Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease.

Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy.

BACKGROUND: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. METHODS: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. RESULTS: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08). CONCLUSIONS: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.

Changes in clinical and imaging variables during withdrawal of heart failure therapy in recovered dilated cardiomyopathy.

AIMS: This study aimed to profile the changes in non-invasive clinical, biochemical, and imaging markers during withdrawal of therapy in patients with recovered dilated cardiomyopathy, providing insights into the pathophysiology of relapse. METHODS AND RESULTS: Clinical, biochemical, and imaging data from patients during phased withdrawal of therapy in the randomized or single-arm cross-over phases of TRED-HF were profiled. Clinical variables were measured at each study visit and imaging variables were measured at baseline, 16 weeks, and 6 months. Amongst the 49 patients [35% women, mean age 53.6 years (standard deviation 11.6)] who withdrew therapy, 20 relapsed. Increases in mean heart rate [7.6 beats per minute (95% confidence interval, CI, 4.5, 10.7)], systolic blood pressure [6.6 mmHg (95% CI 2.7, 10.5)], and diastolic blood pressure [5.8 mmHg (95% CI 3.1, 8.5)] were observed within 4-8 weeks of starting to withdraw therapy. A rise in mean left ventricular (LV) mass [5.1 g/m2 (95% CI 2.8, 7.3)] and LV end-diastolic volume [3.9 mL/m2 (95% CI 1.1, 6.7)] and a reduction in mean LV ejection fraction [-4.2 (95% CI -6.6, -1.8)] were seen by 16 weeks, the earliest imaging follow-up. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) fell immediately after withdrawing beta-blockers and only tended to increase 6 months after beginning therapy withdrawal [mean change in log NT-proBNP at 6 months: 0.2 (95% CI -0.1, 0.4)]. CONCLUSIONS: Changes in plasma NT-proBNP are a late feature of relapse, often months after a reduction in LV function. A rise in heart rate and blood pressure is observed soon after withdrawing therapy in recovered dilated cardiomyopathy, typically accompanied or closely followed by early changes in LV structure and function.

Exposure to Elevated Nitrogen Dioxide Concentrations and Cardiac Remodeling in Patients With Dilated Cardiomyopathy.

BACKGROUND: Empirical evidence suggests a strong link between exposure to air pollution and heart failure incidence, hospitalizations, and mortality, but the biological basis of this remains unclear. We sought to determine the relationship between differential air pollution levels and changes in cardiac structure and function in patients with dilated cardiomyopathy. METHODS AND RESULTS: We undertook a prospective longitudinal observational cohort study of patients in England with dilated cardiomyopathy (enrollment 2009-2015, n = 716, 66% male, 85% Caucasian) and conducted cross sectional analysis at the time of study enrollment. Annual average air pollution exposure estimates for nitrogen dioxide (NO2) and particulate matter with diameter of 2.5 µm or less (PM2.5) at enrolment were assigned to each residential postcode (on average 12 households). The relationship between air pollution and cardiac morphology was assessed using linear regression modelling. Greater ambient exposure to NO2 was associated with higher indexed left ventricular (LV) mass (4.3 g/m2 increase per interquartile range increase in NO2, 95% confidence interval 1.9-7.0 g/m2) and lower LV ejection fraction (-1.5% decrease per interquartile range increase in NO2, 95% confidence interval -2.7% to -0.2%), independent of age, sex, socioeconomic status, and clinical covariates. The associations were robust to adjustment for smoking status and geographical clustering by postcode area. The effect of air pollution on LV mass was greatest in women. These effects were specific to NO2 exposure. CONCLUSIONS: Exposure to air pollution is associated with raised LV mass and lower LV ejection fraction, with the strongest effect in women. Although epidemiological associations between air pollution and heart failure have been established and supported by preclinical studies, our findings provide novel empirical evidence of cardiac remodeling and exposure to air pollution with important clinical and public health implications.

A novel cardiovascular magnetic resonance risk score for predicting mortality following surgical aortic valve replacement.

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm2, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care.Trial Registration ClinicalTrials.gov Identifier: NCT00930735 and ClinicalTrials.gov Identifier: NCT01755936.

The Interstitium in the Hypertrophied Heart.

Pathological left ventricular hypertrophy is a common feature of many cardiac diseases. It results from both myocyte hypertrophy and interstitial expansion. Interstitial expansion is most commonly secondary to the accumulation of mature cross-linked collagen fibers due to dysregulated metabolism, known as interstitial fibrosis. This occurs secondary to a variety of stimuli including ischemic, toxic, metabolic, infective, genetic, and hemodynamic factors. Less commonly, interstitial expansion may occur because of the accumulation of misfolded amyloid protein or interstitial edema. It is now well recognized that the presence and extent of interstitial disease are associated with adverse outcomes. There is therefore interest in the development of novel therapies that target the pathways that drive these disease processes. With the emergence of such therapies, it is becoming increasingly important to be able to characterize the type and extent of interstitial disease to enable the use of such targeted therapies in a personalized manner.

Microvascular Dysfunction in Dilated Cardiomyopathy: A Quantitative Stress Perfusion Cardiovascular Magnetic Resonance Study.

OBJECTIVES: This study sought to quantify myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) in dilated cardiomyopathy (DCM) and examine the relationship between myocardial perfusion and adverse left ventricular (LV) remodeling. BACKGROUND: Although regarded as a nonischemic condition, DCM has been associated with microvascular dysfunction, which is postulated to play a role in its pathogenesis. However, the relationship of the resulting perfusion abnormalities to myocardial fibrosis and the degree of LV remodeling is unclear. METHODS: A total of 65 patients and 35 healthy control subjects underwent adenosine (140 µg/kg/min) stress perfusion cardiovascular magnetic resonance with late gadolinium enhancement imaging. Stress and rest MBF and MPR were derived using a modified Fermi-constrained deconvolution algorithm. RESULTS: Patients had significantly higher global rest MBF compared with control subjects (1.73 ± 0.42 ml/g/min vs. 1.14 ± 0.42 ml/g/min; p < 0.001). In contrast, global stress MBF was significantly lower versus control subjects (3.07 ± 1.02 ml/g/min vs. 3.53 ± 0.79 ml/g/min; p = 0.02), resulting in impaired MPR in the DCM group (1.83 ± 0.58 vs. 3.50 ± 1.45; p < 0.001). Global stress MBF (2.70 ± 0.89 ml/g/min vs. 3.44 ± 1.03 ml/g/min; p = 0.017) and global MPR (1.67 ± 0.61 vs. 1.99 ± 0.50; p = 0.047) were significantly reduced in patients with DCM with LV ejection fraction ≤35% compared with those with LV ejection fraction >35%. Segments with fibrosis had lower rest MBF (mean difference: -0.12 ml/g/min; 95% confidence interval: -0.23 to -0.01 ml/g/min; p = 0.035) and lower stress MBF (mean difference: -0.15 ml/g/min; 95% confidence interval: -0.28 to -0.03 ml/g/min; p = 0.013). CONCLUSIONS: Patients with DCM exhibit microvascular dysfunction, the severity of which is associated with the degree of LV impairment. However, rest MBF is elevated rather than reduced in DCM. If microvascular dysfunction contributes to the pathogenesis of DCM, then the underlying mechanism is more likely to involve stress-induced repetitive stunning rather than chronic myocardial hypoperfusion.

Personalizing Risk Stratification for Sudden Death in Dilated Cardiomyopathy: The Past, Present, and Future.

Results from the DANISH Study (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality) suggest that for many patients with dilated cardiomyopathy (DCM), implantable cardioverter-defibrillators do not increase longevity. Accurate identification of patients who are more likely to die of an arrhythmia and less likely to die of other causes is required to ensure improvement in outcomes and wise use of resources. Until now, left ventricular ejection fraction has been used as a key criterion for selecting patients with DCM for an implantable cardioverter-defibrillator for primary prevention purposes. However, registry data suggest that many patients with DCM and an out-of-hospital cardiac arrest do not have a markedly reduced left ventricular ejection fraction. In addition, many patients with reduced left ventricular ejection fraction die of nonsudden causes of death. Methods to predict a higher or lower risk of sudden death include the detection of myocardial fibrosis (a substrate for ventricular arrhythmia), microvolt T-wave alternans (a marker of electrophysiological vulnerability), and genetic testing. Midwall fibrosis is identified by late gadolinium enhancement cardiovascular magnetic resonance imaging in ≈30% of patients and provides incremental value in addition to left ventricular ejection fraction for the prediction of sudden cardiac death events. Microvolt T-wave alternans represents another promising predictor, supported by large meta-analyses that have highlighted the negative predictive value of this test. However, neither of these strategies have been routinely adopted for risk stratification in clinical practice. More convincing data from randomized trials are required to inform the management of patients with these features. Understanding of the genetics of DCM and how specific mutations affect arrhythmic risk is also rapidly increasing. The finding of a mutation in lamin A/C, the cause of ≈6% of idiopathic DCM, commonly underpins more aggressive management because of the malignant nature of the associated phenotype. With the expansion of genetic sequencing, the identification of further high-risk mutations appears likely, leading to better-informed clinical decision making and providing insight into disease mechanisms. Over the next 5 to 10 years, we expect these techniques to be integrated into the existing algorithm to form a more sensitive, specific, and cost-effective approach to the selection of patients with DCM for implantable cardioverter-defibrillator implantation.

Neoadjuvant chemotherapy for carcinoma of the oesophagus and oesophago-gastric junction: a six-year experience.

BACKGROUND: Oesophageal cancer is a major clinical problem with a generally poor prognosis. As a result there has been interest in combining surgery with neoadjuvant chemotherapy to try and improve outcomes, although the current evidence for benefit is inconsistent. We aimed to compare, in a non-randomised study, the post-operative complication rate and short and long-term survival of patients who underwent surgical resection for carcinoma of the oesophagus and types I and II carcinoma of the oesophago-gastric junction with or without neo-adjuvant chemotherapy. METHODS: Details of all resections for oesophageal/junctional (types I and II) adenocarcinoma or squamous cell carcinoma between April 2000 and July 2006 were collected prospectively. Data from patients with T3 and/or N1 disease who underwent either neoadjuvant chemotherapy (NAC) or not (non-NAC) were compared. Data were analysed using Kaplan-Meier plots, Mann-Whitney U-test, Cox Regression modelling, and Chi-squared test with Yates' correction where sample sizes <10. RESULTS: 167 patients were included (89 NAC and 78 non-NAC). The in-hospital post-operative mortality rate of the NAC group (n = 2 deaths; 2.2%) was significantly lower (p = 0.045) than the non-NAC group (n = 6 deaths; 7.7%). Most deaths were due to cardio-respiratory complications; however, there was no significant difference in rates of chest infections, anastomotic leaks, wound infections, re-operations, readmission to ITU or overall complications between the two groups. Although both the two-year survival rate (60.7%) and long-term survival of NAC patients (median survival = 793 days; 95% CI = 390-1196) was greater than non-NAC patients (two-year survival rate = 48.7%; median survival = 554 days; 95% CI = 246-862 respectively), these differences were not statistically significant. CONCLUSION: This non-randomised study demonstrated that NAC was associated with a significant reduction in post-operative inpatient mortality rate. Whether this can be explained by a decreased co-morbidity in NAC patients or a protective phenomenon associated with NAC remains unclear. This study also demonstrated a greater two-year survival rate and overall median survival time following NAC but this was not statistically significant.