Left ventricular mass regression, all-cause and cardiovascular mortality in chronic kidney disease: a meta-analysis

Background Cardiovascular disease is an important driver of the increased mortality associated with chronic kidney disease (CKD). Higher left ventricular mass (LVM) predicts increased risk of adverse cardiovascular outcomes and total mortality, but previous reviews have shown no clear association between intervention-induced LVM change and all-cause or cardiovascular mortality in CKD. Methods The primary objective of this meta-analysis was to investigate whether treatment-induced reductions in LVM over periods ≥12 months were associated with all-cause mortality in patients with CKD. Cardiovascular mortality was investigated as a secondary outcome. Measures of association in the form of relative risks (RRs) with associated variability and precision (95% confidence intervals [CIs]) were extracted directly from each study, when reported, or were calculated based on the published data, if possible, and pooled RR estimates were determined. Results The meta-analysis included 42 trials with duration ≥12 months: 6 of erythropoietin stimulating agents treating to higher vs. lower hemoglobin targets, 10 of renin-angiotensin-aldosterone system inhibitors vs. placebo or another blood pressure lowering agent, 14 of modified hemodialysis regimens, and 12 of other types of interventions. All-cause mortality was reported in 121/2584 (4.86%) subjects in intervention groups and 168/2606 (6.45%) subjects in control groups. The pooled RR estimate of the 27 trials ≥12 months with ≥1 event in ≥1 group was 0.72 (95% CI 0.57 to 0.90, p = 0.005), with little heterogeneity across studies. Directionalities of the associations in intervention subgroups were the same. Sensitivity analyses of ≥6 months (34 trials), ≥9 months (29 trials), and >12 months (10 trials), and including studies with no events in either group, demonstrated similar risk reductions to the primary analysis. The point estimate for cardiovascular mortality was similar to all-cause mortality, but not statistically significant: RR 0.67, 95% CI 0.39 to 1.16. Conclusions These results suggest that LVM regression may be a useful surrogate marker for benefits of interventions intended to reduce mortality risk in patients with CKD.

Comparative Efficacy of Medical Treatments for Chronic Heart Failure: A Network Meta-Analysis

Background: The medical treatments of chronic heart failure have made remarkable progress in recent years. It is crucial to determine the optimal drug combination based on current evidence.Methods: A search of PubMed, EMBASE, and Cochrane CENTRAL databases was conducted for studies on angiotensin receptor-neprilysin inhibitors (ARNIs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and ivabradine (IVA) between 1987 and 2021. The network meta-analysis was performed to compare the efficacy of drug therapies in heart failure with reduced ejection fraction (HFrEF).Results: Forty-eight randomized controlled trials (RCTs), which overall included 68,074 patients with HF and left ventricular ejection fraction (LVEF) ≤ 40%, were identified and included in the network meta-analysis. The efficacies of 13 intervention classes, including monotherapies or combinations of ACEI, ARB, ARNI, BB, MRA, SGLT2i, IVA, and placebo, on hospitalization for HF, cardiovascular mortality, and all-cause mortality were compared. Among the 13 included interventions, ARNI+BB+MRA, SGLT2i+ACEI+BB+MRA, and IVA+ACEI+BB+MRA were found to be best in terms of all three outcomes. Compared with placebo, these three drug combinations were associated with significant reductions in the risk of all-cause death, cardiovascular mortality and hospitalization for HF.Conclusions: ARNI+BB+MRA, SGLT2i+ACEI+BB+MRA, and IVA+ACEI+BB+MRA were the top three therapies for patients with HFrEF. The increasing use of combinations of conventional and novel drugs contributed to progressive reductions in hospitalization and mortality in patients with HFrEF.

Ethnic disparities in mortality among overweight or obese adults with newly diagnosed type 2 diabetes: a population-based cohort study

Purpose Ethnic variation in risk of type 2 diabetes is well established, but its impact on mortality is less well understood. This study investigated the risk of all-cause and cardiovascular mortality associated with newly diagnosed type 2 diabetes in White, Asian and Black adults who were overweight or obese. Methods This population-based cohort study used primary care records from the UK Clinical Practice Research Datalink, linked with secondary care and death registry records. A total of 193,528 obese or overweight adults (BMI of 25 or greater), with ethnicity records and no pre-existing type 2 diabetes were identified between 01 January 1995 and 20 April 2018. Multivariable Cox proportional hazards regression estimated hazards ratios (HR) for incident type 2 diabetes in different ethnic groups. Adjusted hazards ratios for all-cause and cardiovascular mortality were determined in individuals with newly diagnosed type 2 diabetes. Results During follow-up (median 9.8 years), the overall incidence rate of type 2 diabetes (per 1,000 person-years) was 20.10 (95% CI 19.90–20.30). Compared to Whites, type 2 diabetes risk was 2.2-fold higher in Asians (HR 2.19 (2.07–2.32)) and 30% higher in Blacks (HR 1.34 (1.23–1.46)). In individuals with newly diagnosed type 2 diabetes, the rates (per 1,000 person-years) of all-cause mortality and cardiovascular mortality were 24.34 (23.73–24.92) and 4.78 (4.51–5.06), respectively. Adjusted hazards ratios for mortality were significantly lower in Asians (HR 0.70 (0.55–0.90)) and Blacks (HR 0.71 (0.51–0.98)) compared to Whites, and these differences in mortality risk were not explained by differences in severity of hyperglycaemia. Conclusions/Interpretation Type 2 diabetes risk in overweight and obese adults is greater in Asian and Black compared to White ethnic populations, but mortality is significantly higher in the latter. Greater attention to optimising screening, disease and risk management appropriate to all communities with type 2 diabetes is needed.

Pregnancy Complications and Risk of Cardiovascular Disease Later in Life: A Nationwide Cohort Study

Background The aim of this study was to investigate the associations between pregnancy complications and cardiovascular mortality and hospitalizations of cardiovascular disease (CVD) after adjustment for major confounding. Methods and Results In a nationwide register‐based cohort study, women with singleton births between 1973 and 2014 were included from the Swedish Medical Birth Register. Outcomes of mortality and hospitalizations of CVD were collected from the Cause of Death Register and the National Inpatient Register. The cohort was followed from the date of the first delivery until death or end of follow‐up, whichever occurred first. The pregnancy complications studied were preeclampsia or eclampsia, gestational hypertension, gestational diabetes, preterm birth, small for gestational age, and stillbirth. Among the 2 134 239 women (mean age at first pregnancy, 27.0 [SD, 5.1] and mean parity 1.96 [SD, 0.9]), 19.1% (N=407 597) had 1 of the studied pregnancy complications. All pregnancy complications were associated with all‐cause and cardiovascular mortality and hospitalization for CVD (ischemic heart disease, ischemic stroke, and peripheral artery disease) after adjustment for major confounding in a Cox proportional hazard regression model. The adjusted hazard ratio for cardiovascular mortality was 1.84 (95% CI, 1.38–2.44) for preterm birth and 3.14 (95% CI, 1.81–5.44) for stillbirth. Conclusions In this large cohort study, pregnancy complications were associated with all‐cause mortality, cardiovascular mortality, and hospitalizations for CVD, also after adjusting for confounding, including overweight, smoking, and comorbidities. The study highlights that less established pregnancy complications such as preterm birth and stillbirth are also associated with cardiovascular mortality and CVD.

Serum Uric Acid as a Predictor of cardio-and cerebro-vascular diseases in Maintenance Hemodialysis Patients

Background: Hyperuricemia is associated with an increased risk of cardio-and cerebrovascular disease (CVD) in general population. However, in the hemodialysis (HD) patients, low serum uric acid (SUA) increases the risk of mortality. Considering that CVD is the principal cause of death among maintenance HD patients, the present study aimed to determine the predictive value of SUA for CVD outcome in this population. Methods: In this two-year follow-up prospective study, 205 outpatients under maintenance HD were enrolled from March 2017 to 2020. Patients’ demographic data, underlying diseases, and the results of serum tests, as well as two-year follow-up results of CVD events and mortality were recorded. Results: A total of 130 (63%) patients were eligible for analysis; 62.9% were male; mean age of participants was 59±13years. At follow-up, coronary artery disease was observed in 43.2%, peripheral artery disease in 26.5%, and cerebrovascular disease in 20.5%; angiography was required in 52.3% and 4.5% died of CVD. SUA was ≤5.4 mg/dL in 52 patients, 5.5-6.1 mg/dL in 19, and ≥6.2 mg/dL in 59 patients with significant difference based on mean age, sex distribution, occurrence of cerebrovascular disease and cardiovascular mortality (P<0.05). Patients with cerebrovascular disease had a significantly lower SUA levels (P=0.006). Logistic regression showed the significant effect of SUA on the occurrence of cerebrovascular disease (P=0.008). Conclusion: Low SUA can predict two-year incidence of cerebrovascular disease in HD patients. However, SUA levels did not show significant predictive effect on two-year coronary events, peripheral artery disease and cardiovascular mortality.

Annual change in the extracellular fluid/intracellular fluid ratio and mortality in patients undergoing maintenance hemodialysis

We aimed to investigate whether annual change in the extracellular fluid to intracellular fluid (ΔECF/ICF) ratio can accurately predict mortality in hemodialysis patients. Totally, 247 hemodialysis patients were divided into two groups according to the median baseline ECF/ICF ratio of 0.563 and ΔECF/ICF ≥ 0% or < 0% during the first year, respectively. Thereafter, they were divided into four groups according to each cutoff point and were followed up for mortality assessment. The ECF/ICF ratio increased from 0.566 ± 0.177 to 0.595 ± 0.202 in the first year (P = 0.0016). During the 3.4-year median follow-up, 93 patients died (42 cardiovascular-specific causes). The baseline ECF/ICF ≥ 0.563 and ΔECF/ICF ≥ 0% were independently associated with all-cause mortality (adjusted hazard ratio [aHR] 4.55, 95% confidence interval [CI] 2.60–7.98 and aHR 8.11, 95% CI 3.47–18.96, respectively). The aHR for ECF/ICF ≥ 0.563 and ΔECF/ICF ≥ 0% vs. ECF/ICF < 0.563 and ΔECF/ICF < 0% was 73.49 (95% CI 9.45–571.69). For model discrimination, adding the ΔECF/ICF (0.859) alone and both the baseline ECF/ICF and ΔECF/ICF (0.903) to the established risk model (0.746) significantly improved the C-index. Similar results were obtained for cardiovascular mortality. In conclusion, the ΔECF/ICF ratio could not only predict all-cause and cardiovascular mortality but also improve predictability of mortality in hemodialysis patients.

Association of circulating MR-proADM with all-cause and cardiovascular mortality in the general population: Results from the KORA F4 cohort study

Background and aim Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort. Methods Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8–9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603–1551). Results MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72–3.26) and 2.31 (1.67–3.20)) and cardiovascular mortality (4.28 (2.19–8.39) and 4.44 (2.25–8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality. Conclusions We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.

Isolated Diastolic Hypertension and Risk of Cardiovascular Events: A Systematic Review and Meta-Analysis of Cohort Studies With 489,814 Participants

Background: The association between isolated diastolic hypertension (IDH) and cardiovascular events has been inconsistently reported. This meta-analysis of cohort studies was designed to investigate the effect of the 2018 European Society of Cardiology (ESC) definition of IDH on the risk of composite cardiovascular events, cardiovascular mortality, all-cause mortality, and all strokes including ischemic stroke (IS) and hemorrhagic stroke (HS).Methods: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to July 6, 2021. Cohort studies that investigated the association between IDH and cardiovascular events risk, compared to normotension, were included. Pooled hazard ratios (HRs) and 95% CIs were calculated using a random-effects models and heterogeneity was evaluated using Q-test and I2 statistic. The robustness of the associations was identified using sensitivity analysis. The methodological quality of the studies was assessed using the Newcastle–Ottawa scale. Publication bias was assessed using funnel plot, trim-and-fill method, Begg's test, and Egger's test.Results: A total of 15 cohort studies (13 articles) including 489,814 participants were included in this meta-analysis. The follow-up period ranged from 4.3 to 29 years. IDH was significantly associated with an increased risk of composite cardiovascular events (HR 1.28, 95% CI: 1.07–1.52, p = 0.006), cardiovascular mortality (HR 1.45, 95% CI: 1.07–1.95, p = 0.015), all strokes (HR 1.44, 95% CI: 1.04–2.01, p = 0.03), and HS (HR 1.64, 95% CI: 1.18–2.29, p = 0.164), but not associated with all-cause mortality (HR 1.20, 95% CI: 0.97–1.47, p = 0.087) and IS (HR 1.56, 95% CI: 0.87–2.81, p = 0.137). Subgroup analysis further indicated that IDH in the younger patients (mean age ≤ 55 years) and from Asia were significantly associated with an increased risk of composite cardiovascular events, while the elderly patients (mean age ≥ 55 years), Americans, and Europeans were not significantly associated with an increased risk of composite cardiovascular events.Conclusion: This meta-analysis provides evidence that IDH defined using the 2018 ESC criterion is significantly associated with an increased risk of composite cardiovascular events, cardiovascular mortality, all strokes and HS, but not significantly associated with all-cause death and IS. These findings also emphasize the importance for patients with IDH to have their blood pressure within normal, especially in the young adults and Asians.Trial Registration: PROSPERO, Identifier: CRD42021254108.