Aggregate Clinical and Biomarker-Based Model Predicts Adverse Outcomes in Patients With Coronary Artery Disease.

Despite guideline-based therapy, patients with coronary artery disease (CAD) are at widely variable risk for cardiovascular events. This variability demands a more individualized risk assessment. Herein, we evaluate the prognostic value of 6 biomarkers: high-sensitivity C-reactive protein, heat shock protein-70, fibrin degradation products, soluble urokinase plasminogen activator receptor, high-sensitivity troponin I, and B-type natriuretic peptide. We then develop a multi-biomarker-based cardiovascular event prediction model for patients with stable CAD. In total, 3,115 subjects with stable CAD who underwent cardiac catheterization at Emory (mean age 62.8 years, 17% Black, 35% female, 57% obstructive CAD, 31% diabetes mellitus) were randomized into a training cohort to identify biomarker cutoff values and a validation cohort for prediction assessment. Main outcomes included (1) all-cause death and (2) a composite of cardiovascular death and nonfatal myocardial infarction (MI) within 5 years. Elevation of each biomarker level was associated with higher event rates in the training cohort. A biomarker risk score was created using optimal cutoffs, ranging from 0 to 6 for each biomarker exceeding its cutoff. In the validation cohort, each unit increase in the biomarker risk score was independently associated with all-cause death (hazard ratio 1.62, 95% confidence interval [CI] 1.45 to 1.80) and cardiovascular death/MI (hazard ratio 1.52, 95% CI 1.35 to 1.71). A biomarker risk prediction model for cardiovascular death/MI improved the c-statistic (∆ 6.4%, 95% CI 3.9 to 8.8) and net reclassification index by 31.1% (95% CI 24 to 37), compared with clinical risk factors alone. Integrating multiple biomarkers with clinical variables refines cardiovascular risk assessment in patients with CAD.

Circulating progenitor cells and outcomes in patients with coronary artery disease.

BACKGROUND: Low quantities of circulating progenitor cells (CPCs), specifically CD34+ populations, reflect impairment of intrinsic regenerative capacity. This study investigates the relationship between subsets of CPCs and adverse outcomes. METHODS: 1366 individuals undergoing angiography for evaluation of coronary artery disease (CAD) were enrolled into the Emory Cardiovascular Biobank. Flow cytometry identified CPCs as CD45med blood mononuclear cells expressing the CD34 epitope, with further enumeration of hematopoietic CPCs as CD133+/CXCR4+ cells and endothelial CPCs as vascular endothelial growth factor receptor-2 (VEGFR2+) cells. Adjusted Cox or Fine and Gray's sub-distribution hazard regression models analyzed the relationship between CPCs and 1) all-cause death and 2) a composite of cardiovascular death and non-fatal myocardial infarction (MI). RESULTS: Over a median 3.1-year follow-up period (IQR 1.3-4.9), there were 221 (16.6%) all-cause deaths and 172 (12.9%) cardiovascular deaths/MIs. Hematopoietic CPCs were highly correlated, and the CD34+/CXCR4+ subset was the best independent predictor. Lower counts (≤median) of CD34+/CXCR4+ and CD34+/VEGFR2+ cells independently predicted all-cause mortality (HR 1.46 [95% CI 1.06-2.01], p = 0.02 and 1.59 [95% CI 1.15-2.18], p = 0.004) and cardiovascular death/MI (HR 1.50 [95% CI 1.04-2.17], p = 0.03 and 1.47 [95% CI 1.01-2.03], p = 0.04). A combination of low CD34+/CXCR4+ and CD34+/VEGFR2+ CPCs predicted all-cause death (HR 2.1, 95% CI 1.4-3.0; p = 0.0002) and cardiovascular death/MI (HR 2.0, 95% CI 1.3-3.2; p = 0.002) compared to those with both lineages above the cut-offs. CONCLUSIONS: Lower levels of hematopoietic and endothelial CPCs indicate diminished endogenous regenerative capacity and independently correlate with greater mortality and cardiovascular risk in patients with CAD.

Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations.

Importance: Previous studies have shown lower cardiovascular risk with higher high-density lipoprotein cholesterol (HDL-C) levels. However, recent data in the general population have shown increased risk of adverse outcomes at very high HDL-C concentrations. Objective: To study the association between very high HDL-C levels (>80 mg/dL) and mortality in patients with coronary artery disease (CAD) and to investigate the association of known HDL-C genotypes with high HDL-C level outcomes. Design, Setting, and Participants: This prospective, multicenter, cohort study, conducted from 2006 to present in the UK and from 2003 to present in Atlanta, Georgia, recruited patients with CAD from the UK Biobank (UKB) and the Emory Cardiovascular Biobank (EmCAB), respectively. Patients without confirmed CAD were excluded from the study. Data analyses were conducted from May 10, 2020, to April 28, 2021. Exposure: High HDL-C levels (>80 mg/dL). Main Outcomes and Measures: The primary outcome was all-cause death. The secondary outcome was cardiovascular death. Results: A total of 14 478 participants (mean [SD] age, 62.1 [5.8] years; 11 034 men [76.2%]) from the UKB and 5467 participants (mean [SD] age, 63.8 [12.3] years; 3632 men [66.4%]) from the EmCAB were included in the study. Over a median follow-up of 8.9 (IQR, 8.0-9.7) years in the UKB and 6.7 (IQR, 4.0-10.8) years in the EmCAB, a U-shaped association with outcomes was observed with higher risk in those with both low and very high HDL-C levels compared with those with midrange values. Very high HDL-C levels (>80 mg/dL) were associated with increased risk of all-cause death (hazard ratio [HR], 1.96; 95% CI, 1.42-2.71; P < .001) and cardiovascular death (HR, 1.71; 95% CI, 1.09-2.68; P = .02) compared with those with HDL-C levels in the range of 40 to 60 mg/dL in the UKB after adjustment for confounding factors. These results were replicated in the EmCAB. These associations persisted after adjustment for the HDL-C genetic risk score within the UKB. Sensitivity analyses demonstrated that the risk of all-cause mortality in the very high HDL-C group was higher among men than women in the UKB (HR, 2.63; 95% CI, 1.75-3.95; P < .001 vs HR, 1.39; 95% CI, 0.82-2.35; P = .23). Conclusions and Relevance: Results of this cohort study suggest that very high HDL-C levels are paradoxically associated with higher mortality risk in individuals with CAD. This association was independent of the common polymorphisms associated with high HDL-C levels.

Independent Association of Lipoprotein(a) and Coronary Artery Calcification With Atherosclerotic Cardiovascular Risk.

BACKGROUND: Elevated lipoprotein(a) [Lp(a)] and coronary artery calcium (CAC) score are individually associated with increased atherosclerotic cardiovascular disease (ASCVD) risk but have not been studied in combination. OBJECTIVES: This study sought to investigate the independent and joint association of Lp(a) and CAC with ASCVD risk. METHODS: Plasma Lp(a) and CAC were measured at enrollment among asymptomatic participants of the MESA (Multi-Ethnic Study of Atherosclerosis) (n = 4,512) and DHS (Dallas Heart Study) (n = 2,078) cohorts. Elevated Lp(a) was defined as the highest race-specific quintile, and 3 CAC score categories were studied (0, 1-99, and ≥100). Associations of Lp(a) and CAC with ASCVD risk were evaluated using risk factor-adjusted Cox regression models. RESULTS: Among MESA participants (61.9 years of age, 52.5% women, 36.8% White, 29.3% Black, 22.2% Hispanic, and 11.7% Chinese), 476 incident ASCVD events were observed during 13.2 years of follow-up. Elevated Lp(a) and CAC score (1-99 and ≥100) were independently associated with ASCVD risk (HR: 1.29; 95% CI: 1.04-1.61; HR: 1.68; 95% CI: 1.30-2.16; and HR: 2.66; 95% CI: 2.07-3.43, respectively), and Lp(a)-by-CAC interaction was not noted. Compared with participants with nonelevated Lp(a) and CAC = 0, those with elevated Lp(a) and CAC ≥100 were at the highest risk (HR: 4.71; 95% CI: 3.01-7.40), and those with elevated Lp(a) and CAC = 0 were at a similar risk (HR: 1.31; 95% CI: 0.73-2.35). Similar findings were observed when guideline-recommended Lp(a) and CAC thresholds were considered, and findings were replicated in the DHS. CONCLUSIONS: Lp(a) and CAC are independently associated with ASCVD risk and may be useful concurrently for guiding primary prevention therapy decisions.

Vascular Regenerative Capacity and the Obesity Paradox in Coronary Artery Disease.

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Premature atherosclerotic peripheral artery disease: An underrecognized and undertreated disorder with a rising global prevalence.

Premature atherosclerotic peripheral artery disease (PAD) of the lower extremities is characterized by disease diagnosis before the age of 50 years. The global prevalence of premature PAD has increased, and the disease is often underdiagnosed given heterogenous patient symptoms. Traditional cardiovascular risk factors like smoking, diabetes, hypertension, and hyperlipidemia as well as non-traditional risk factors like elevated lipoprotein(a), family history of PAD, hypercoagulability, and systemic inflammation are associated with premature PAD. Patients with premature PAD tend to have an aggressive vascular disease process, a high burden of cardiovascular risk factors, and other concomitant atherosclerotic vascular diseases like coronary artery disease. Prevention of cardiovascular events, improvement of symptoms and functional status, and prevention of adverse limb events are the main goals of patient management. In this review, we discuss the epidemiology, risk factors, clinical evaluation, and management of patients with premature PAD.

Circulating Progenitor Cells in Patients With Coronary Artery Disease and Renal Insufficiency.

Patients with coronary artery disease and renal insufficiency (RI) (estimated glomerular filtration rate <60 ml/min/1.73 m2) are at an increased risk of cardiovascular events. The contribution of regenerative capacity, measured as circulating progenitor cell (CPC) counts, to this increased risk is unclear. CPCs were enumerated as cluster of differentiation (CD) 45med+ mononuclear cells expressing CD34+, CD133+, CXCR4+ (chemokine [C-X-C motif] receptor 4), and VEGF2R+ (vascular endothelial growth factor receptor 2) epitopes in 1,281 subjects with coronary artery disease (35% with RI). Patients with RI and low (median) were at a similar risk as those without RI.

Sex Differences in Circulating Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels and Adverse Outcomes in Coronary Artery Disease.

Background Women have higher circulating levels of soluble urokinase-type plasminogen activator receptor (suPAR), and elevated suPAR is associated with cardiovascular risk. The independent association of sex with suPAR and the impact of sex on its association with cardiovascular risk are unknown. Methods and Results Plasma suPAR was measured using ELISA in 2 cohorts of 666 asymptomatic individuals (49 years, 65% women) and 4184 patients with coronary artery disease (63 years, 37% women). Independent association of sex with suPAR was studied using linear regression models adjusted for demographics, risk factors, and visceral adiposity in asymptomatic participants. Impact of sex on association of suPAR with all-cause mortality was studied in patients with coronary artery disease using multivariable-adjusted Cox models. Sex-specific suPAR cutoffs for predicting all-cause mortality were calculated. Asymptomatic women had 10% higher suPAR compared with men after adjusting for confounders, and visceral adiposity partly accounted for this association. Over a median follow-up of 5.2 years, 795 deaths were recorded in patients with coronary artery disease. Log2-transformed suPAR was independently associated with mortality (hazard ratio per 1-SD 1.72, 95% CI 1.60-1.85) and an interaction with sex was noted (P=0.005). Association of suPAR with mortality was slightly weaker in women (hazard ratio 1.61, 95% CI 1.41-1.83) compared with men (hazard ratio 1.83, 95% CI 1.67-2.00). However, using sex-specific suPAR cut-offs (4392 pg/mL for women and 3187 pg/mL for men), a similar mortality incidence was observed for both sexes (38.5% and 35.5%, respectively, P=0.3). Conclusions Women have 10% higher plasma suPAR levels compared with men. Elevated sex-specific plasma suPAR levels are equally predictive of risk of adverse events in both sexes.

Metformin-associated lactic acidosis precipitated by liraglutide use: adverse effects of aggressive antihyperglycaemic therapy.

Older patients with type 2 diabetes are prone to developing adverse events with aggressive antihyperglycaemic therapy. Metformin-associated lactic acidosis (MALA) is one such rare, life-threatening adverse drug effect. We report the case of a 70-year-old man with a glycated haemoglobin of 7.9% who was on a stable, maximally tolerated dose of metformin for managing his type 2 diabetes. He was initiated on liraglutide injections with hopes to achieve better glycaemic control, but developed unrelenting nausea and vomiting during the third week of treatment. He presented to the hospital with these symptoms and was noted to have severe MALA. He sustained an in-hospital cardiac arrest requiring emergent resuscitation along with vasopressor and mechanical ventilator support. He underwent continuous venovenous haemodiafiltration to remove metformin and correct the acidosis, following which he stabilised and supportive therapy was weaned off. He was discharged from the hospital on insulin therapy with incomplete renal recovery.