Optimizing the Potential for Telehealth in Cardiovascular Care (in the Era of COVID-19): Time Will Tell.

Before the coronavirus disease 2019 (COVID-19) pandemic, use of telehealth services had been limited in cardiovascular care. Potential benefits of telehealth include improved access to care, more efficient care management, reduced costs, the ability to assess patients within their homes while involving key caretakers in medical decisions, maintaining social distance, and increased patient satisfaction. Challenges include changes in payment models, issues with data security and privacy, potential depersonalization of the patient-clinician relationship, limitations in the use of digital health technologies, and the potential impact on disparities, including socioeconomic, gender, and age-related issues and access to technology and broadband. Implementation and expansion of telehealth from a policy and reimbursement practice standpoint are filled with difficult decisions, yet addressing these are critical to the future of health care.

Natural Approaches in Diabetes Management: A Review of Diet, Exercise, and Natural Products.

Diabetes mellitus (DM) is a highly prevalent condition that causes significant morbidity and mortality in the United States and worldwide. Conventional therapies include lifestyle modification, oral pharmacological agents, and subcutaneous insulin. Emerging data suggest that natural approaches to the treatment of DM may help supplement current therapies for further glycemic control. Herein, we review the evidence of several natural modalities for DM treatment. We describe the pathophysiology of diabetes and its complications, provide an overview of current pharmacologic treatments, and finally, discuss natural approaches to diabetes management. Specifically, we will describe on the utility of diet, physical activity, and common natural products in the treatment of DM and focus on recent, high-quality studies. Adverse effects and potential interactions of each therapy will be highlighted where applicable.

Biomarkers to Predict Cardiovascular Death.

This article reviews biomarkers that have been shown to identify subjects at increased risk for cardiovascular death within the general population, in those with established coronary artery disease, and in those with heart failure. Use of biomarkers for risk stratification for sudden cardiac death continues to evolve. It seems that a multimarker strategy for risk stratification using simple measures of circulating proteins and usual clinical risk factors, particularly in patients with known coronary artery disease, can be used to identify patients at near-term risk of death. Whether similar strategies in the general population will prove to be cost-effective needs to be investigated.

Changes in truncal obesity and fat distribution predict arterial health.

BACKGROUND: Truncal obesity is associated with metabolic syndrome and cardiovascular risk. Although vascular health is influenced by weight, it is not known whether changes in fat distribution modulate arterial function. OBJECTIVE: We assessed how changes in truncal (android) fat at 1 year affect arterial stiffness and endothelial function. METHODS: We recruited 711 healthy volunteers (235 males, age 48 ± 11 years) into the Emory Predictive Health Study; 498 returned at 1 year. Measurements included anthropometric and chemistry panels, fat mass using dual-energy X-ray absorptiometry, arterial stiffness indices (pulse wave velocity [PWV], augmentation index [AIx], and subendocardial viability ratio [SEVR]; Sphygmocor), flow-mediated dilation (FMD), and reactive hyperemia index (Endo-PAT). RESULTS: At baseline, measures of body mass correlated with PWV, AIx, SEVR, and FMD. In a multivariable analysis including body mass index (BMI) and traditional risk factors, BMI remained an independent predictor of PWV, AIx, SEVR, and FMD. In a model including BMI and measures of fat distribution, android fat remained an independent predictor of PWV (ß = 0.31, P = .004), AIx (ß = 0.24, P = .008), and SEVR (ß = -0.41, P < .001). The 1-year change in android fat correlated negatively with change in SEVR (ß = -0.13, P = .005) and FMD (ß = -0.13, P = .006) after adjustment for change in gynoid fat. CONCLUSION: In addition to BMI, android fat is a determinant of arterial stiffness, independent of traditional risk factors. Changes in android fat over time are associated with simultaneous changes in vascular function, indicating fat distribution's effect on vascular health.

Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death.

BACKGROUND: Inflammation, coagulation, and cell stress contribute to atherosclerosis and its adverse events. A biomarker risk score (BRS) based on the circulating levels of biomarkers C-reactive protein, fibrin degradation products, and heat shock protein-70 representing these 3 pathways was a strong predictor of future outcomes. We investigated whether soluble urokinase plasminogen activator receptor (suPAR), a marker of immune activation, is predictive of outcomes independent of the aforementioned markers and whether its addition to a 3-BRS improves risk reclassification. METHODS AND RESULTS: C-reactive protein, fibrin degradation product, heat shock protein-70, and suPAR were measured in 3278 patients undergoing coronary angiography. The BRS was calculated by counting the number of biomarkers above a cutoff determined using the Youden's index. Survival analyses were performed using models adjusted for traditional risk factors. A high suPAR level ≥3.5 ng/mL was associated with all-cause death and myocardial infarction (hazard ratio, 1.83; 95% confidence interval, 1.43-2.35) after adjustment for risk factors, C-reactive protein, fibrin degradation product, and heat shock protein-70. Addition of suPAR to the 3-BRS significantly improved the C statistic, integrated discrimination improvement, and net reclassification index for the primary outcome. A BRS of 1, 2, 3, or 4 was associated with a 1.81-, 2.59-, 6.17-, and 8.80-fold increase, respectively, in the risk of death and myocardial infarction. The 4-BRS was also associated with severity of coronary artery disease and composite end points. CONCLUSIONS: SuPAR is independently predictive of adverse outcomes, and its addition to a 3-BRS comprising C-reactive protein, fibrin degradation product, and heat shock protein-70 improved risk reclassification. The clinical utility of using a 4-BRS for risk prediction and management of patients with coronary artery disease warrants further study.

Cardiovascular disease risk reduction in diabetes through conventional and natural approaches.

Type 2 diabetes mellitus (DM) is a significant cause of premature complications and mortality in patients with cardiovascular disease (CVD). In addition to lifestyle modifications, conventional treatment of DM consists of oral hypoglycemic agents, insulin sensitizers, and subcutaneous insulin. In diabetic individuals with or at risk for CVD, aspirin and statin therapy reduce CVD morbidity and mortality. Several natural or herbal supplements have shown potential benefit in patients with CVD and DM. We provide an overview of the current guidelines for treatment of DM and CVD. We then review the literature to describe the efficacy of natural approaches to CVD risk reduction in diabetic patients, with a focus on physical activity, dietary modification, and natural/herbal supplements. Activity and diet improve cardiovascular outcomes in patients with CVD and DM. Natural and herbal supplements have potential for benefit but require further research to determine their efficacy and safety.

Comprehensive Cardiovascular Risk Reduction and Cardiac Rehabilitation in Diabetes and the Metabolic Syndrome.

The epidemic of obesity has contributed to a growing burden of metabolic syndrome (MetS) and diabetes mellitus (DM) worldwide. MetS is defined as central obesity along with associated factors such as hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperglycemia, and hypertension. MetS and DM are associated with significant cardiovascular morbidity and mortality. Healthy behavioural modification is the cornerstone for reducing the atherosclerotic cardiovascular disease burden in this population. Comprehensive, multidisciplinary cardiac rehabilitation (CR) programs reduce mortality and hospitalizations in patients with MetS and DM. Despite this benefit, patients with MetS and DM are less likely to attend and complete CR because of numerous barriers. Implementation of innovative CR delivery models might improve utilization of CR and cardiovascular outcomes in this high-risk population.

Physical activity in the prevention of coronary heart disease: implications for the clinician.

Cardiovascular disease (CVD) continues to be a leading cause of death worldwide. Because regular physical activity (PA) independently decreases the risk of coronary heart disease (CHD) while also having a positive, dose-related impact on other cardiovascular (CV) risk factors, it has increasingly become a focus of CHD prevention. Current guidelines recommend 30 min of moderate-intensity PA 5 days a week, but exercise regimens remain underused. PA adherence can be fostered with a multilevel approach that involves active individual participation, physician counselling and health coaching, community involvement, and policy change, with incorporation of cardiac rehabilitation for patients requiring secondary prevention. Viewing exercise quantity as a vital sign, prescribing PA like a medication, and using technology, such as smartphone applications, encourage a global shift in focus from CVD treatment to prevention. Community-wide, home-based and internet-based prevention initiatives may also offer a developing pool of resources that can be tapped into to promote education and PA compliance. This review summarises the underlying rationale, current guidelines for and recommendations to cultivate a comprehensive focus in the endorsement of PA in the primary and secondary prevention of CHD.

Elevated Levels of Serum Fibrin and Fibrinogen Degradation Products Are Independent Predictors of Larger Coronary Plaques and Greater Plaque Necrotic Core.

BACKGROUND: Co-existence of vulnerable plaque and pro-thrombotic state may provoke acute coronary events. It was hypothesized that elevated serum levels of fibrin and fibrinogen degradation products (FDP) are associated with larger total plaque and necrotic core (NC) areas. METHODS AND RESULTS: Seventy-five patients presenting with stable anginal symptoms (69%) or stabilized acute coronary syndrome (ACS; 31%), and found to have non-obstructive coronary artery disease (CAD) with a fractional flow reserve >0.8, were studied. Invasive virtual histology intravascular ultrasound (VH-IVUS) was performed in 68 LAD arteries, 6 circumflex arteries, and 1 right coronary artery. Serum FDP levels were measured using ELISA technique. Plaque volumetrics and composition were assessed in each VH-IVUS frame and averaged. The median age of patients was 56 (47-63) years; 52% were men and 23% had diabetes. The average length of coronary artery studied was 62 mm. After adjustment for systemic risk factors, medications, CRP levels and ACS, male gender (P<0.001) and serum FDP levels (P=0.02) were independent predictors of a larger NC area. Older age (P<0.001), male gender (P<0.0001) and increased serum FDP level (P=0.03) were associated with a larger plaque area. CONCLUSIONS: In patients with CAD, a higher serum level of FDP is independently associated with larger plaques and greater plaque NC.

Novel Biomarker of Oxidative Stress Is Associated With Risk of Death in Patients With Coronary Artery Disease.

BACKGROUND: Free radical scavengers have failed to improve patient outcomes, promoting the concept that clinically important oxidative stress may be mediated by alternative mechanisms. We sought to examine the association of emerging aminothiol markers of nonfree radical mediated oxidative stress with clinical outcomes. METHODS AND RESULTS: Plasma levels of reduced (cysteine and glutathione) and oxidized (cystine and glutathione disulphide) aminothiols were quantified by high performance liquid chromatography in 1411 patients undergoing coronary angiography (mean age 63 years, male 66%). All patients were followed for a mean of 4.7 ± 2.1 years for the primary outcome of all-cause death (n=247). Levels of cystine (oxidized) and glutathione (reduced) were associated with risk of death (P<0.001 both) before and after adjustment for covariates. High cystine and low glutathione levels (>+1 SD and <-1 SD, respectively) were associated with higher mortality (adjusted hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.19-2.21; HR, 2.19; 95% CI, 1.50-3.19; respectively) compared with those outside these thresholds. Furthermore, the ratio of cystine/glutathione was also significantly associated with mortality (adjusted HR, 1.92; 95% CI, 1.39-2.64) and was independent of and additive to high-sensitivity C-reactive protein level. Similar associations were found for other outcomes of cardiovascular death and combined death and myocardial infarction. CONCLUSIONS: A high burden of oxidative stress, quantified by the plasma aminothiols, cystine, glutathione, and their ratio, is associated with mortality in patients with coronary artery disease, a finding that is independent of and additive to the inflammatory burden. Importantly, these data support the emerging role of nonfree radical biology in driving clinically important oxidative stress.

Novel biomarkers for cardiovascular risk assessment: current status and future directions.

Cardiovascular disease (CVD) is the leading cause of mortality in the modern world. Traditional risk algorithms may miss up to 20% of CVD events. Therefore, there is a need for new cardiac biomarkers. Many fields of research are dedicated to improving cardiac risk prediction, including genomics, transcriptomics and proteomics. To date, even the most promising biomarkers have only demonstrated modest associations and predictive ability. Few have undergone randomized control trials. A number of biomarkers are targets to new therapies aimed to reduce cardiovascular risk. Currently, some of the most promising risk prediction has been demonstrated with panels of multiple biomarkers. This article reviews the current state and future of proteomic biomarkers and aggregate biomarker panels.

Low testosterone in men predicts impaired arterial elasticity and microvascular function.

BACKGROUND: A low testosterone level in men is associated with increased adiposity, insulin resistance, and dyslipidemia. Whether low testosterone level is associated with arterial stiffness and endothelial and microvascular dysfunction remains unknown and was investigated in this study. METHODS: Serum testosterone was measured in 237 healthy men aged 50 years (SD 12). Endothelial and microvascular function were assessed as brachial artery flow-mediated dilation (FMD) and digital reactive hyperemia index (RHI), respectively. Arterial stiffness was evaluated by tonometry-derived pulse wave velocity (PWV) and central augmentation index (AIX). RESULTS: Mean total testosterone level was 16.3 nmol/L (SD 6.11) and 25% of subjects had low levels (<12.0 nmol/L). Testosterone level correlated positively with RHI (r=0.24, p<0.001) and inversely with AIX (r=-0.14, p=0.033) but not with FMD or PWV, indicating impaired microvascular hyperemia and arterial elasticity with lower testosterone levels. After multivariate adjustment for the Framingham Risk Score and weight, testosterone level remained an independent predictor of RHI and AIX (ß=0.23, -0.13; p=0.001, 0.04, respectively). CONCLUSION: In men with few co-morbidities, lower serum testosterone level is associated with microvascular dysfunction and increased pulse wave reflections, mechanisms by which lower testosterone levels may confer increased cardiovascular risk. Whether normalization of low testosterone level improves vascular function needs further investigation.

Plasma soluble urokinase-type plasminogen activator receptor level is independently associated with coronary microvascular function in patients with non-obstructive coronary artery disease.

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) is a novel biomarker released from leukocytes and endothelial cells that has been associated with atherosclerotic cardiovascular disease. We hypothesized that plasma suPAR level is an independent predictor of coronary microvascular function. METHODS: Coronary blood flow velocity and plasma suPAR levels were evaluated in patients with non-obstructive coronary artery disease. Coronary flow reserve (CFR) was calculated as the ratio of hyperemic to basal average peak blood flow velocity and coronary microvascular dysfunction was defined as CFR ≤ 2.0 in the setting of a fractional flow reserve value of ≥0.75. Plasma suPAR levels were measured using ELISA technique. The association between suPAR and CFR was investigated using univariate and multivariate regression analyses. RESULTS: In 66 patients, 47% were men, 26% had diabetes, 68% had hypertension and 76% had dyslipidemia. Mean age was 55 ± 12 years and median suPAR level 2.82 (2.08-3.40) ng/mL. Plasma suPAR levels correlated with age (r = 0.31, p = 0.01), body mass index (r = 0.25, p = 0.04) and high-sensitivity C-reactive protein (hs-CRP) (r = 0.33, p = 0.009). While median suPAR level was not significantly different in patients with different cardiovascular risk factors, patients on statin therapy had significantly higher suPAR level (p = 0.03). SuPAR correlated negatively with CFR and, after multivariate adjustment for established cardiovascular risk factors, medications profiles and hs-CRP, suPAR remained an independent predictor of CFR (B = -0.30, p = 0.04), indicating an independent association between suPAR level and coronary microvascular function. CONCLUSIONS: In this cross-sectional study, plasma suPAR level was an independent predictor of coronary microvascular function. Larger prospective clinical trials are warranted to investigate the prognostic value of this novel biomarker and the role of immune dysregulation in coronary microvascular disease.

Plasma stromal cell-derived factor 1α/CXCL12 level predicts long-term adverse cardiovascular outcomes in patients with coronary artery disease.

OBJECTIVE: Stromal derived factor-1α/CXCL12 is a chemoattractant responsible for homing of progenitor cells to ischemic tissues. We aimed to investigate the association of plasma CXCL12 with long-term cardiovascular outcomes in patients with coronary artery disease (CAD). METHODS: 785 patients aged: 63 ± 12 undergoing coronary angiography were independently enrolled into discovery (N = 186) and replication (N = 599) cohorts. Baseline levels of plasma CXCL12 were measured using Quantikine CXCL12 ELISA assay (R&D systems). Patients were followed for cardiovascular death and/or myocardial infarction (MI) for a mean of 2.6 yrs. Cox proportional hazard was used to determine independent predictors of cardiovascular death/MI. RESULTS: The incidence of cardiovascular death/MI was 13% (N = 99). High CXCL12 level based on best discriminatory threshold derived from the ROC analysis predicted risk of cardiovascular death/MI (HR = 4.81, p = 1 × 10(-6)) independent of traditional risk factors in the pooled cohort. Addition of CXCL12 to a baseline model was associated with a significant improvement in c-statistic (AUC: 0.67-0.73, p = 0.03). Addition of CXCL12 was associated with correct risk reclassification of 40% of events and 10.5% of non-events. Similarly for the outcome of cardiovascular death, the addition of the CXCL12 to the baseline model was associated with correct reclassification of 20.7% of events and 9% of non-events. These results were replicated in two independent cohorts. CONCLUSION: Plasma CXCL12 level is a strong independent predictor of adverse cardiovascular outcomes in patients with CAD and improves risk reclassification.

Circulating CD34+ progenitor cells and risk of mortality in a population with coronary artery disease.

RATIONALE: Low circulating progenitor cell numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. OBJECTIVES: To investigate whether low numbers of progenitor cells associate with a greater risk of mortality in a population at high cardiovascular risk. METHODS AND RESULTS: Patients undergoing coronary angiography were recruited into 2 cohorts (1, n=502 and 2, n=403) over separate time periods. Progenitor cells were enumerated by flow cytometry as CD45(med+) blood mononuclear cells expressing CD34, with additional quantification of subsets coexpressing CD133, vascular endothelial growth factor receptor 2, and chemokine (C-X-C motif) receptor 4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary end point of all-cause death. There was an inverse association between CD34(+) and CD34(+)/CD133(+) cell counts and risk of death in cohort 1 (ß=-0.92, P=0.043 and ß=-1.64, P=0.019, respectively) that was confirmed in cohort 2 (ß=-1.25, P=0.020 and ß=-1.81, P=0.015, respectively). Covariate-adjusted hazard ratios in the pooled cohort (n=905) were 3.54 (1.67-7.50) and 2.46 (1.18-5.13), respectively. CD34(+)/CD133(+) cell counts improved risk prediction metrics beyond standard risk factors. CONCLUSIONS: Reduced circulating progenitor cell counts, identified primarily as CD34(+) mononuclear cells or its subset expressing CD133, are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction, and cell selection for cell-based therapies.

Statins in the elderly: a patient-focused approach.

Individuals age >65 years represent the fastest-growing subpopulation in the United States. Although these individuals with the highest cardiovascular risk profile would be anticipated to be the most aggressively treated, paradoxically, treatment and baseline risk are inversely related. Presumably, the elderly population would benefit from high-intensity statin therapy; however, as per the 2013 American College of Cardiology/American Heart Association guidelines, given the scarcity of evidence in patients age >75, there are only sufficient data from randomized controlled trials to support use of moderate-intensity statin therapy for secondary prevention. Despite evidence demonstrating statins are beneficial in the elderly, the decision to initiate and sustain treatment should be a well-informed and collaborative decision. One must balance the benefits (secondary atherosclerotic cardiovascular prevention, stroke reduction, decreased morbidity and mortality) with the potential risks to the elderly (altered metabolism, comorbidities, polypharmacy and drug-drug interactions, side effects, cognitive limitations, and cost).

Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events.

INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging inflammatory and immune biomarker. Whether suPAR level predicts the presence and the severity of coronary artery disease (CAD), and of incident death and myocardial infarction (MI) in subjects with suspected CAD, is unknown. METHODS AND RESULTS: We measured plasma suPAR levels in 3367 subjects (67% with CAD) recruited in the Emory Cardiovascular Biobank and followed them for adverse cardiovascular (CV) outcomes of death and MI over a mean 2.1±1.1 years. Presence of angiographic CAD (≥50% stenosis in ≥1 coronary artery) and its severity were quantitated using the Gensini score. Cox's proportional hazard survival and discrimination analyses were performed with models adjusted for established CV risk factors and C-reactive protein levels. Elevated suPAR levels were independently associated with the presence of CAD (P<0.0001) and its severity (P<0.0001). A plasma suPAR level ≥3.5 ng/mL (cutoff by Youden's index) predicted future risk of MI (hazard ratio [HR]=3.2; P<0.0001), cardiac death (HR=2.62; P<0.0001), and the combined endpoint of death and MI (HR=1.9; P<0.0001), even after adjustment of covariates. The C-statistic for a model based on traditional risk factors was improved from 0.72 to 0.74 (P=0.008) with the addition of suPAR. CONCLUSION: Elevated levels of plasma suPAR are associated with the presence and severity of CAD and are independent predictors of death and MI in patients with suspected or known CAD.

Gene expression profiles associated with acute myocardial infarction and risk of cardiovascular death.

BACKGROUND: Genetic risk scores have been developed for coronary artery disease and atherosclerosis, but are not predictive of adverse cardiovascular events. We asked whether peripheral blood expression profiles may be predictive of acute myocardial infarction (AMI) and/or cardiovascular death. METHODS: Peripheral blood samples from 338 subjects aged 62 ± 11 years with coronary artery disease (CAD) were analyzed in two phases (discovery N = 175, and replication N = 163), and followed for a mean 2.4 years for cardiovascular death. Gene expression was measured on Illumina HT-12 microarrays with two different normalization procedures to control technical and biological covariates. Whole genome genotyping was used to support comparative genome-wide association studies of gene expression. Analysis of variance was combined with receiver operating curve and survival analysis to define a transcriptional signature of cardiovascular death. RESULTS: In both phases, there was significant differential expression between healthy and AMI groups with overall down-regulation of genes involved in T-lymphocyte signaling and up-regulation of inflammatory genes. Expression quantitative trait loci analysis provided evidence for altered local genetic regulation of transcript abundance in AMI samples. On follow-up there were 31 cardiovascular deaths. A principal component (PC1) score capturing covariance of 238 genes that were differentially expressed between deceased and survivors in the discovery phase significantly predicted risk of cardiovascular death in the replication and combined samples (hazard ratio = 8.5, P < 0.0001) and improved the C-statistic (area under the curve 0.82 to 0.91, P = 0.03) after adjustment for traditional covariates. CONCLUSIONS: A specific blood gene expression profile is associated with a significant risk of death in Caucasian subjects with CAD. This comprises a subset of transcripts that are also altered in expression during acute myocardial infarction.