A comparison of echocardiographic and circulating cardiac biomarkers for predicting incident cardiovascular disease.

BACKGROUND: Echocardiographic measures are known predictors of cardiovascular disease (CVD) in the general population. This study compared the predictive value of such measures to that of circulating cardiac biomarkers for a composite cardiovascular disease outcome in an aging population. METHODS: In this prospective population-based cohort study, echocardiography was performed at baseline together with assessments of traditional CVD risk factors and circulating cardiac biomarkers, NT-proBNP and troponin I, in 1016 individuals all aged 70 years. Assessments were repeated at ages 75 and 80. A composite CVD outcome (myocardial infarction, heart failure or ischemic stroke) was charted over 15 years. All echocardiography variables, except for the E/A ratio, were analyzed on a continuous scale. RESULTS: Over 10 years, left atrial (LA) diameter, left ventricular mass index (LVMI) and high E/A ratio (>1.5) increased, while left ventricular ejection fraction (LVEF) remained unchanged. Using Cox proportional hazard analyses with time-updated variables for echocardiographic measures and traditional risk factors, an enlarged LA diameter and a low LVEF were independently related to incident CVD in 222 participants. The addition of LA diameter and LVEF to traditional risk factors increased the C-statistic by 1.5% (p = 0.008). However, the addition of troponin I and NT-proBNP to traditional risk factors increased the C-statistic by 3.0% (p<0.001). CONCLUSION: An enlarged LA diameter and a low LVEF improved the prediction of incident CVD compared to traditional risk factors. However, given that troponin I and NT-proBNP improved prediction to a similar extent, the use of simple blood tests to improve clinical cardiovascular disease risk prediction is only further supported by this study.

Renin-Angiotensin Aldosterone System Inhibitors and COVID-19: A Systematic Review and Meta-Analysis Revealing Critical Bias Across a Body of Observational Research.

Background Renin-angiotensin aldosterone system (RAAS) inhibitor-COVID-19 studies, observational in design, appear to use biased methods that can distort the interaction between RAAS inhibitor use and COVID-19 risk. This study assessed the extent of bias in that research and reevaluated RAAS inhibitor-COVID-19 associations in studies without critical risk of bias. Methods and Results Searches were performed in MEDLINE, EMBASE, and CINAHL databases (December 1, 2019 to October 21, 2021) identifying studies that compared the risk of infection and/or severe COVID-19 outcomes between those using or not using RAAS inhibitors (ie, angiotensin-converting enzyme inhibitors or angiotensin II type-I receptor blockers). Weighted hazard ratios (HR) and 95% CIs were extracted and pooled in fixed-effects meta-analyses, only from studies without critical risk of bias that assessed severe COVID-19 outcomes. Of 169 relevant studies, 164 had critical risks of bias and were excluded. Ultimately, only two studies presented data relevant to the meta-analysis. In 1 351 633 people with uncomplicated hypertension using a RAAS inhibitor, calcium channel blocker, or thiazide diuretic in monotherapy, the risk of hospitalization (angiotensin-converting enzyme inhibitor: HR, 0.76; 95% CI, 0.66-0.87; P<0.001; angiotensin II type-I receptor blockers: HR, 0.86; 95% CI, 0.77-0.97; P=0.015) and intubation or death (angiotensin-converting enzyme inhibitor: HR, 0.64; 95% CI, 0.48-0.85; P=0.002; angiotensin II type-I receptor blockers: HR, 0.74; 95% CI, 0.58-0.95; P=0.019) with COVID-19 was lower in those using a RAAS inhibitor. However, these protective effects are probably not clinically relevant. Conclusions This study reveals the critical risk of bias that exists across almost an entire body of COVID-19 research, raising an important question: Were research methods and/or peer-review processes temporarily weakened during the surge of COVID-19 research or is this lack of rigor a systemic problem that also exists outside pandemic-based research? Registration URL: www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021237859.

Renin-Angiotensin Aldosterone System Inhibitors in Primary Prevention and COVID-19.

Background Considering the widespread risk of collider bias and confounding by indication in previous research, the associations between renin-angiotensin aldosterone system (RAAS) inhibitor use and COVID-19 remain unknown. Accordingly, this study tested the hypothesis that RAAS inhibitors influence the summation effect of COVID-19 and its progression to severe outcomes. Methods and Results This nationwide cohort study compared all residents of Sweden, without prior cardiovascular disease, in monotherapy (as of January 1, 2020) with a RAAS inhibitor to those using a calcium channel blocker or a thiazide diuretic. Comparative cohorts were balanced using machine-learning-derived propensity score methods. Of 165 355 people in the analysis (51% women), 367 were hospitalized or died with COVID-19 (246 using a RAAS inhibitor versus 121 using a calcium channel blocker or thiazide diuretic; Cox proportional hazard ratio [HR], 0.97; 95% CI, 0.74-1.27). When each outcome was assessed separately, 335 people were hospitalized with COVID-19 (HR, 0.92; 95% CI, 0.70-1.22), and 64 died with COVID-19 (HR, 1.22; 95% CI, 0.68-2.19). The severity of COVID-19 outcomes did not differ between those using a RAAS inhibitor and those using a calcium channel blocker or thiazide diuretic (ordered logistic regression odds ratio, 1.01; 95% CI, 0.89-1.14). Conclusions Despite potential limitations, this study is among the best available evidence that RAAS inhibitor use in primary prevention does not increase the risk of severe COVID-19 outcomes; presenting strong data from which scientists and policy makers alike can base, with greater confidence, their current position on the safety of using RAAS inhibitors during the COVID-19 pandemic.

The continuums of impairment in vascular reactivity across the spectrum of cardiometabolic health: A systematic review and network meta-analysis.

This study aimed to assess, for the first time, the change in vascular reactivity across the full spectrum of cardiometabolic health. Systematic searches were conducted in MEDLINE and EMBASE databases from their inception to March 13, 2017, including studies that assessed basal vascular reactivity in two or more of the following health groups (aged ≥18 years old): healthy, overweight, obesity, impaired glucose tolerance, metabolic syndrome, or type 2 diabetes with or without complications. Direct and indirect comparisons of vascular reactivity were combined using a network meta-analysis. Comparing data from 193 articles (7226 healthy subjects and 19344 patients), the network meta-analyses revealed a progressive impairment in vascular reactivity (flow-mediated dilation data) from the clinical onset of an overweight status (-0.41%, 95% CI, -0.98 to 0.15) through to the development of vascular complications in those with type 2 diabetes (-4.26%, 95% CI, -4.97 to -3.54). Meta-regressions revealed that for every 1 mmol/l increase in fasting blood glucose concentration, flow-mediated dilation decreased by 0.52%. Acknowledging that the time course of disease may vary between patients, this study demonstrates multiple continuums of vascular dysfunction where the severity of impairment in vascular reactivity progressively increases throughout the pathogenesis of obesity and/or insulin resistance, providing information that is important to enhancing the timing and effectiveness of strategies that aim to improve cardiovascular outcomes.

Prevalence and profile of "seasonal frequent flyers" with chronic heart disease: Analysis of 1598 patients and 4588 patient-years follow-up.

BACKGROUND: Peaks and troughs in cardiovascular events correlated with seasonal change is well established from an epidemiological perspective but not a clinical one. METHODS: Retrospective analysis of the recruitment, baseline characteristics and outcomes during minimum 12-month exposure to all four seasons in 1598 disease-management trial patients hospitalised with chronic heart disease. Seasonality was prospectively defined as ≥4 hospitalisations (all-cause) AND >45% of related bed-days occurring in any one season during median 988 (IQR 653, 1394) days follow-up. RESULTS: Patients (39% female) were aged 70 ±â€¯12 years and had a combination of coronary artery disease (58%), heart failure (54%), atrial fibrillation (50%) and multimorbidity. Overall, 29.9% of patients displayed a pattern of seasonality. Independent correlates of seasonality were female gender (adjusted OR 1.27, 95% CI 1.01-1.61; p = 0.042), mild cognitive impairment (adjusted OR 1.51, 95% CI 1.16-1.97; p = 0.002), greater multimorbidity (OR 1.20, 95% CI 1.15-1.26 per Charlson Comorbidity Index Score; p < 0.001), higher systolic (OR 1.01, 95%CI 1.00-1.01 per 1 mmHg; p = 0.002) and lower diastolic (OR 0.99, 95% CI 0.98-1.00 per 1 mmHg; p = 0.002) blood pressure. These patients were more than two-fold more likely to die (adjusted HR 2.16, 95% CI 1.60-2.90; p < 0.001) with the highest and lowest number of deaths occurring during spring (31.7%) and summer (19.9%), respectively. CONCLUSIONS: Despite high quality care and regardless of their diagnosis, we identified a significant proportion of "seasonal frequent flyers" with concurrent poor survival in this real-world cohort of patients with chronic heart disease.

Transient endothelial dysfunction induced by sugar-sweetened beverage consumption may be attenuated by a single bout of aerobic exercise.

BACKGROUND: This study assessed whether aerobic exercise would attenuate microvascular endothelial dysfunction induced by commercial sugar-sweetened beverage (SSB) consumption. METHODS: Eleven healthy males participated in this randomized, single-blind crossover study. Cutaneous microvascular endothelial function was assessed using laser speckle contrast imaging coupled with post-occlusive reactive hyperemia before and after a) consumption of water; b) consumption of a commercial SSB; c) 30min of aerobic exercise followed by water consumption; and d) 30 minutes of aerobic exercise followed by SSB consumption. Blood glucose and arterial pressure responses were also monitored. Volumes of water and SSB consumed (637.39±29.15 mL) were individualized for each participant, ensuring SSB consumption delivered 1 g of sucrose per kg of body weight. Exercise was performed at 75% of the maximal oxygen uptake heart rate. RESULTS: Compared to water consumption, the commercial SSB elevated blood glucose concentrations in both sedentary (4.69±0.11 vs. 7.47±0.28 mmol/L, P<0.05) and exercised states (4.95±0.13 vs. 7.93±0.15 mmol/L, P<0.05). However, the decrease in microvascular endothelial function observed following sedentary SSB consumption, expressed as the percentage increase from baseline (208.60±22.40 vs. 179.83±15.80%, P=0.01) and the change in peak hyperemic blood flux from basal to post-intervention assessments (-0.04±0.03 vs. -0.12±0.02 ΔCVC, P=0.01), was attenuated following 30min of aerobic exercise. CONCLUSIONS: To our knowledge, this is the first study to provide evidence that a single bout of aerobic exercise may prevent transient SSB-mediated microvascular endothelial dysfunction.

Assessing cutaneous microvascular function with iontophoresis: Avoiding non-specific vasodilation.

AIM: Iontophoresis of vasoactive agents is commonly used to assess cutaneous microvascular reactivity. However, it is known that iontophoresis can be limited by confounding non-specific vasodilatory effects. Despite this, there is still no standardization of protocols or data expression. Therefore, this study evaluated commonly used protocols of iontophoresis by assessing each for evidence of non-specific vasodilatory effects and examined the reproducibility of those protocols that are free of non-specific responses. METHODS: Twelve healthy participants were administered doses of acetylcholine (ACh) 1-2% and sodium nitroprusside (SNP) 1%, diluted in sodium chloride 0.9% or deionized water, and insulin 100U/mL in a sterile diluent using iontophoresis coupled with laser speckle contrast imaging (LSCI). Increases in blood flux at a control electrode, containing the diluent only, indicated a non-specific response. Reproducibility of iontophoresis protocols that were free of non-specific vasodilatory effects were subsequently compared to that of post-occlusive reactive hyperemia (PORH), used as a standard, in 20 healthy participants. RESULTS: Iontophoresis of ACh or SNP in sodium choloride (0.02mA for 200 and 400s, respectively) and ACh in deionized water (0.1mA for 30s) mediated the least non-specific vasodilatory effects. Microvascular responses to insulin were mediated mainly by non-specific effects. Compared to PORH, the intraday and interday reproducibility for iontophoresis of ACh and SNP (0.02mA for 200 and 400s, respectively) with LSCI was weaker, but still deemed good to excellent when data was expressed, in perfusion units or cutaneous vascular conductance, as the absolute peak blood flux response to the vascular reactivity test or as the change in blood flux between peak and baseline values. CONCLUSION: This study provides updated recommendations for assessing cutaneous microvascular function with iontophoresis.

Effects of Sugar-Sweetened Beverage Consumption on Microvascular and Macrovascular Function in a Healthy Population.

OBJECTIVE: To assess vascular function during acute hyperglycemia induced by commercial sugar-sweetened beverage (SSB) consumption and its effect on underlying mechanisms of the nitric oxide pathway. APPROACH AND RESULTS: In a randomized, single-blind, crossover trial, 12 healthy male participants consumed 600 mL (20 oz.) of water or a commercial SSB across 2 visits. Endothelial and vascular smooth muscle functions were assessed in the microcirculation using laser speckle contrast imaging coupled with iontophoresis and in the macrocirculation using brachial artery ultrasound with flow- and nitrate-mediated dilation. Compared with water, SSB consumption impaired microvascular and macrovascular endothelial function as indicated by a decrease in the vascular response to acetylcholine iontophoresis (208.3±24.3 versus 144.2±15.7%, P<0.01) and reduced flow-mediated dilation (0.019±0.002 versus 0.014±0.002%/s, P<0.01), respectively. Systemic vascular smooth muscle remained preserved. Similar decreases in endothelial function were observed during acute hyperglycemia in an in vivo rat model. However, function was fully restored by treatment with the antioxidants, N-acetylcysteine and apocynin. In addition, ex vivo experiments revealed that although the production of reactive oxygen species was increased during acute hyperglycemia, the bioavailability of nitric oxide in the endothelium was decreased, despite no change in the activation state of endothelial nitric oxide synthase. CONCLUSIONS: To our knowledge, this is the first study to assess the vascular effects of acute hyperglycemia induced by commercial SSB consumption alone. These findings suggest that SSB-mediated endothelial dysfunction is partly due to increased oxidative stress that decreases nitric oxide bioavailability. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366442&isReview=true. Australian New Zealand Clinical Trials Registry Number: ACTRN12614000614695.

Effect of Linagliptin on Vascular Function: A Randomized, Placebo-controlled Study.

CONTEXT: The dipeptidyl peptidase-4 inhibitor, linagliptin, possesses pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties in animals, independent of its glucose-lowering properties. Although large, randomized clinical trials are being conducted to better evaluate the efficacy and safety of linagliptin on cardiovascular outcomes, little is known about its effects on vascular function in humans. OBJECTIVE: This study sought to evaluate the effect of linagliptin on surrogates of vascular and mitochondrial function. DESIGN AND SETTING: This was a randomized, double-blind, placebo-controlled trial at a tertiary care center with a large type 2 diabetes referral base. PATIENTS AND INTERVENTION: Forty participants with type 2 diabetes were included in a 12-wk treatment of either linagliptin 5mg/d or placebo. MAIN OUTCOME MEASURES: Micro- and macrovascular functions were assessed using laser Doppler coupled with iontophoresis and with brachial flow-mediated dilation, respectively. Mitochondrial function was assessed by phosphorus-31 metabolites changes in the calf muscle measured by magnetic resonance spectroscopy. Circulating endothelial progenitor cells, as well as inflammatory cytokines, growth factors, and biomarkers of endothelial function were also quantified. RESULTS: Linagliptin was associated with an increase in axon reflex-dependent vasodilation, a marker of neurovascular function (P = .05). A trend indicating increased endothelium-dependent microvascular reactivity was observed (P = .07). These were associated with decreases in concentrations of IFNγ (P < .05), IL-6 (P = .03), IL-12 (P < .03), and MIP-1 (P < .04) following linagliptin treatment when compared with placebo. CONCLUSIONS: This study demonstrates that linagliptin tends to improve endothelial and neurovascular microvascular function and is associated with decreased markers of inflammation in patients with type 2 diabetes. There was no significant effect of linagliptin on mitochondrial function, macrovascular function, or endothelial progenitor cells.

Endothelial Dysfunction as a Link Between Cardiovascular Risk Factors and Peripheral Neuropathy in Diabetes.

CONTEXT: Cardiovascular risk factors are well-known predictors of the development of diabetic peripheral neuropathy (DPN), which has traditionally been considered as a manifestation of diabetes-associated microangiopathy. Because endothelial dysfunction is strongly associated with all cardiovascular risk factors, we hypothesized that it may be a link between cardiovascular risk factors and DPN. OBJECTIVE: The primary objective of this study was to test whether endothelial dysfunction is a predictor of DPN. DESIGN AND SETTING: This is a cross-sectional analysis of a cohort composed of patients followed at the Microcirculatory Laboratory, Beth Israel Deaconess Medical Center. PATIENTS: Participants with diabetes without DPN (n = 192) and with DPN (n = 166), subjects with prediabetes (n = 75), and nondiabetic controls (n = 59) were included. INTERVENTIONS: Endothelial function was assessed with flow-mediated dilation (FMD) of the brachial artery. Inflammatory cytokines and biomarkers of endothelial function (soluble intercellular and vascular cell adhesion molecules) were quantified using a multiplex bead-based immunoassay. Neurological assessment included the neuropathy disability score (NDS). MAIN OUTCOME MEASURE: The relationship between FMD and NDS assessed using multiple linear regression. RESULTS: In addition to already known risk factors of DPN, FMD was strongly associated with NDS (ß = -0.24; P < .001). Sensitivity analysis that removed FMD from the model provided similar results for soluble intercellular cell adhesion molecule-1, another biomarker of endothelial function. Confirmatory factor analysis further showed that endothelial dysfunction is a significant mediator between glycosylated hemoglobin and diabetes duration and diabetic complications. CONCLUSIONS: This study shows that endothelial dysfunction occurs early in the pathophysiology of diabetes and is a link between cardiovascular risk factors and DPN.

Acute Hyperglycemia Impairs Vascular Function in Healthy and Cardiometabolic Diseased Subjects: Systematic Review and Meta-Analysis.

OBJECTIVES: Controversy exists over the effect of acute hyperglycemia on vascular function. In this systematic review, we compared the effect of acute hyperglycemia on endothelial and vascular smooth muscle functions across healthy and cardiometabolic diseased subjects. APPROACH AND RESULTS: A systematic search of MEDLINE, EMBASE, and Web of Science from inception until July 2014 identified articles evaluating endothelial or vascular smooth muscle function during acute hyperglycemia and normoglycemia. Meta-analyses compared the standardized mean difference (SMD) in endothelial and vascular smooth muscle functions between acute hyperglycemia and normoglycemia. Subgroup analyses and metaregression identified sources of heterogeneity. Thirty-nine articles (525 healthy and 540 cardiometabolic subjects) were analyzed. Endothelial function was decreased (39 studies; n=1065; SMD, -1.25; 95% confidence interval, -1.52 to -0.98; P<0.01), whereas vascular smooth muscle function was preserved (6 studies; n=144; SMD, -0.07; 95% confidence interval, -0.30 to 0.16; P=0.55) during acute hyperglycemia compared with normoglycemia. Significant heterogeneity was detected among endothelial function studies (P<0.01). A subgroup analysis revealed that endothelial function was decreased in the macrocirculation (30 studies; n=884; SMD, -1.40; 95% confidence interval, -1.68 to -1.12; P<0.01) but not in the microcirculation (9 studies; n=181; SMD, -0.63; 95% confidence interval, -1.36 to 0.11; P=0.09). Similar results were observed according to health status. Macrovascular endothelial function was inversely associated with age, blood pressure, and low-density lipoprotein cholesterol and was positively associated with the postocclusion interval of vascular assessment. CONCLUSIONS: To our knowledge, this is the first systematic review and meta-analysis of its kind. In healthy and diseased subjects, we found evidence for macrovascular but not microvascular endothelial dysfunction during acute hyperglycemia.