Search

Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight. Methods: Uncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. Results: Higher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45–2.49]; P =3.23×10 −6 ) and reduced birthweight (OR=0.83 [95% CI=0.79–0.86]; P =3.96×10 −18 ), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44–1.94]; P =7.45×10 −12 ; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04–1.19]; P =1.19×10 −3 ), but not with reduced birthweight. Conclusions: Our results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Obesity is associated with higher risks of cardiac arrhythmias. Although this may be partly explained by concurrent cardiometabolic ill-health, growing evidence suggests that increasing adiposity independently confers risk for arrhythmias. Among fat depots, epicardial adipose tissue (EAT) exhibits a proinflammatory secretome and, given the lack of fascial separation, has been implicated as a transducer of inflammation to the underlying myocardium. The present review explores the mechanisms underpinning adverse electrophysiological remodeling as a consequence of EAT accumulation and the consequent inflammation. We first describe the physiological and pathophysiological function of EAT and its unique secretome and subsequently discuss the evidence for ionic channel and connexin expression modulation as well as fibrotic remodeling induced by cytokines and free fatty acids that are secreted by EAT. Finally, we highlight how weight reduction and regression of EAT volume may cause reverse remodeling to ameliorate arrhythmic risk.

ImportanceHypertensive disorders in pregnancy (HDPs) are major causes of maternal and fetal morbidity and are observationally associated with future maternal risk of cardiovascular disease. However, observational results may be subject to residual confounding and bias.ObjectiveTo investigate the association of HDPs with multiple cardiovascular diseases.Design, Setting, and ParticipantsA genome-wide genetic association study using mendelian randomization (MR) was performed from February 16 to March 4, 2022. Primary analysis was conducted using inverse-variance-weighted MR. Mediation analyses were performed using a multivariable MR framework. All studies included patients predominantly of European ancestry. Female-specific summary-level data from FinnGen (sixth release).ExposuresUncorrelated (r2Main Outcomes and MeasuresGenetic association estimates for outcomes were extracted from genome-wide association studies of 122 733 cases for coronary artery disease, 34 217 cases for ischemic stroke, 47 309 cases for heart failure, and 60 620 cases for atrial fibrillation.ResultsGenetically predicted HDPs were associated with a higher risk of coronary artery disease (odds ratio [OR], 1.24; 95% CI, 1.08-1.43; P = .002); this association was evident for both gestational hypertension (OR, 1.08; 95% CI, 1.00-1.17; P = .04) and preeclampsia/eclampsia (OR, 1.06; 95% CI, 1.01-1.12; P = .03). Genetically predicted HDPs were also associated with a higher risk of ischemic stroke (OR, 1.27; 95% CI, 1.12-1.44; P = 2.87 × 10−4). Mediation analysis revealed a partial attenuation of the effect of HDPs on coronary artery disease after adjustment for systolic blood pressure (total effect OR, 1.24; direct effect OR, 1.10; 95% CI, 1.02-1.08; P = .02) and type 2 diabetes (total effect OR, 1.24; direct effect OR, 1.16; 95% CI, 1.04-1.29; P = .008). No associations were noted between genetically predicted HDPs and heart failure (OR, 0.97; 95% CI, 0.76-1.23; P = .79) or atrial fibrillation (OR, 1.11; 95% CI, 0.65-1.88; P = .71).Conclusions and RelevanceThe findings of this study provide genetic evidence supporting an association between HDPs and higher risk of coronary artery disease and stroke, which is only partially mediated by cardiometabolic factors. This supports classification of HDPs as risk factors for cardiovascular disease.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health Research Background/purpose: Small-scale studies have associated obesity and metabolic ill-health with QTc interval prolongation. Whether these associations are modulated by an underlying genetic predilection and translate into higher risks of ventricular arrhythmias (VA) is unknown. Methods Using the UK Biobank and adjusted multivariate regression analysis, we studied the associations between QTc and clinical measures of adiposity and metabolic ill-health. A polygenic risk score was used to determine whether these associations are modulated by a genetic predilection for QTc prolongation. We compared QTc between four clinical phenotypes defined according to presence (+) or absence (-) of obesity (Ob), and metabolic ill-health (MU). Logistic regression was used to calculate odds ratios (OR) for VA amongst these groups. Results 23,683 individuals (11,563 male, mean age 61.0 + 7.5years) had ECG and clinical data available. QTc prolongs with increasing body mass index (0.76ms/kg/m2, 95%CI: 0.68-0.83ms/kg/m2), body fat (0.45ms/%, 95%CI:0.39-0.50ms/%), hip girth (0.35ms/cm, 95%CI:0.31-0.39ms/cm) and waist girth (0.32ms/cm, 95%CI:0.29-0.35ms/cm); all p Conclusion Adiposity and metabolic perturbation prolong QTc to a similar extent, and their co-existence exerts an additive effect. These effects are independent of genetically determined repolarisation reserve. Despite their comparable QTc prolonging effects, metabolic ill-health is associated with higher OR for VA than obesity. VA in obesity and metabolic dysfunctionReference phenotypeOb + MU-Ob-MU+Ob + MU+Ob-MU+male1.10(0.87-1.39)ns5.96 (4.70-7.55)***6.99(5.72-8.54)***female0.87(0.64-1.18)ns5.10(3.34-7.80)***3.56(2.66-4.77)***Ob + MU-male--6.01(4.98-7.26)***female--5.61(4.18-7.52)***Ob + MU+male--1.25(1.05-1.49)*female--1.16(0.80-1.68)nsOb, obese; MU, metabolically unhealthy; +, presence; -, absence; ns, non-significant; *p

Background Survivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction–reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis. Methods and Results Infarction–reperfusion surgery was carried out in male Sprague‐Dawley rats followed by 7 days of rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion‐weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7‐day postinfarction administration of rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, P =0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: −5% versus −15%; P =0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, P =0.042), and remodeling of the 3‐dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, P =0.013) and the dispersion (9° versus 12°, P =0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality. Conclusions Enhancement of gap junctions function by rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation–induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarction management to reduce late arrhythmic risk.

BackgroundAlthough obesity, defined by body mass index (BMI), has been associated with a higher risk of hospitalisation and more severe course of illness in Covid-19 positive patients amongst the British population, it is unclear if this translates into increased mortality. Furthermore, given that BMI is an insensitive indicator of adiposity, the effect of adipose volume on Covid-19 outcomes is also unknown.MethodsWe used the UK Biobank repository, which contains clinical and anthropometric data and is linked to Public Health England Covid-19 healthcare records, to address our research question. We performed age- and sex- adjusted logistic regression and Chi-squared test to compute the odds for Covid-19-related mortality as a consequence of increasing BMI, and other more sensitive indices of adiposity such as waist:hip ratio (WHR) and percent body fat, as well as concomitant cardiometabolic illness.Results13,502 participants were tested for Covid-19 (mean age 70 ± 8 years, 48.9% male). 1582 tested positive (mean age 68 ± 9 years, 52.8% male), of which 305 died (mean age 75 ± 6 years, 65.5% male). Increasing adiposity was associated with higher odds for Covid-19-related mortality. For every unit increase in BMI, WHR and body fat, the odds of death amongst Covid19-positive participants increased by 1.04 (95% CI 1.01–1.07), 10.71 (95% CI 1.57–73.06) and 1.03 (95% CI 1.01–1.05), respectively (allp 2), Covid-19 positive participants with BMI > 35 kg/m2had significantly higher odds of Covid-19-related death (OR 1.70, 95% CI 1.06–2.74,p ConclusionsAnthropometric indices that are more sensitive to adipose volume and its distribution than BMI, as well as concurrent cardiometabolic illness, are associated with higher odds of Covid-19-related mortality amongst the UK Biobank cohort that tested positive for the infection. These results suggest adipose volume may contribute to adverse Covid-19-related outcomes associated with obesity.

Chronic inflammatory disorders, including rheumatoid arthritis (RA), are associated with a twofold increase in the incidence of sudden cardiac death (SCD) compared with the healthy population. Although this is partly explained by an increased prevalence of coronary artery disease, growing evidence suggests that ischemia alone cannot completely account for the increased risk. The present review explores the mechanisms of cardiac electrophysiological remodeling in response to chronic inflammation in RA. In particular, it focuses on the roles of nonischemic structural remodeling, altered cardiac ionic currents, and autonomic nervous system dysfunction in ventricular arrhythmogenesis and SCD. It also explores whether common genetic elements predispose to both RA and SCD. Finally, it evaluates the potential dual effects of disease-modifying therapy in both diminishing and promoting the risk of ventricular arrhythmias and SCD.

The subcutaneous implantable cardioverter-defibrillator (S-ICD) represents an exciting development in ICD technology. It has relative advantages over traditional transvenous systems, particularly for young patients in whom the lifetime risk of device-related complications may be deemed to be unacceptably high. While data relating to device longevity and long term safety profile is yet to be accrued, several recent studies have demonstrated good clinical efficacy comparable to transvenous ICDs. Indeed, new techniques have also been developed to simplify the S-ICD implantation procedure and attempts have been made to address challenges pertaining to T-wave oversensing to reduce the delivery of inappropriate shocks. The impact of inappropriate shocks and lack of anti-tachycardia pacing (ATP) function are not only contentious matters, but also have important implications for patients in whom the S-ICD would be suitable. It is envisaged that subsequent models of this device will be less cumbersome, with the possibility that an entirely leadless pacemaker-defibrillator will one day be possible. Although the S-ICD may not completely replace transvenous devices in its current form, evidence suggests that it is a viable alternative particularly in preventing sudden cardiac death in non-pacing dependent patients.