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Background: Integration of large proteomics and genetic data in population-based studies can provide insights into discovery of novel biomarkers and potential therapeutic targets for cardiometabolic diseases (CMD). We aimed to synthesise existing evidence on the observational and genetic associations between circulating proteins and CMD.

Methods: PubMed, Embase and Web of Science were searched until July 2023 for potentially relevant prospective observational and Mendelian randomisation (MR) studies investigating associations between circulating proteins and CMD, including coronary heart disease, stroke, type 2 diabetes, heart failure, atrial fibrillation and atherosclerosis. Two investigators independently extracted study characteristics using a standard form and pooled data using random effects models.

Results: 50 observational, 25 MR and 10 studies performing both analyses were included, involving 26 414 160 non-overlapping participants. Meta-analysis of observational studies revealed 560 proteins associated with CMD, of which 133 proteins were associated with ≥2 CMDs (ie, pleiotropic). There were 245 potentially causal protein biomarkers identified in MR pooled results, involving 23 pleiotropic proteins. IL6RA and MMP12 were each causally associated with seven diseases. 22 protein-disease pairs showed directionally concordant associations in observational and MR pooled estimates. Addition of protein biomarkers to traditional clinical models modestly improved the accuracy of predicting incident CMD, with the highest improvement for heart failure (ΔC-index ~0.2). Of the 245 potentially causal proteins (291 protein-disease pairs), 3 pairs were validated by evidence of drug development from existing drug databases, 288 pairs lacked evidence of drug development and 66 proteins were drug targets approved for other indications.

Conclusions: Combined analyses of observational and genetic studies revealed the potential causal role of several proteins in the aetiology of CMD. Novel protein biomarkers are promising targets for drug development and risk stratification.

Prospero registration number: CRD42022350327.

For patients with heart failure and reduced or mildly reduced left ventricular ejection fraction, iron deficiency is common and associated with more severe symptoms, worse quality of life and an increased risk of hospitalisations and death. Iron deficiency can be swiftly, effectively and safely treated by administering intravenous iron, either as ferric carboxymaltose or ferric derisomaltose, which improves patient well-being and reduces the risk of hospitalisations including those for heart failure. However, the current definition of iron deficiency in heart failure has serious flaws. A serum ferritin <100 µg/L does not identify patients more likely to respond to intravenous iron. In contrast, patients with transferrin saturations <20%, most of whom are also anaemic, are more likely to have a beneficial response to intravenous iron. In this review, we summarise the available evidence for use of intravenous iron in heart failure and provide recommendations for targeted future research and practical considerations for the general cardiologist.

Background: The best management of symptomatic patients with low-gradient (LG) severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) has not been established. The Randomised study for the Optimal Treatment of symptomatic patients with low-gradient severe Aortic valve Stenosis (ROTAS) trial aimed to assess the superiority of aortic valve replacement (AVR) versus medical treatment (MT) in this specific group of AS patients.

Methods: Patients with symptomatic LG severe AS and preserved LVEF (>50%) underwent dobutamine stress echocardiography and/or CT-aortic calcium score to confirm AS severity and were then randomised 1:1 to AVR or MT. The primary endpoint was a composite of overall death and/or cardiovascular hospitalisation.

Results: The ROTAS study was stopped early because of insufficient recruitment. In the end, only 52 patients (age 79±7 years; women 54%; NYHA III-IV 27%; median STS score 3.3%) were included in the study. During follow-up (mean: 14±7 months), the primary endpoint occurred in 12 (23%) patients. Compared with MT, AVR was not associated with a significant prognostic benefit (events: 5/26 (19%) vs 7/26 (27%) (HR 0.76, 95% CI 0.24 to 2.39, p=0.63). During follow-up, 11 (42%) patients in the MT group developed class I criteria for AVR or severe symptoms justifying a cross-over to the AVR group.

Conclusions: Because of the small number of included patients and short follow-up the ROTAS trial was underpowered and unable to demonstrate a difference in the study endpoint between treatment arms. In patients in the MT arm, a regular echocardiographic and clinical assessment might be useful to disclose those developing class I indications of AVR or severe AS-related symptoms.

Trial registration number: NCT01835028.

Background: The relationships between various obesity measures and hypertensive disorders of pregnancy (HDP) remain inadequately explored, and their causal links are not well understood. This study aims to clarify these associations and investigate the mediating role of triglycerides.

Methods: We conducted a comprehensive meta-analysis of observational studies alongside Mendelian randomisation (MR) analysis to assess the impact of 10 obesity measures on HDP risk. Additionally, we evaluated the mediating effect of triglycerides.

Results: Our meta-analysis revealed significant associations between maternal prepregnancy overweight/obesity and increased risks of gestational hypertension (GH) (overweight: OR=1.98, 95% CI 1.83 to 2.15; obesity: OR=3.77, 95% CI 3.45 to 4.13) and pre-eclampsia (overweight: OR=1.78, 95% CI 1.67 to 1.90; obesity: OR=3.46, 95% CI 3.16 to 3.79). Higher maternal waist circumference (WC) was also linked to increased pre-eclampsia risk (OR=1.45, 95% CI 1.14 to 1.83). MR analyses indicated that each 1-SD increase in genetically predicted obesity measures (whole body fat mass, body fat percentage, trunk fat mass, trunk fat percentage, body mass index, WC, hip circumference) was associated with higher risks of GH and pre-eclampsia. Triglycerides mediated 4.3%-14.1% of the total genetic effect of these obesity measures on GH and pre-eclampsia risks.

Conclusions: This study demonstrates that various obesity measures are causally linked to increased HDP risk and highlights the mediating role of triglycerides. These findings could inform clinical practices and public health strategies aimed at reducing HDP through targeted obesity and triglyceride management.

Background: Participation in regular exercise activities is recommended for patients with chronic heart failure. However, less is known about the effect of exercise in patients with genetic dilated cardiomyopathy (DCM). We sought to examine the effect of vigorousintensity training on physical capacity in patients with DCM caused by truncating titin variants (TTNtv).

Trial design: Non-randomised clinical pre-post trial of exercise training.

Methods: Individuals with DCM-TTNtv were included from outpatient clinics for inherited cardiac diseases. The trial consisted of 8 weeks of usual care followed by 8 weeks of regular vigorous-intensity cycling exercise, enclosed by three test days. The primary outcome was change in peak oxygen uptake (VO₂). Secondary outcomes included change in blood volume, total haemoglobin mass, measures of systolic function and cardiac output/stroke volume during exercise.

Results: Thirteen out of 14 included participants (43% women, age 48±11 years, body mass index: 30±6 kg/m²) completed the trial. In the exercise training period, peak VO₂ increased by +1.9 mL/kg^/min (95% CI +0.9 to +2.9, p=0.002). Compared with usual care, exercise training improved peak VO₂ by +2.9 mL/kg/min (95% CI +1.2 to +4.5, p=0.002), corresponding to a 10% increase. Adaptations to exercise training included an increase in resting cardiac output (+0.8 L/min, p=0.042), total blood volume (+713 mL, p<0.001), total haemoglobin mass (+73 g, p<0.001), and improved left ventricular (LV) systolic function (LV ejection fraction: +3.2% (p=0.053) and global longitudinal strain: -2.0% (p=0.044)). No exercise-related adverse events or change in plasma biomarkers of cardiac or skeletal muscle damage were observed.

Conclusions: Our study shows that vigorous intensity exercise training improved peak VO₂ in patients with DCM-TTNtv. Exercise training was associated with improved LV systolic function and increased blood volume and oxygen carrying capacity. Future research should investigate the effect of long-term exercise in this group.

Trial registration number: NCT05180188.

Background: Resveratrol, a dietary supplement that intervenes in cellular metabolism, has been shown to reduce aortic growth rate in a mouse model of Marfan syndrome (MFS), a condition associated in humans with life-threatening aortic complications, often preceded by aortic dilatation. The primary objective of this study was to investigate the effects of resveratrol on aortic growth rate in patients with MFS .

Methods: In this investigator-initiated, single-arm open-label multicentre trial, we analysed resveratrol treatment in adults aged 18-50 years with MFS. The primary endpoint was the change in estimated annual aortic growth at five predefined levels in the thoracic aorta after 1 year of resveratrol treatment, evaluated using a linear mixed model. Aortic diameters were measured by cardiac MRI at three time points to analyse the annual aortic expansion rate before and after initiation of treatment. Additionally, annual aortic growth was compared with growth in a previously conducted losartan randomised clinical trial.

Results: 898 patients were screened of which 19% (168/898) patients met the inclusion criteria.36% (61/168) patients signed informed consent and 93% (57/61) aged 37±9 years, of which 28 males (49%) were included in the final analysis of the study. 46% (26/57) had undergone aortic root replacement prior to the study. Aortic root diameters remained stable after 1.2±0.3 years of resveratrol administration. A trend towards a decrease in estimated growth rate (mm/year) was observed in the aortic root (from 0.39±0.06 to -0.13±0.23, p=0.072), ascending aorta (from 0.40±0.05 to -0.01±0.18, p=0.072) and distal descending aorta (from 0.32±0.04 to 0.01±0.14, p=0.072).

Conclusion: Resveratrol treatment for 1 year may stabilise the aortic growth rate in adult patients with MFS. However, a subsequent randomised clinical trial with a longer follow-up duration and a larger study cohort is needed to establish an actual long-term beneficial effect of this dietary supplement in patients with MFS.

Trial registration number: NL66127.018.18.

Despite significant progress in cardiovascular pharmacotherapy and interventional strategies, cardiovascular disease (CVD), in particular ischaemic heart disease, remains the leading cause of morbidity and mortality among women in the UK and worldwide. Women are underdiagnosed, undertreated and under-represented in clinical trials directed at management strategies for CVD, making their results less applicable to this subset. Women have additional sex-specific risk factors that put them at higher risk of future cardiovascular events. Psychosocial risk factors, socioeconomic deprivation and environmental factors have an augmented impact on women's cardiovascular health, highlighting the need for a holistic approach to care that considers risk factors specifically related to female biology alongside the traditional risk factors. Importantly, in the UK, even in the context of a National Health Service, there exist significant regional variations in age-standardised mortality rates among patients with CVD. Given most CVDs are preventable, concerted efforts are necessary to address the unmet needs and ensure parity of care for women with CVD. The present consensus document, put together by the British Cardiovascular Society (BCS)'s affiliated societies, specifically portrays the current status on the sex-related differences in the diagnosis and treatment of each of the major CVD areas and proposes strategies to overcome the barriers in accessing diagnoses and treatments among women. This document aims at raising awareness of the scale of the current problem and hopes to stimulate a multifaceted approach to address sex disparities and enable future comprehensive sex- and gender-based research through collaboration across different affiliated societies within the BCS.

Background and aims: Current ESC guidelines on the management of patients after acute myocardial infarction only include the evaluation of left ventricular (LV) function by assessment of the ejection fraction in addition to clinical risk scores to estimate the patient's prognosis. We aimed to determine, whether comprehensive evaluation of cardiac function using LV and right ventricular (RV) global longitudinal strain (GLS) and left atrial (LA) reservoir strain improves the prediction of survival in patients with acute myocardial infarction.

Methods: In patients with non-ST segment elevation or ST segment elevation myocardial infarction receiving echocardiography within 1 year after revascularisation, LV-GLS, RV-GLS and LA reservoir strain were quantified. In multivariable Cox regression analysis, HRs and 95% CIs were calculated per 1 SD increase in strain measure, adjusting for age, sex, systolic blood pressure, low-density lipoprotein cholesterol, smoking, diabetes and family history of premature coronary artery disease.

Results: During a median follow-up of 1.5 (0.5-4.2) years, 157 (11.1%) out of 1409 patients (64.4±13.5 years, 24.7% female) died. LV-GLS (1.68 (1.37-2.06), p<0.001), RV-GLS (1.39 (1.16-1.67), p<0.001) and LA reservoir strain (0.57 (0.47-0.69), p<0.001) were associated with mortality. Adding LV ejection fraction, tricuspid annular plane systolic excursion (TAPSE) or LA volume index to these models did not alter the association of strain measures of the LV (1.41 (1.06-1.89), p=0.02), RV (1.48 (1.03-2.13), p=0.04) or LA (0.61 (0.49-0.76), p<0.001). In receiver operating characteristics, combining the three strain measures improved the prediction of mortality above risk factors (AUC: 0.67 (0.63-0.71) to 0.75 (0.70-0.80)), while further addition of LV ejection fraction, TAPSE and LA volume index did not (0.75 (0.70-0.81)).

Conclusion: The comprehensive evaluation of contractility of various cardiac chambers via transthoracic echocardiography using myocardial strain analysis, when routinely performed after acute myocardial infarction, may help to detect patients at increased mortality risk.