Faculty Bibliography

BACKGROUND:There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). METHODS:We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. RESULTS:Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. CONCLUSIONS:We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.

Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.

Background Detection of flow-limiting left main (LM) coronary artery disease (CAD) has both prognostic and therapeutic implications. Stress testing is the most common method to detect obstructive CAD, however stress markers of LM CAD remain unclear. We set out to identify markers of LM CAD using clinical and stress testing parameters. Methods The population consisted of patients enrolled in the ISCHEMIA trial who underwent non-imaging exercise tolerance testing, stress nuclear imaging or stress echocardiography (SE) and who underwent coronary computed tomography angiography (CCTA). Patients were enrolled based on local determination of moderate or severe ischemia. Those with prior coronary artery bypass grafting were excluded. Multivariate modeling was used to identify predictors of >=50% LM diameter stenosis ("LM disease"), first without and then with stress testing parameters included in the model. Results Of the 5145 patients included (mean age: 63 years, male: 74%), 414 (8%) had LM disease. Predictors of LM disease are shown in the Table. The models were weakly predictive of LM disease (C index 0.643 for clinical model, 0.671 for clinical + stress model). Conclusion In patients with moderate or severe ischemia on stress testing, clinical and stress testing parameters were weakly predictive of LM disease on CCTA. SE-detected TID and ST depression during ETT provided incremental information independent of clinical and other stress modality specific parameters for the prediction of LM disease. [Figure presented]
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Background Heart failure (HF) and chronic kidney disease (CKD) commonly co-exist, and are associated with adverse postoperative cardiovascular outcomes. The impact of CKD in HF patients undergoing noncardiac surgery is uncertain. Methods Patients with HF undergoing non-cardiac surgery were identified from the National Surgical Quality Improvement Program between 2009-2015. Patients were classified into 5 groups based on estimated glomerular filtration rate (eGFR) and requirement of dialysis and were followed prospectively for the primary outcome of death and major adverse cardiovascular events (MACE; a composite of death, myocardial infarction (MI), and stroke) within 30-days post-operatively. Multivariable logistic regression models adjusted for age, sex, race, surgery type, and clinical history and surgery type were generated to estimate the association between CKD stage and outcomes. Results Among 27,612 HF patients undergoing surgery, 65.1% had CKD (19.7% with eGFR 45-60, 20.3% eGFR 30-45, and 25.1% eGFR < 30 with or without dialysis). The incidence of postoperative death and MACE increased with worsening CKD (Table). After multivariable adjustment, eGFR <60 was associated with increased odds of MI and cardiac arrest and eGFR <45 was associated with postoperative mortality. No association was observed between CKD and stroke. Conclusion Among HF patients, the presence of CKD is common and is associated with increased risk for postoperative mortality and MACE. [Figure presented]
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Importance/UNASSIGNED:While many features of stable ischemic heart disease vary by sex, differences in ischemia, coronary anatomy, and symptoms by sex have not been investigated among patients with moderate or severe ischemia. The enrolled ISCHEMIA trial cohort that underwent coronary computed tomographic angiography (CCTA) was required to have obstructive coronary artery disease (CAD) for randomization. Objective/UNASSIGNED:To describe sex differences in stress testing, CCTA findings, and symptoms in ISCHEMIA trial participants. Design, Setting, and Participants/UNASSIGNED:This secondary analysis of the multicenter ISCHEMIA randomized clinical trial analyzed baseline characteristics of patients with stable ischemic heart disease. Individuals were enrolled from July 2012 to January 2018 based on local reading of moderate or severe ischemia on a stress test, after which blinded CCTA was performed in most. Core laboratories reviewed stress tests and CCTAs. Participants with no obstructive CAD or with left main CAD of 50% or greater were excluded. Those who met eligibility criteria including CCTA (if performed) were randomized to a routine invasive or a conservative management strategy (N = 5179). Angina was assessed using the Seattle Angina Questionnaire. Analysis began October 1, 2018. Interventions/UNASSIGNED:CCTA and angina assessment. Main Outcomes and Measures/UNASSIGNED:Sex differences in stress test, CCTA findings, and symptom severity. Results/UNASSIGNED:Of 8518 patients enrolled, 6256 (77%) were men. Women were more likely to have no obstructive CAD (<50% stenosis in all vessels on CCTA) (353 of 1022 [34.4%] vs 378 of 3353 [11.3%]). Of individuals who were randomized, women had more angina at baseline than men (median [interquartile range] Seattle Angina Questionnaire Angina Frequency score: 80 [70-100] vs 90 [70-100]). Women had less severe ischemia on stress imaging (383 of 919 [41.7%] vs 1361 of 2972 [45.9%] with severe ischemia; 386 of 919 [42.0%] vs 1215 of 2972 [40.9%] with moderate ischemia; and 150 of 919 [16.4%] vs 394 of 2972 [13.3%] with mild or no ischemia). Ischemia was similar by sex on exercise tolerance testing. Women had less extensive CAD on CCTA (205 of 568 women [36%] vs 1142 of 2418 men [47%] with 3-vessel disease; 184 of 568 women [32%] vs 754 of 2418 men [31%] with 2-vessel disease; and 178 of 568 women [31%] vs 519 of 2418 men [22%] with 1-vessel disease). Female sex was independently associated with greater angina frequency (odds ratio, 1.41; 95% CI, 1.13-1.76). Conclusions and Relevance/UNASSIGNED:Women in the ISCHEMIA trial had more frequent angina, independent of less extensive CAD, and less severe ischemia than men. These findings reflect inherent sex differences in the complex relationships between angina, atherosclerosis, and ischemia that may have implications for testing and treatment of patients with suspected stable ischemic heart disease. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01471522.

Background Sex differences in ischemia, coronary anatomy and symptoms have not been investigated among patients who have moderate or severe ischemia. The enrolled ISCHEMIA trial cohort that underwent coronary CT angiography (CCTA) was required to have obstructive CAD to undergo randomization. We describe sex differences in stress testing and CCTA findings as well as symptoms in the ISCHEMIA trial. Methods ISCHEMIA enrolled patients based on local reading of moderate or severe ischemia on a stress test, after which blinded CCTA was performed in most participants. Stress tests and CCTAs were reviewed at core laboratories. Those with no obstructive coronary artery disease (CAD) or with left main CAD >=50% were excluded. Angina was assessed using the Seattle Angina Questionnaire (SAQ). Results Women were more likely to have no obstructive CAD (<50% stenosis in all vessels on CCTA), 34% versus 11%, p<0.001, resulting in more women excluded after enrollment. Randomized women (n=1168) had more angina at baseline than randomized men (n=4011), despite less extensive CAD on CCTA and less severe ischemia in women vs. men with stress imaging (Figure). Conclusion Women randomized in the ISCHEMIA trial had more frequent angina despite less extensive CAD and less ischemia than men. Our findings likely reflect inherent sex differences in the complex relationships between angina, atherosclerosis and ischemia that may have implications for testing and treatment of patients with suspected ischemic heart disease. [Formula presented]
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A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.

In the second part of this JACC State-of-the-Art Review, an early and sustainable preventive care plan is described for cardiometabolic-based chronic disease. This plan can improve cardiometabolic health by targeting early mechanistic events to decrease the risk for certain cardiovascular diseases (e.g., coronary heart disease, heart failure, and atrial fibrillation). Included are various prevention modalities, intensive lifestyle interventions, pharmacotherapy and cardiovascular outcome trial evidence, and bariatric/metabolic procedures. A tactical approach of implementing published clinical practice guidelines/algorithms for early behavioral, adiposity, and dysglycemia targeting is emphasized, as well as relevant educational and research implications.

BACKGROUND:Risk factor control is the cornerstone of managing stable ischemic heart disease but is often not achieved. Predictors of risk factor control in a randomized clinical trial have not been described. METHODS AND RESULTS/RESULTS:The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) randomized individuals with at least moderate inducible ischemia and obstructive coronary artery disease to an initial invasive or conservative strategy in addition to optimal medical therapy. The primary aim of this analysis was to determine predictors of meeting trial goals for LDL-C (low-density lipoprotein cholesterol, goal <70 mg/dL) or systolic blood pressure (SBP, goal <140 mm Hg) at 1 year post-randomization. We included all randomized participants in the ISCHEMIA trial with baseline and 1-year LDL-C and SBP values by January 28, 2019. Among the 3984 ISCHEMIA participants (78% of 5179 randomized) with available data, 35% were at goal for LDL-C, and 65% were at goal for SBP at baseline. At 1 year, the percent at goal increased to 52% for LDL-C and 75% for SBP. Adjusted odds of 1-year LDL-C goal attainment were greater with older age (odds ratio [OR], 1.11 [95% CI, 1.03-1.20] per 10 years), lower baseline LDL-C (OR, 1.19 [95% CI, 1.17-1.22] per 10 mg/dL), high-intensity statin use (OR, 1.30 [95% CI, 1.12-1.51]), nonwhite race (OR, 1.32 [95% CI, 1.07-1.63]), and North American enrollment compared with other regions (OR, 1.32 [95% CI, 1.06-1.66]). Women were less likely than men to achieve 1-year LDL-C goal (OR, 0.68 [95% CI, 0.58-0.80]). Adjusted odds of 1-year SBP goal attainment were greater with lower baseline SBP (OR, 1.27 [95% CI, 1.22-1.33] per 10 mm Hg) and with North American enrollment (OR, 1.35 [95% CI, 1.04-1.76]). CONCLUSIONS:In ISCHEMIA, older age, male sex, high-intensity statin use, lower baseline LDL-C, and North American location predicted 1-year LDL-C goal attainment, whereas lower baseline SBP and North American location predicted 1-year SBP goal attainment. Future studies should examine the effects of sex disparities, international practice patterns, and provider behavior on risk factor control.