Understanding Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a highly disabling condition, increasingly recognized as both a disorder of mental health and social burden, but also as an anxiety disorder characterized by fear, stress, and negative alterations in mood. PTSD is associated with structural, metabolic, and molecular changes in several brain regions and the neural circuitry. Brain areas implicated in the traumatic stress response include the amygdala, hippocampus, and prefrontal cortex, which play an essential role in memory function. Abnormalities in these brain areas are hypothesized to underlie symptoms of PTSD and other stress-related psychiatric disorders. Conventional methods of studying PTSD have proven to be insufficient for diagnosis, measurement of treatment efficacy, and monitoring disease progression, and currently, there is no diagnostic biomarker available for PTSD. A deep understanding of cutting-edge neuroimaging genetic approaches is necessary for the development of novel therapeutics and biomarkers to better diagnose and treat the disorder. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review article explains the rationale and practical utility of neuroimaging genetics in PTSD and how the resulting information can aid the diagnosis and clinical management of patients with PTSD.Sidra Medicine funded this research to Mohammad Haris (5071012001) and Ajaz A. Bhat (5011041002)

Multicenter Randomized Controlled Crossover Trial Comparing Hemodynamic Optimization Against Echocardiographic Optimization of AV and VV Delay of Cardiac Resynchronization Therapy:The BRAVO Trial

Objectives: BRAVO (British Randomized Controlled Trial of AV and VV Optimization) is a multicenter, randomized, crossover, noninferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular delay with a noninvasive blood pressure method. Background: Cardiac resynchronization therapy including AV delay optimization confers clinical benefit, but the optimization requires time and expertise to perform. Methods: This study randomized patients to echocardiographic optimization or hemodynamic optimization using multiple-replicate beat-by-beat noninvasive blood pressure at baseline; after 6 months, participants were crossed over to the other optimization arm of the trial. The primary outcome was exercise capacity, quantified as peak exercise oxygen uptake. Secondary outcome measures were echocardiographic left ventricular (LV) remodeling, quality-of-life scores, and N-terminal pro–B-type natriuretic peptide. Results: A total of 401 patients were enrolled, the median age was 69 years, 78% of patients were men, and the New York Heart Association functional class was II in 84% and III in 16%. The primary endpoint, peak oxygen uptake, met the criterion for noninferiority (pnoninferiority = 0.0001), with no significant difference between the hemodynamically optimized arm and echocardiographically optimized arm of the trial (mean difference 0.1 ml/kg/min). Secondary endpoints for noninferiority were also met for symptoms (mean difference in Minnesota score 1; pnoninferiority = 0.002) and hormonal changes (mean change in N-terminal pro–B-type natriuretic peptide -10 pg/ml; pnoninferiority = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; pnoninferiority < 0.001; LV diastolic dimension 0 mm; pnoninferiority <0.001). In 30% of patients the AV delay identified as optimal was more than 20 ms from the nominal setting of 120 ms. Conclusions: Optimization of cardiac resynchronization therapy devices by using noninvasive blood pressure is noninferior to echocardiographic optimization. Therefore, noninvasive hemodynamic optimization is an acceptable alternative that has the potential to be automated and thus more easily implemented. (British Randomized Controlled Trial of AV and VV Optimization [BRAVO]; NCT01258829

Phenotype and Clinical Outcomes of Titin Cardiomyopathy.

BACKGROUND: Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification. OBJECTIVES: The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM. METHODS: In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events. RESULTS: Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m2 reduction; padjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv+/- groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82). CONCLUSIONS: In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis

Phenotype and Clinical Outcomes of Titin Cardiomyopathy

BACKGROUND: Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification. OBJECTIVES: The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM. METHODS: In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events. RESULTS: Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m2 reduction; padjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv+/- groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82). CONCLUSIONS: In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis

Evaluation of Acute Supplementation With the Ketone Ester ( R )-3-Hydroxybutyl-(R)-3-Hydroxybutyrate (deltaG) in Healthy Volunteers by Cardiac and Skeletal Muscle 31 P Magnetic Resonance Spectroscopy

In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (31P-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23–70 years for cardiac 31P-MRS, and 16 aged 60–75 years for skeletal muscle 31P-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle 31P-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG®, was administered after the baseline scan. Administration was timed so that post-intervention 31P-MRS would take place 30 min after deltaG® ingestion. The deltaG® ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (−28.8%, p ≪ 0.001; −28.2%, p = 0.02; and −49.1%, p ≪ 0.001, respectively), while levels of the ketone body D-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (p ≪ 0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in 31P-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function

Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy

Objective: The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM. Methods: Prospective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; &gt;14 units/week for women, &gt;21 units/week for men) at cohort enrollment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited. Results: DCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared to patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group– n =92, 94% vs n =306, 61%, p=&lt;0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in mid-wall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 0.73 to 2.26, p=0.38) during median follow up of 3.9 years. Conclusion: Dilated cardiomyopathy patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with dilated cardiomyopathy

Report from the Annual Conference of the British Society of Echocardiography, November 2016, Queen Elizabeth II Conference Centre, London.

Peer reviewedPublisher PD

Sex differences in the clinical presentation and natural history of dilated cardiomyopathy

Background Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved. Objectives This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors. Methods We conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events. Results Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P &lt; 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors. Conclusions We identify a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences