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.

Clinical spectrum of hypertrophic cardiomyopathy (HC) has been expanded to include patients with mild or no thickening of the left ventricle (LV), who nevertheless have outflow tract obstruction at rest or after exercise, due to systolic anterior motion (SAM) and ventricular septal contact, with mitral valve elongation and papillary muscles anomalies. Apical ballooning mimicking a takotsubo syndrome (TS) wall motion pattern can occur in HC with mild septal thickening when latent obstruction becomes unrelenting. To define the prevalence of anatomic abnormalities characteristic of HC in patients diagnosed with TS, we analyzed echocardiograms of 44 unselected TS patients, age 67±12 years, 95% women including studies performed before the event (n = 11, median 515 days) and after recovery of left ventricular function (n = 33, median 92 days, interquartile range = 29 to 327) and compared the findings to 60 age and sexed matched controls. Analysis of echocardiograms was blinded to event timing, and patient vs. control status. During the ballooning event, 13 patients (30%) had SAM including 9 with LV outflow obstruction, peak gradients 71±40 mmHg, as well as: ventricular septal thickening (16 ± 4 mm), elongated anterior leaflets (30 ± 3mm), and increased mitral coaptation to posterior wall distance (17 ± 5 mm), consistent with diagnosis of the HC phenotype. Compared to 31 TS patients without SAM, study patients with SAM had longer anterior leaflets (30 ± 3 vs 26 ± 4 mm, p = 0.006), thicker septum (16 ± 4 vs 12 ± 3 mm), increased coaptation to posterior wall distance (17 ± 5 vs 14 ± 4 mm, p < 0.04) and reduced distance from coaptation to septum (19 ± 5 vs 27 ± 5, p < 0.001). In the 13 patients with SAM, morphologic characteristics of HC persisted after normalization of LV function. In conclusion, a subset of patients experiencing TS events demonstrates a constellation of morphologic abnormalities characteristic of HC that persist after recovery of LV wall motion. These findings suggest that dynamic outflow obstruction may cause apical ballooning in susceptible patients.

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:or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status. METHODS:We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy. RESULTS:Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, -0.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, -2.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, -1.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, -2.2 to 3.4). CONCLUSIONS:Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy. (Funded by the National Heart, Lung, and Blood Institute; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Background Recently the clinical spectrum of hypertrophic cardiomyopathy (HCM) has been expanded to include patients with mild or no thickening of the left ventricle (LV) yet who have outflow tract obstruction at rest or after exercise, principally due to characteristic HCM anterior mitral leaflet (AML) elongation and papillary muscle anomalies. Apical ballooning mimicking a takotsubo syndrome (TTS) wall motion pattern can occur in mild-septal-thickening HCM when latent obstruction becomes unrelenting. The objective of this study is to define the prevalence of anatomic abnormalities characteristic of HCM in an unselected population of patients diagnosed clinically with TTS. Methods We analyzed echocardiograms of 44 admitted TTS patients including studies performed during admission, before the event (n=11, median 515 days before) and after recovery of left ventricular function (n=33, median 92 days, IQR=29-327) and compared them to 60 controls, age-matched normal women. Analysis of 148 echocardiograms was blinded to timing, and patient vs. control status. Results Age was 67+/-12 years, 42 female (95%). During the ballooning event, 13 (30%) had SAM and 9 patients (20%) had LV outflow tract obstruction (LVOTO), gradients 71+/-40 mmHg. Compared to TTS patients without SAM, those with SAM had longer AML (30 vs. 26mm), and thicker septum (16 vs. 12 mm) and less distance from septum to coaptation (19 vs. 27mm), all p <=0.006. Eleven of the SAM patients had >=2 anatomic abnormalities predisposing to obstruction (defined as > 2 SD above normal), and/or an anomalous papillary muscle/chordae. In the 44 TTS patients each parameter differed from controls before, during and after the TTS event. Eight (18%) had abnormal right ventricular wall motion, none of whom were obstructed. Conclusion Thirty percent of unselected TTS patients have SAM and 20% have significant LVOT gradients. This subset had AML abnormalities and septal thickening typical of obstructive HCM and known to predispose to LVOT obstruction. They are phenotypically identical to patients with documented HCM with mild septal thickening and LVOT obstruction, who have experienced episodes of ballooning.

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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BACKGROUND:Ambient air pollution is a modifiable risk factor for cardiovascular disease, yet uncertainty remains about the size of risks at lower levels of fine particulate matter (PM2.5) exposure which now occur in the USA and elsewhere. METHODS:We investigated the relationship of ambient PM2.5 exposure with cause-specific cardiovascular disease mortality in 565 477 men and women, aged 50 to 71 years, from the National Institutes of Health-AARP Diet and Health Study. During 7.5 x 106 person-years of follow up, 41 286 cardiovascular disease deaths, including 23 328 ischaemic heart disease (IHD) and 5894 stroke deaths, were ascertained using the National Death Index. PM2.5 was estimated using a hybrid land use regression (LUR) geostatistical model. Multivariate Cox regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CI). RESULTS:Each increase of 10  μg/m3 PM2.5 (overall range, 2.9-28.0  μg/m3) was associated, in fully adjusted models, with a 16% increase in mortality from ischaemic heart disease [hazard ratio (HR) 1.16; 95% CI 1.09-1.22] and a 14% increase in mortality from stroke (HR 1.14; CI 1.02-1.27). Compared with PM2.5 exposure <8  μg/m3 (referent), risks for CVD were increased in relation to PM2.5 exposures in the range of 8-12  μg/m3 (CVD: HR 1.04; 95% CI 1.00-1.08), in the range 12-20  μg/m3 (CVD: HR 1.08; 95% CI 1.03-1.13) and in the range 20+ μg/m3 (CVD: HR 1.19; 95% CI 1.10-1.28). Results were robust to alternative approaches to PM2.5 exposure assessment and statistical analysis. CONCLUSIONS:Long-term exposure to fine particulate air pollution is associated with ischaemic heart disease and stroke mortality, with excess risks occurring in the range of and below the present US long-term standard for ambient exposure to PM2.5 (12  µg/m3), indicating the need for continued improvements in air pollution abatement for CVD prevention.

Myocardial infarction in the absence of obstructive coronary artery disease is found in ≈5% to 6% of all patients with acute infarction who are referred for coronary angiography. There are a variety of causes that can result in this clinical condition. As such, it is important that patients are appropriately diagnosed and an evaluation to uncover the correct cause is performed so that, when possible, specific therapies to treat the underlying cause can be prescribed. This statement provides a formal and updated definition for the broadly labelled term MINOCA (incorporating the definition of acute myocardial infarction from the newly released "Fourth Universal Definition of Myocardial Infarction") and provides a clinically useful framework and algorithms for the diagnostic evaluation and management of patients with myocardial infarction in the absence of obstructive coronary artery disease.