Assessing the association between genetic and phenotypic features of dilated cardiomyopathy and outcome in patients with coronary artery disease.

AIMS: To examine the relevance of genetic and cardiovascular magnetic resonance (CMR) features of dilated cardiomyopathy (DCM) in individuals with coronary artery disease (CAD). METHODS AND RESULTS: This study includes two cohorts. First, individuals with CAD recruited into the UK Biobank (UKB) were evaluated. Second, patients with CAD referred to a tertiary centre for evaluation with late gadolinium enhancement (LGE)-CMR were recruited (London cohort); patients underwent genetic sequencing as part of the research protocol and long-term follow-up. From 31 154 individuals with CAD recruited to UKB, rare pathogenic variants in DCM genes were associated with increased risk of death or major adverse cardiac events (hazard ratio 1.57, 95% confidence interval [CI] 1.22-2.01, p < 0.001). Of 1619 individuals with CAD included from the UKB CMR substudy, participants with a rare variant in a DCM-associated gene had lower left ventricular ejection fraction (LVEF) compared to genotype negative individuals (mean 47 ± 10% vs. 57 ± 8%, p < 0.001). Of 453 patients in the London cohort, 63 (14%) had non-infarct pattern LGE (NI-LGE) on CMR. Patients with NI-LGE had lower LVEF (mean 38 ± 18% vs. 48 ± 16%, p < 0.001) compared to patients without NI-LGE, with no significant difference in the burden of rare protein altering variants in DCM-associated genes between groups (9.5% vs. 6.7%, odds ratio 1.5, 95% CI 0.4-4.3, p = 0.4). NI-LGE was not independently associated with adverse clinical outcomes. CONCLUSION: Rare pathogenic variants in DCM-associated genes impact left ventricular remodelling and outcomes in stable CAD. NI-LGE is associated with adverse remodelling but is not an independent predictor of outcome and had no rare genetic basis in our study.

Torrential mitral regurgitation following right ventricular apical pacing in rheumatic mitral valve disease: a case report.

Background: Mitral regurgitation may develop or worsen following right ventricular apical pacing due to dyssynchronous left ventricular contraction. Pre-existing secondary mitral annular dilation is a well-recognized and important contributing factor. This description of pacing-induced torrential mitral regurgitation in the setting of rheumatic mitral valve disease is a rare case in which a primary mitral valve lesion was the antecedent mechanism. Case summary: A 60-year-old man was admitted with dizziness and pre-syncope. Twelve-lead electrocardiogram showed complete heart block. A dual-chamber pacemaker was implanted and programmed in DDD mode. Transthoracic echocardiography performed a day later demonstrated a left ventricular ejection fraction (LVEF) of 63% and moderate mitral regurgitation. The patient presented 4 months later with breathlessness and orthopnoea. Pacemaker interrogation demonstrated a 98% right ventricular pacing burden. Echocardiography revealed torrential mitral regurgitation secondary to left ventricular dyssynchrony and complete loss of leaflet coaptation with preserved systolic function. Post-capillary pulmonary hypertension was diagnosed following right heart catheterization. The patient underwent metallic mitral valve replacement, tricuspid annuloplasty, and left internal mammary artery grafting to the left anterior descending artery for a severe proximal stenosis. On inspection, the native mitral valve was notably rheumatic in appearance, and this was confirmed histologically. Discussion: It is important to closely monitor the progression of mitral regurgitation in those with primary mitral valve disease undergoing right ventricular pacing. Early follow-up may prevent the adverse haemodynamic consequences of worsening mitral regurgitation, with a greater chance of recovery of left ventricular function following surgery.

Decongestion strategies in patients presenting with acutely decompensated heart failure: A worldwide survey among physicians.

AIMS: Decongestion strategies for acute decompensated heart failure (ADHF) characterized by volume overload differ widely. The aim of this independent international academic web-based survey was to capture the therapeutic strategies that physicians use to treat ADHF and to assess differences in therapeutic approaches between cardiologists versus non-cardiologists. METHODS AND RESULTS: Physicians were invited to complete a web-based questionnaire, capturing anonymized data on physicians' characteristics and treatment preferences based on a hypothetical clinical scenario of a patient hospitalized with ADHF. A total of 641 physicians from 60 countries participated. A wide variation in the management of the patient was observed. There was conservative use of diuretics, i.e. only 7% started intravenous furosemide at a dose ≥2 times the baseline oral dose, and infrequent use of ultrasound in assessing congestion (20.4%). Spot urinary sodium was infrequently or never measured by ≥85% of physicians. A third considered a patient with ongoing oedema as being stabilized. There were significant differences between cardiologists and non-cardiologists in the management of ADHF, the targets for daily body weight loss and urine output, diuretic escalation strategies (66.3% vs. 40.7% would escalate diuresis by adding a thiazide) and assessment of response to treatment (27.0% vs. 52.9% considered patients with minimal congestion as stabilized). CONCLUSIONS: There is substantial variability amongst physicians and between cardiologists and non-cardiologists in the management of patients with ADHF, with regard to clinical parameters used to tailor treatment, treatment goals, diuretic dosing and escalation strategies.

Sleep-disordered breathing and cardiovascular disease: who and why to test and how to intervene?

Sleep-disordered breathing (SDB) is common in individuals with established cardiovascular disease (CVD), particularly those with heart failure (HF). There are two main types of SDB, central sleep apnoea (CSA) and obstructive sleep apnoea (OSA) which frequently overlap as mixed SDB. Investigating for SDB could be considered in patients with excessive daytime sleepiness, male sex, high body mass index, low ejection fraction, atrial fibrillation (AF), in patients with no dipping blood pressure pattern, recurrent paroxysms of nocturnal dyspnoea or when an apnoea is witnessed. Excessive daytime sleepiness is less likely to be reported by patients with HF than by the general population. In patients with CVD and OSA, continuous positive airway pressure (CPAP) ventilation for over 4 hours daily reduced the risk of major adverse cardiovascular events, but there was no reduction in mortality. In patients with AF and OSA treated with AF ablation, CPAP use was associated with a reduced risk of recurrence of AF. In patients with HF and OSA, small studies have demonstrated that CPAP improves symptoms, brain natriuretic peptide levels and ejection fraction, but data on survival are lacking. Treatment remains unclear in patients with HF and CSA. The presence of CSA may be a defensive adaptive response to HF, and effectively treating CSA as demonstrated in a randomised clinical trial of adaptive servo-ventilation caused more harm than benefit when compared to optimal medical therapy. Thus, the focus of treating CSA should remain on improving the underlying HF by optimising medical therapy and, if indicated, cardiac resynchronisation therapy.

Iatrogenic Tricuspid Regurgitation Associated With Pacemakers: A Case Compounded by Tricuspid Stenosis.

A patient presented with severe tricuspid regurgitation 20 years after dual-chamber pacing. Transesophageal echocardiography suggested ventricular pacing wire adherence to the tricuspid valve (TV) and atrial wire prolapse across the tricuspid annulus. Surgical extraction of the pacing wires revealed TV commissural fusion and subvalvular thickening causing tricuspid stenosis, requiring TV replacement. (Level of Difficulty: Intermediate.).

Comprehensive Phenotypic Characterization of Late Gadolinium Enhancement Predicts Sudden Cardiac Death in Coronary Artery Disease.

BACKGROUND: Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD). OBJECTIVES: The authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD). METHODS: Patients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD. RESULTS: Of 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell's C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell's C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models. CONCLUSIONS: Comprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

Paradoxical Left-to-Right Device Embolization Complicating Transcatheter Mitral Valve Edge-to-Edge Repair.

We describe an unusual presentation of transcatheter mitral valve edge-to-edge repair device embolization into the left common femoral vein in a patient with primary degenerative mitral regurgitation. We hypothesize a possible mechanism for this phenomenon, factors that may increase the risk of this complication, and outline the patient's clinical course. (Level of Difficulty: Intermediate.).

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.

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.

Heart Rate as a Marker of Relapse During Withdrawal of Therapy in Recovered Dilated Cardiomyopathy.

OBJECTIVES: The objective of this study was to determine the relationship between heart rate and relapse among patients in the TRED-HF (Therapy withdrawal in REcovered Dilated cardiomyopathy trial). BACKGROUND: Understanding markers and mechanisms of relapse among patients with recovered dilated cardiomyopathy (DCM) may enable personalized management. METHODS: The relationship between serial heart rate measurements and relapse was examined among patients in the TRED-HF trial, a randomized trial which examined the safety and feasibility of withdrawing heart failure therapy from 51 patients with recovered DCM over 6 months. In total, 25 patients were randomized to therapy withdrawal and 26 to continue therapy, of whom 25 subsequently began therapy withdrawal in a single arm crossover phase. RESULTS: The mean ± SD heart rate for those who had therapy withdrawn and did not relapse was 64.6 ± 10.7 beats/min at baseline and 74.7 ± 10.4 beats/min at follow-up, compared to 68.3 ± 11.3 beats/min at baseline and 86.1 ± 11.8 beats/min at follow-up for those who relapsed. After adjusting for differences in heart rate at baseline, patients who had therapy withdrawn and relapsed had a 10.4 beats/min (95% CI: 4.0-16.8) greater rise in heart rate than patients who had therapy withdrawn and did not relapse (P = 0.002). After data were adjusted for age, log N-terminal pro-B-type natriuretic peptide, and left ventricular ejection fraction (LVEF), heart rate (per 10 beats/min; hazard ratio [HR]: 1.65; 95% CI: 1.10-2.57; P = 0.01) and change in heart rate from baseline (per 10 beats/min; HR: 1.70; 95% CI: 1.12-2.57; p = 0.01) were associated with relapse. The results remained qualitatively the same after adjusting for beta-blocker dose. CONCLUSIONS: For patients with DCM and improved LVEF, the rise in heart rate after treatment is withdrawn treatment identifies patients who are more likely to relapse. Whether the increase in heart rate is a marker or a mediator of relapse requires investigation. (Therapy withdrawal in REcovered Dilated cardiomyopathy trial [TRED]; NCT02859311).

Cardiac tamponade from anticoagulant-related spontaneous haemopericardium in a patient with ischaemic cardiomyopathy and heart failure.

We describe the case of an 86-year-old man with a background of severe left ventricular dysfunction and ischaemic cardiomyopathy who, having been optimised for heart failure therapy in hospital, unexpectedly deteriorated again with hypotension and progressive renal failure over the course of 2 days. Common causes of decompensation were ruled out and a bedside echocardiogram unexpectedly diagnosed new pericardial effusion with tamponade physiology. The patient underwent urgent pericardiocentesis and 890 mL of haemorrhagic fluid was drained. Common causes for haemopericardium were ruled out, and the spontaneous haemopericardium was thought to be related to introduction of rivaroxaban anticoagulation. The patient made a full recovery and was well 2 months following discharge. This case highlights the challenges of diagnosing cardiac tamponade in the presence of more common disorders that share similar non-specific clinical features. In addition, this case adds to growing evidence that therapy with direct oral anticoagulants can be complicated by spontaneous haemopericardium, especially when coadministered with other agents that affect clotting, renal dysfunction and cytochrome P3A5 inhibitors.

Correlation Between Echocardiographic and Hemodynamic Variables in Cardiothoracic Intensive Care Unit.

OBJECTIVES: The echocardiographic indices have not been validated in critically ill population. The authors investigated the correlation between some echocardiographic and hemodynamic parameters. DESIGN: Prospective, spontaneous, noninterventional observational study. SETTING: Adult cardiothoracic intensive care unit, single center (Royal Brompton Hospital, London, United Kingdom). PARTICIPANTS: Consecutive adult patients admitted to the cardiothoracic intensive care unit for severe respiratory failure, primary cardiocirculatory failure, and post-aortic surgery. INTERVENTIONS: Clinical hemodynamic parameters (stroke volume [SV], cardiac output [CO], mean arterial pressure [MAP], and cardiac power index [CPI]) and echocardiographic indices of ventricular function (left ventricular total isovolumic time [t-IVT], mitral annular plane systolic excursion [MAPSE], and left ventricular fraction [LVEF]) were evaluated offline. MEASUREMENTS AND MAIN RESULTS: The study comprised 117 patients (age 57.2 ± 19; 60.6% male). The t-IVT showed an inverse correlation with SV, CO, MAP, and CPI (r -67%; -38%; -45%; -51%, respectively). MAPSE exhibited a positive correlation with SV, CO, MAP, and CPI (r 43%; 44%; 34%; 31%, respectively). LVEF did not show any correlation. In the multivariate analysis the association between t-IVT and hemodynamics was confirmed for SV, CO, MAP, and CPI, with the highest partial correlation between t-IVT and MAP (R = -58%). CONCLUSIONS: MAPSE and t-IVT are 2 reproducible and reliable echocardiographic indices of systolic function and ventricular efficacy associated with hemodynamic variables in cardiothoracic critically ill patients, whereas LVEF did not show any correlation.

Impact on survival of combination inhalers in patients with COPD at high risk of cardiovascular events.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and cardiovascular disease often co-exist and are both leading causes of death worldwide. Published data have previously suggested trends toward improved survival for patients taking long-acting ß agonists combined with inhaled corticosteroids (LABA-ICS) through beneficial actions on the respiratory and cardiovascular systems. We sought to explore this in a real-world setting. METHODS: A population-based longitudinal propensity score-matched cohort study was conducted in the United Kingdom, 1998-2015. Patients were identified from the Clinical Practice Research Datalink (CPRD) which is linked to Hospital Episode Statistics (HES) and Office for National Statistics (ONS) mortality records. All patients had a validated diagnosis of COPD and were at high risk for cardiovascular events (history of myocardial infarction, diabetes mellitus, ischaemic heart disease, stroke and peripheral arterial disease). The primary outcome was all-cause mortality. RESULTS: The treatment group was composed of 2687 new users of LABA-ICS with COPD and comparisons were made in a control population of 2687 COPD patients prescribed LABAs alone. At three years follow-up death occurred in 358 (13.3%) patients in the treatment group and 427 (15.9%) patients in the control group. The use of LABA-ICS was modestly associated with improved survival compared to use of LABAs (hazard ratio 0.82, 95% CI 0.71-0.95, P = 0.007). CONCLUSIONS: Among patients with COPD with either established cardiovascular disease or at high risk of an index cardiovascular event, LABA-ICS inhaled therapy, compared with LABAs alone, was associated with a significantly improved survival.

Relationship between heart rate and outcomes in patients in sinus rhythm or atrial fibrillation with heart failure and reduced ejection fraction.

AIMS: To investigate the relationship between heart rate and outcomes in heart failure and reduced ejection fraction (HFrEF) patients in sinus rhythm (SR) and atrial fibrillation (AF) adjusting for natriuretic peptide concentration, a powerful prognosticator. METHODS AND RESULTS: Of 13 562 patients from two large HFrEF trials, 10 113 (74.6%) were in SR and 3449 (25.4%) in AF. The primary endpoint was the composite of cardiovascular death or heart failure hospitalization. Heart rate was analysed as a categorical (tertiles, T1-3) and continuous variable (per 10 bpm), separately in patients in SR and AF. Outcomes were adjusted for prognostic variables, including N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and also examined using change from baseline heart rate to 1 year (≤ -10 bpm, ≥ +10 bpm, < ±10 bpm). SR patients with a higher heart rate had worse symptoms and quality of life, more often had diabetes and higher NT-proBNP concentrations. They had higher risk of the primary endpoint [T3 vs. T1 adjusted hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.35-1.66; P < 0.001; per 10 bpm: 1.12, 95% CI 1.09-1.16; P < 0.001]. In SR, heart rate was associated with a relatively higher risk of pump failure than sudden death (adjusted HR per 10 bpm 1.17, 95% CI 1.09-1.26; P < 0.001 vs. 1.07, 95% CI 1.02-1.13; P = 0.011). Heart rate was not predictive of any outcome in AF. CONCLUSIONS: In HFrEF, an elevated heart rate was an independent predictor of adverse cardiovascular outcomes in patients in SR, even after adjustment for NT-proBNP. There was no relationship between heart rate and outcomes in AF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01035255 and NCT00853658.

Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study.

Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. Thirty-one participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d = 0.89; p = 0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d = 0.86-1.08; all p-values < 0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p > 0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.

¿Deberíamos usar la ecografía para estratificar el riesgo en los pacientes con hemorragia digestiva? / Should we use ultrasound for risk stratification in patients with gastrointestinal hemorrhage?

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