Anxiety Disorders Are Associated With Coronary Endothelial Dysfunction in Women With Chest Pain and Nonobstructive Coronary Artery Disease.

Background Anxiety disorders are the most prevalent mental disorders and are an emerging risk factor for coronary artery disease and its complications. We determine the relationship between having a clinical diagnosis of an anxiety disorder and coronary endothelial dysfunction (CED) using invasive coronary reactivity testing across both sexes. Methods and Results Patients presenting with chest pain and nonobstructive coronary artery disease (stenosis <40%) at coronary angiography underwent an invasive assessment of CED. Patients were categorized as having a clinical diagnosis of an anxiety disorder at the time of coronary angiography by chart review. The frequency of CED was compared between patients with versus without an anxiety disorder and after stratifying patients by sex. Between 1992 and 2020, 1974 patients (mean age, 51.3 years; 66.2% women) underwent invasive coronary reactivity testing, of which 550 (27.9%) had a documented anxiety disorder at the time of angiography. There was a significantly higher proportion of patients with any type of CED in those with an anxiety disorder in all patients (343 [62.7%] versus 790 [56.4%]; P=0.011) that persisted in women but not in men. After adjusting for covariables, anxiety was significantly associated with any CED among all patients (odds ratio [95% CI], 1.36 [1.10-1.68]; P=0.004), and after stratifying by sex in women but not in men. Conclusions Anxiety disorders are significantly associated with CED in women presenting with chest pain and nonobstructive coronary artery disease. Thus, CED may represent a mechanism underpinning the association between anxiety disorders and coronary artery disease and its complications, highlighting the role of anxiety as a potential therapeutic target to prevent cardiovascular events.

Prognostic impact and clinical outcomes of coronary flow reserve and hyperaemic microvascular resistance.

BACKGROUND: Most studies dichotomise indices of coronary microvascular function to assess their prognostic values. AIMS: We aimed to investigate whether coronary flow reserve (CFR) and hyperaemic microvascular resistance (HMR) as continua predict major adverse cardiovascular events (MACE), comprising all-cause death, myocardial infarction, revascularisation, and stroke in patients with ischaemia and non-obstructive coronary artery disease. METHODS: A total of 610 patients were included and followed up over a median of 8.0 years (199 individual MACE in 174 patients). RESULTS: Both CFR and HMR as continua predicted MACE with an odds ratio (OR) of 0.70 (per 1-unit increase, 95% confidence interval [CI]: 0.53, 0.92; p=0.01) and 1.63 (per 1 mmHg/cm/s, 95% CI: 1.20, 2.21; p=0.002), respectively. This relationship remained significant after adjustment for age and sex with an adjusted OR of 0.66 (per 1 unit increase, 95% CI: 0.49, 0.89; p=0.01) and 1.42 (per 1 mmHg/cm/s, 95% CI: 1.03, 1.94; p=0.03). HMR added prognostic value to CFR in predicting MACE (net reclassification index 0.17, 95% CI: 0.02, 0.31; p=0.03; integrated discrimination improvement 0.01, 95% CI: 0.0001, 0.02; p=0.046). CONCLUSIONS: Both CFR and HMR as continuous variables predict future risk of MACE.

Clinical decision-making: Challenging traditional assumptions.

Clinical decision-making that best serves the interests of our patients requires the synthesis of evidence-based medicine, sound clinical judgment and guidelines. However, a relatively low percentage of clinical guidelines are based on well-designed prospective randomized clinical trials. Thus the foundation on which good clinical outcomes can be reasonably expected should be based on i) data derived from the most applicable and highest quality clinical studies available, and ii) 'tried and tested' clinical maxims acquired through experience that are, in turn, those ideas that are in keeping with a reasonable body of medical opinion. It follows that poor decision-making and unfavorable clinical outcomes can be linked to inappropriate or inferior quality evidence, or incorrectly conceived or implemented clinical judgment. Here we review selected areas of recent controversy in clinical cardiology, highlighting the critical role of evidence-based medicine when making informed clinical decisions to help avoid harm in our patients.

Prevalence of myocardial bridging associated with coronary endothelial dysfunction in patients with chest pain and non-obstructive coronary artery disease.

AIMS: Myocardial bridging (MB), characterised by the epicardial coronary vessel diving into the myocardium, is present in up to one third of adults and is associated with angina and acute coronary syndromes. MB is accompanied by altered blood flow mechanics and regional changes in wall sheer stress. The purpose of this study was to determine the association between myocardial bridging and coronary endothelial dysfunction. METHODS AND RESULTS: Patients presenting with chest pain and found to have non-obstructive CAD (stenosis <40%) on angiography underwent an invasive assessment of epicardial and microvascular endothelial function. Epicardial endothelial function was assessed by measuring the percent change in coronary artery diameter in response to intracoronary infusions of acetylcholine (%ΔCADAch). Epicardial endothelial dysfunction was defined as a %ΔCADAch of <-20%. Microvascular endothelial function was assessed by the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction was defined as a %ΔCBFAch of <50%. MB was diagnosed angiographically by identifying the characteristic reduction in minimal luminal diameter during systole. Patients were divided into those with and those without MB, and the frequency of epicardial endothelial dysfunction and microvascular endothelial dysfunction was compared between patients with versus those without MB. Between 1993 and 2012, 1,469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing of endothelial function. Two hundred and eight (14.2%) patients were found to have MB in the LAD. Patients with any MB had a significantly higher frequency of endothelial dysfunction within the mid and/or distal vessel segment compared to patients without MB (60.1% vs 50.4%, p=0.012). In multivariate analyses, mid and/or distal vessel MB was a significant predictor of mid and/or distal vessel epicardial endothelial dysfunction (OR 1.44, 95% CI: 1.04-2.00, p=0.029) and of microvascular endothelial dysfunction (OR 1.34, 95% CI: 1.00-1.82, p=0.050). CONCLUSIONS: MB co-localises with epicardial endothelial dysfunction and is significantly associated with microvascular endothelial dysfunction in symptomatic patients with non-obstructive CAD, supporting its potential role as a mechanism for angina in symptomatic patients with MB.

Attenuated peripheral endothelial function among women treated with aromatase inhibitors for breast cancer.

PURPOSE: Data on long-term cardiovascular effects of aromatase inhibitors (AIs) are limited and conflicting. We sought to evaluate the effect of AIs on peripheral endothelial function in patients with breast cancer. PATIENTS AND METHODS: This is an observational, prospective study of postmenopausal women with breast cancer who were enrolled at the initiation of cancer treatment. All participants underwent baseline and 6-12 months of follow-up, with peripheral endothelial function testing to measure reactive hyperemia index (RHI). The primary aim was to assess endothelial function deterioration between baseline and follow-up. The secondary aim was to assess the correlation of cardiovascular risk factors with RHI change in women treated with versus without AIs. RESULTS: Among 97 patients, mean (SD) age was 66 (7) years; 59 (61%) women had AI treatment, and 38 women did not (control group). There were no significant differences in baseline characteristics between the groups. Mean (SD) RHI at baseline in the treatment group did not differ significantly from that in the control group [2.2 (0.6) vs. 2.1 (0.5); P=0.15]. The mean (SD) time between baseline and follow-up studies was 262 (60) days. RHI deterioration, evaluated as a dichotomous variable with a 20% cutoff, was significantly more common in the AI group [17 (29%) vs. 4 (11%); P=0.04]. After adjusting for age, treatment with AIs was significantly associated with an RHI deterioration of at least 20% from baseline (odds ratio: 3.6; 95% confidence interval: 1.10-12.07; P=0.03). Further, in the intervention group, women with at least three traditional cardiovascular risk factors were more likely to have RHI deterioration compared to women with λ2 risk factors [10 (42%) vs. 7 (20%); P=0.04]. Amongst women with three or more cardiovascular risk factors, the percentage with RHI deterioration was higher in the AI group than the control group [10/24 (42%) vs. 3/22 (14%); P=0.04], whereas in women with up to two risk factors, the percentage with RHI deterioration was similar between the groups [7/35 (20%) vs. 1/16 (6%); P=0.21]. CONCLUSION: This study suggests that AIs may be associated with vascular injury. The effect is more pronounced among women with a higher baseline cardiovascular risk factor burden. These findings have potentially important implications, particularly among women at high risk for cardiovascular disease who are treated with AIs for hormone receptor-positive breast cancer.

High-sensitivity C-reactive protein is an independent marker of abnormal coronary vasoreactivity in patients with non-obstructive coronary artery disease.

BACKGROUND: Coronary endothelial dysfunction (CED) is an early stage of atherosclerosis and is associated with adverse cardiovascular events. Inflammation may play a role in the development of endothelial dysfunction. To date no study has evaluated the relationship between C-reactive protein and CED. We aimed to determine if C-reactive protein is associated with CED. METHODS: In 1016 patients (mean age 50.7±12.3 years, 34% male) presenting to the catheterization laboratory with chest pain and non-obstructive coronary artery disease, coronary vasoreactivity was assessed by measuring the percent change in coronary blood flow (%ΔCBF) and coronary artery diameter (%ΔCAD) in response to intracoronary acetylcholine. Plasma high sensitivity C-reactive protein (hs-CRP) was measured and patients were divided into 2 groups: hs-CRP≤3.0 mg/L (low-intermediate cardiovascular risk n=169) and 3 mg/L

What is the association of hypothyroidism with risks of cardiovascular events and mortality? A meta-analysis of 55 cohort studies involving 1,898,314 participants.

BACKGROUND: Whether hypothyroidism is an independent risk factor for cardiovascular events is still disputed. We aimed to assess the association between hypothyroidism and risks of cardiovascular events and mortality. METHODS: We searched PubMed and Embase from inception to 29 February 2016. Cohort studies were included with no restriction of hypothyroid states. Priori main outcomes were ischemic heart disease (IHD), cardiac mortality, cardiovascular mortality, and all-cause mortality. RESULTS: Fifty-five cohort studies involving 1,898,314 participants were identified. Patients with hypothyroidism, compared with euthyroidism, experienced higher risks of IHD (relative risk (RR): 1.13; 95% confidence interval (CI): 1.01-1.26), myocardial infarction (MI) (RR: 1.15; 95% CI: 1.05-1.25), cardiac mortality (RR: 1.96; 95% CI: 1.38-2.80), and all-cause mortality (RR: 1.25; 95% CI: 1.13-1.39); subclinical hypothyroidism (SCH; especially with thyrotropin level ≥10 mIU/L) was also associated with higher risks of IHD and cardiac mortality. Moreover, cardiac patients with hypothyroidism, compared with those with euthyroidism, experienced higher risks of cardiac mortality (RR: 2.22; 95% CI: 1.28-3.83) and all-cause mortality (RR: 1.51; 95% CI: 1.26-1.81). CONCLUSIONS: Hypothyroidism is a risk factor for IHD and cardiac mortality. Hypothyroidism is associated with higher risks of cardiac mortality and all-cause mortality compared with euthyroidism in the general public or in patients with cardiac disease.

Left Internal Mammary Artery Versus Coronary Stents: Impact on Downstream Coronary Stenoses and Conduit Patency.

BACKGROUND: The study compared downstream coronary and conduit disease progression in the left anterior descending coronary artery treated with coronary artery bypass grafting using the left internal mammary artery (LIMA) versus percutaneous coronary intervention with bare metal stent (BMS) or drug eluting stent (DES). METHODS AND RESULTS: A total of 12 301 consecutive patients underwent isolated primary coronary revascularization, of which 2386 met our inclusion criteria (Percutaneous coronary intervention, n=1450; coronary artery bypass grafting, n=936). Propensity score analysis matched 628 patients, of which 468 were treated to the left anterior descending with coronary artery bypass grafting with LIMA (n=314), percutaneous coronary intervention with BMS (n=94), and DES (n=60). Coronary angiograms were analyzed by quantitative coronary angiography (QCA; n=433). Cumulative downstream coronary and conduit disease progression were estimated by Kaplan-Meier method and effect of treatment type by Cox proportional hazard models. Patients treated with LIMA had significantly lower risk of downstream coronary disease progression at follow-up angiogram compared with BMS and DES (hazard ratio [HR] [95% CI], 0.34; [0.20-0.59]; P=0.0002; and HR [95% CI], 0.39; [0.20-0.79]; P=0.01, respectively). LIMA was associated with a lower risk of conduit disease progression compared to BMS and DES (HR [95% CI], 0.18; [0.12-0.28]; P<0.001; and HR [95% CI], 0.27; [0.16-0.46]; P<0.001, respectively). BMS was associated with higher HR for downstream coronary and conduit disease progression compared with DES, but the difference did not reach statistical significance (HR [95% CI], 1.13; [0.57-2.36]; P=0.73; and HR [95% CI], 1.46; [0.88-2.50]; P=0.14, respectively). CONCLUSIONS: LIMA grafting to left anterior descending is associated with significantly lower risk of downstream coronary and conduit disease progression compared to percutaneous coronary intervention with BMS and DES.

Utility of the Framingham Risk Score in predicting secondary events in patients following percutaneous coronary intervention: A time-trend analysis.

BACKGROUND: The Framingham Risk Score (FRS) effectively predicts the risk of cardiovascular events in the primary prevention setting. However, its use in identifying the risk of cardiovascular events among patients with established coronary heart disease is unknown. This study aimed to evaluate the utility of the FRS in predicting long-term secondary events in patients following percutaneous coronary intervention (PCI) across a 17-year period. METHODS: Consecutive patients (N=25,519, male=71%, mean age=66.5±12.1years) undergoing PCI at Mayo Clinic between January 1, 1994, and December 31, 2010, were screened for cardiovascular risk factors to determine their FRS at baseline (mean score 7.0±3.3). Patients were divided into 4 groups according to their FRS 10-year predicted risk of cardiovascular disease (CVD) and were followed up for a median duration of 109months (Q1-Q3, 63-155) for the primary composite end point of cardiac death and myocardial infarction (MI) and the secondary end points of all-cause death, noncardiac death, and revascularization (surgical and percutaneous). Patients were separately divided into 5 equal temporal subsets depending on the date of PCI and were fit to a Cox model with an interaction between the FRS 10-year predicted risk and time. RESULTS: The FRS was significantly associated with the 10-year actual risk of cardiac death and MI (both combined and separately, P<.001 respectively), noncardiac death (P<.001), all-cause death (P<.001), and revascularization (P=.018). However, the FRS discriminated risk poorly for all end points (C-statistic: cardiac death and MI, 56.8; all-cause death, 58.7; noncardiac death, 51.8; and revascularization, 51.3) even among patients presenting with acute coronary syndrome or stable angina. Over the 17-year period of time, the association between the FRS 10-year predicted risk and the 10-year actual risk of events did not change (P=.72). CONCLUSIONS: The FRS discriminates the risk of long-term secondary events, including cardiac death, MI, and revascularization, in patients following PCI poorly, even among those presenting with acute coronary syndrome. The current study supports the development of novel secondary prevention risk models.

Clinical outcomes of patients with hypothyroidism undergoing percutaneous coronary intervention.

AIMS: The aim of this study was to investigate the association between hypothyroidism and major adverse cardiovascular and cerebral events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: Two thousand four hundred and thirty patients who underwent PCI were included. Subjects were divided into two groups: hypothyroidism (n = 686) defined either as a history of hypothyroidism or thyroid-stimulating hormone (TSH) ≥5.0 mU/mL, and euthyroidism (n = 1744) defined as no history of hypothyroidism and/or 0.3 mU/mL ≤ TSH < 5.0 mU/mL. Patients with hypothyroidism were further categorized as untreated (n = 193), or those taking thyroid replacement therapy (TRT) with adequate replacement (0.3 mU/mL ≤ TSH < 5.0 mU/mL, n = 175) or inadequate replacement (TSH ≥ 5.0 mU/mL, n = 318). Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards models. Median follow-up was 3.0 years (interquartile range, 0.5-7.0). After adjustment for covariates, the risk of MACCE and its constituent parts was higher in patients with hypothyroidism compared with those with euthyroidism (MACCE: HR: 1.28, P = 0.0001; myocardial infarction (MI): HR: 1.25, P = 0.037; heart failure: HR: 1.46, P = 0.004; revascularization: HR: 1.26, P = 0.0008; stroke: HR: 1.62, P = 0.04). Compared with untreated patients or those with inadequate replacement, adequately treated hypothyroid patients had a lower risk of MACCE (HR: 0.69, P = 0.005; HR: 0.78, P = 0.045), cardiac death (HR: 0.43, P = 0.008), MI (HR: 0.50, P = 0.0004; HR: 0.60, P = 0.02), and heart failure (HR: 0.50, P = 0.02; HR: 0.52, P = 0.017). CONCLUSION: Hypothyroidism is associated with a higher incidence of MACCE compared with euthyroidism in patients undergoing PCI. Maintaining adequate control on TRT is beneficial in preventing MACCE.

Lack of correlation between the optimal glycaemic control and coronary micro vascular dysfunction in patients with diabetes mellitus: a cross sectional study.

BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with cardiovascular events in type 2 diabetes mellitus (T2DM). Optimal glycaemic control does not always preclude future events. We sought to assess the effect of the current target of HBA1c level on the coronary microcirculatory function and identify predictive factors for CMD in T2DM patients. METHODS: We studied 100 patients with T2DM and 214 patients without T2DM. All of them with a history of chest pain, non-obstructive angiograms and a direct assessment of coronary blood flow increase in response to adenosine and acetylcholine coronary infusion, for evaluation of endothelial independent and dependent CMD. Patients with T2DM were categorized as having optimal (HbA1c < 7%) vs. suboptimal (HbA1c ≥ 7%) glycaemic control at the time of catheterization. RESULTS: Baseline characteristics and coronary endothelial function parameters differed significantly between T2DM patients and control group. The prevalence of endothelial independent CMD (29.8 vs. 39.6%, p = 0.40) and dependent CMD (61.7 vs. 62.2%, p = 1.00) were similar in patients with optimal vs. suboptimal glycaemic control. Age (OR 1.10; CI 95% 1.04-1.18; p < 0.001) and female gender (OR 3.87; CI 95% 1.45-11.4; p < 0.01) were significantly associated with endothelial independent CMD whereas glomerular filtrate (OR 0.97; CI 95% 0.95-0.99; p < 0.05) was significantly associated with endothelial dependent CMD. The optimal glycaemic control was not associated with endothelial independent (OR 0.60, CI 95% 0.23-1.46; p 0.26) or dependent CMD (OR 0.99, CI 95% 0.43-2.24; p = 0.98). CONCLUSIONS: The current target of HBA1c level does not predict a better coronary microcirculatory function in T2DM patients. The appropriate strategy for prevention of CMD in T2DM patients remains to be addressed.

Fundamental concepts of effective troponin use: important principles for internists.

Troponin testing is an essential component of our diagnostic approach to patients in acute medical care settings. With the advent of high-sensitivity troponin assays, its importance will extend to patients in chronic disease settings. Although elevated troponin levels provide diagnostic information, inform treatment decisions, and influence patient prognosis, proper interpretation of the values is essential. This requires an understanding of the operating characteristics of troponin testing; the likelihood ratios associated with a positive/negative test result and the pre- and post-test probabilities related to individual clinical settings. These principles will become more important as high-sensitivity assays become introduced over the coming years in the United States. This article reviews the important principles of troponin testing focusing in particular on acute settings and is aimed at internal medicine and hospital specialists.