Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies

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

May Measurement Month 2017: an analysis of blood pressure screening results from the United Arab Emirates-Northern Africa and Middle East

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programmes worldwide. United Arab Emirates has a young population, but cardiovascular disease (CVD) is the commonest cause of death (40%). Myocardial infarction and stroke occurs at least a decade earlier than in western countries. Previous screening in our young population showed that 85% of the population had at least one CVD risk factor and about 62% of them were unaware of it. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. Screening was held in 23 sites such as mosques, sports, and men's/ladies' clubs, airports, parks, shopping malls, work places as well as their residences, and in the public areas of hospitals or outpatient clinics. A total of 6193 individuals were screened during MMM17. The mean age was 39.2 ± 13.1 years. After multiple imputation, 1867 (30.2%) had hypertension. Of individuals not receiving anti-hypertensive medication, 813 (15.8%) were hypertensive. Of 1054 individuals receiving anti-hypertensive medication, 427 (40.6%) had uncontrolled BP. MMM17 was a useful screening model as it makes BP measurement easily accessible. Eight hundred and thirteen (16%) possibly new hypertensives were uncovered and 427(40.6%) of those on treatment for hypertension were found to be uncontrolled. These results suggest that opportunistic screening can identify significant numbers with raised BP

Correlation between echocardiographic and hemodynamic variables in cardiothoracic intensive care unit

Objectives the echocardiographic indices have not been validated in critically ill population. We investigated the correlation between some echocardiographic and hemodynamics parameters. Design Prospective Spontaneous non-interventional observational study. Setting Adult cardiothoracic intensive care unit, single center (Royal Brompton Hospital, London UK). Participants Consecutive adult patients admitted to cardiothoracic intensive care unit for severe respiratory failure, primary cardio-circulatory 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 117 patients were studied (age 57.2 ± 19; 60.6% male). t-IVT showed an inverse correlation with SV, CO, MAP and CPI (respectively r: -67%; -38%; -45%; -51%). MAPSE exhibited a positive correlation with SV, CO, MAP and CPI (respectively r: 43%; 44%; 34%; 31%). LVEF did not show any correlation. In the multivariate analysis the association of 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 two reproducible and reliable echocardiographic indices of systolic function and ventricular efficacy associated with hemodynamic variables in cardiothoracic critically ill patients, while LVEF did not show any correlation

Association between mid-wall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction

Background—Current guidelines only recommend the use of an implantable cardioverter defibrillator (ICD) in patients with dilated cardiomyopathy (DCM) for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF)35%. Patients with a LVEF>35% also have low competing risks of death from non-sudden causes. Therefore, those at high-risk of SCD may gain longevity from successful ICD therapy. We investigated whether late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) identified patients with DCM without severe LV systolic dysfunction at high-risk of SCD. Methods—We prospectively investigated the association between mid-wall late gadolinium enhancement (LGE) and the pre-specified primary composite outcome of SCD or aborted SCD amongst consecutive referrals with DCM and a LVEF≥40% to our center between January 2000 and December 2011, who did not have a pre-existing indication for ICD implantation. Results—Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the pre-specified end-point, compared to 7 of 298 (2.3%) without (HR 9.2; 95% CI 3.9-21.8; p5% compared to those without LGE were 10.6 (95%CI 3.9-29.4), 4.9 (95% CI 1.3-18.9) and 11.8 (95% CI 4.3-32.3) respectively. Conclusions—Mid-wall LGE identifies a group of patients with DCM and LVEF≥40% at increased risk of SCD and low-risk of non-sudden death who may benefit from ICD implantation

Prognostic Significance of Changes in Heart Rate Following Uptitration of Beta-Blockers in Patients with Sub-Optimally Treated Heart Failure with Reduced Ejection Fraction in Sinus Rhythm versus Atrial Fibrillation

Background: In patients with heart failure with reduced ejection fraction (HFrEF) on sub-optimal doses of beta-blockers, it is conceivable that changes in heart rate following treatment intensification might be important regardless of underlying heart rhythm. We aimed to compare the prognostic significance of both achieved heart rate and change in heart rate following beta-blocker uptitration in patients with HFrEF either in sinus rhythm (SR) or atrial fibrillation (AF). Methods: We performed a post hoc analysis of the BIOSTAT-CHF study. We evaluated 1548 patients with HFrEF (mean age 67 years, 35% AF). Median follow-up was 21 months. Patients were evaluated at baseline and at 9 months. The combined primary outcome was all-cause mortality and heart failure hospitalisation stratified by heart rhythm and heart rate at baseline. Results: Despite similar changes in heart rate and beta-blocker dose, a decrease in heart rate at 9 months was associated with reduced incidence of the primary outcome in both SR and AF patients [HR per 10 bpm decrease—SR: 0.83 (0.75–0.91), p < 0.001; AF: 0.89 (0.81–0.98), p = 0.018], whereas the relationship was less strong for achieved heart rate in AF [HR per 10 bpm higher—SR: 1.26 (1.10–1.46), p = 0.001; AF: 1.08 (0.94–1.23), p = 0.18]. Achieved heart rate at 9 months was only prognostically significant in AF patients with high baseline heart rates (p for interaction 0.017 vs. low). Conclusions: Following beta-blocker uptitration, both achieved and change in heart rate were prognostically significant regardless of starting heart rate in SR, however, they were only significant in AF patients with high baseline heart rate

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

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)