Coronary Optical Coherence Tomography and Cardiac Magnetic Resonance Imaging to Determine Underlying Causes of Myocardial Infarction With Nonobstructive Coronary Arteries in Women.

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 6% to 15% of myocardial infarctions (MIs) and disproportionately affects women. Scientific statements recommend multimodality imaging in MINOCA to define the underlying cause. We performed coronary optical coherence tomography (OCT) and cardiac magnetic resonance (CMR) imaging to assess mechanisms of MINOCA. METHODS: In this prospective, multicenter, international, observational study, we enrolled women with a clinical diagnosis of myocardial infarction. If invasive coronary angiography revealed <50% stenosis in all major arteries, multivessel OCT was performed, followed by CMR (cine imaging, late gadolinium enhancement, and T2-weighted imaging and T1 mapping). Angiography, OCT, and CMR were evaluated at blinded, independent core laboratories. Culprit lesions identified by OCT were classified as definite or possible. The CMR core laboratory identified ischemia-related and nonischemic myocardial injury. Imaging results were combined to determine the mechanism of MINOCA, when possible. RESULTS: Among 301 women enrolled at 16 sites, 170 were diagnosed with MINOCA, of whom 145 had adequate OCT image quality for analysis; 116 of these underwent CMR. A definite or possible culprit lesion was identified by OCT in 46.2% (67/145) of participants, most commonly plaque rupture, intraplaque cavity, or layered plaque. CMR was abnormal in 74.1% (86/116) of participants. An ischemic pattern of CMR abnormalities (infarction or myocardial edema in a coronary territory) was present in 53.4% (62/116) of participants undergoing CMR. A nonischemic pattern of CMR abnormalities (myocarditis, takotsubo syndrome, or nonischemic cardiomyopathy) was present in 20.7% (24/116). A cause of MINOCA was identified in 84.5% (98/116) of the women with multimodality imaging, higher than with OCT alone (P<0.001) or CMR alone (P=0.001). An ischemic cause was identified in 63.8% of women with MINOCA (74/116), a nonischemic cause was identified in 20.7% (24/116) of the women, and no mechanism was identified in 15.5% (18/116). CONCLUSIONS: Multimodality imaging with coronary OCT and CMR identified potential mechanisms in 84.5% of women with a diagnosis of MINOCA, 75.5% of which were ischemic and 24.5% of which were nonischemic, alternate diagnoses to myocardial infarction. Identification of the cause of MINOCA is feasible and has the potential to guide medical therapy for secondary prevention. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02905357.

Alternative causes of myocardial ischemia in women: An update on spontaneous coronary artery dissection, vasospastic angina and coronary microvascular dysfunction.

Although coronary obstruction due to atherosclerosis is the most common cause of myocardial ischemia, a significant proportion of patients have myocardial ischemia in the absence of obstructive epicardial coronary artery disease (CAD). This finding is more common among women and alternative causes can mediate myocardial ischemia. Abnormalities in vascular structure, alterations in coronary vasomotion and dysfunction of the coronary microcirculation can all cause ischemia in the absence of obstructive CAD due to atherosclerosis. In this review, we provide an update on three alternative causes of myocardial ischemia: spontaneous coronary artery dissection (SCAD), vasospastic angina (VSA) and coronary microvascular dysfunction (CMVD). We review pathophysiology, clinical presentation, diagnosis, treatment and outcomes related to these important clinical entities. There is increasing interest in better defining this patient population with use of advanced imaging and testing tools. Despite the increased associated risk with future cardiac events, evidence-based treatments for these diagnoses remain under-studied and poorly defined. These alternative diagnoses should be kept in mind when evaluating women with myocardial ischemia without obstructive CAD due to atherosclerosis.

Gender related differences in predictors of vascular complications: role of vessel size and BMI.

Women undergoing cardiac catheterization have an increased risk of vascular complications (VC) compared to men. Whether this is due to gender differences in common femoral artery (CFA) anatomy remains unknown. Therefore, we examined angiographic features of CFA to identify differences in predictors of VC between the genders. A case control study design enrolled 59 (30 women and 29 men) consecutive patients with VC and 59 age, gender and procedure matched controls from 2004 to 2009. VC were defined as hematoma >6 cm, any access site related bleeding requiring transfusion or injury requiring mechanical intervention. Quantitative angiography was performed on all femoral angiograms. Univariate and multivariate regression was performed to define clinical and angiographic predictors of VC. Among all patients, cases had significantly lower BMI than controls (28.4 ± 7.7 vs. 32.0 ± 6.7, p ≤ 0.01) and were more than twice likely to have CFA reference vessel diameter <5.5 mm (p = 0.04). This finding was entirely driven by the inverse relationship between BMI, CFA and VC among women. On multivariate analysis, BMI was a potent predictor of VC (OR 0.94; 95 % CI 0.89-0.99; p = 0.04). When comparing men and women, BMI and CFA size were predictors of VC among women only. Among men, site of arteriotomy and diabetes mellitus predicted risk of VC. Smaller BMI correlates with smaller CFA diameter and both are predictive of increased risk of VC. This may explain the female predisposition to VC. Risk stratification for bleeding and VC should address these gender specific findings.

Two hour bivalirudin infusion after PCI for ST elevation myocardial infarction.

The standard of care for STEMI PCI for the past decade has been aspirin, clopidogrel, heparin, and a glycoprotein IIbIIIa receptor inhibitor (GPI). A bivalirudin strategy was shown to be superior to a GPI strategy in the HORIZONS AMI trial for net adverse clinical events (combined MACE and bleeding). An increased risk of acute stent thrombosis in the bivalirudin arm may have prevented broader adoption of bivalirudin for this indication. We hypothesized that acute stent thrombosis risk could be ameliorated by a 2 h infusion of bivalirudin following STEMI PCI. We implemented a multicenter, prospective registry for all STEMI patients in Vermont treated at a single PCI center. Each patient was routinely pre-loaded with dual antiplatelet therapy and 75% received an unfractionated heparin bolus prior to PCI. The utilization of bivalirudin bolus and continued 2 h infusion after PCI was routine with GPI bailout optional. 128 consecutive STEMI patients underwent primary PCI from October 1, 2008 to September 30, 2009. 92% of primary PCI patients received bivalrudin during and after the procedure with a 9% rate of bail out GPI. There was one case of probable or definite acute stent thrombosis (0.7%), and this single case occurred despite use of bailout GPI. Despite the prolonged infusion of bivalirudin, major bleeding occurred in only 1.7% of STEMI patients. In conclusion, prolonging bivalirudin for 2 h after STEMI PCI may be a promising method to alleviate acute stent thrombosis risk without losing the bleeding complication benefit of the bivalirudin strategy.

Frequency and safety of switching antithrombin therapy at a regional PCI center.

The impact of switching antithrombin therapy in patients presenting with acute coronary syndromes (ACS) and undergoing percutaneous intervention (PCI) has varied in clinical trials. We sought to assess the incidence and safety of switching antithrombin therapy in ACS patients undergoing PCI at a regional medical center. All patients with ACS undergoing PCI (n = 728) during a specified time period in 2005 and 2007 were identified. Patients who were switched to the antithrombin bivalirudin were defined as the "switch" group (n = 323) and all others were defined as the "consistent" therapy group (n = 405). Primary endpoints were major adverse cardiac event (MACE) (death, MI or urgent revascularization), major bleeding and net adverse clinical event (NACE) (MACE or major bleeding). Multivariate analysis was performed to determine if switching antithrombotic therapy predicted primary outcomes. Among 728 patients undergoing PCI for ACS, 44% were switched to bivalirudin. Switch patient were more likely to be transfers from outside hospitals, older, female, and diabetic. Angiographic characteristics were similar in the two groups. Switch patients had a similar incidence of MACE (7 vs. 8%, P = 0.72), major bleeding (2 vs. 2%) and NACE (9 vs. 10%, P = 0.51) when compared to those who received consistent therapy. On multivariate analysis, switching did not predict MACE (OR = 0.94, 95% CI = 0.53-1.67, P = 0.84) or NACE (OR = 0.82, 95%CI = 0.48-1.41, P = 0.47). In a regional clinical practice of patients presenting with ACS and undergoing PCI, switching of antithrombin therapy to bivalirudin is a common practice and patient who are switched have similar outcomes compared to patients who receive consistent therapy.

Feasibility and Utility of a Cardiovascular Risk Screening Tool in Women Undergoing Routine Gynecology Evaluation.

Background: The goals of this multicenter survey were to examine the prevalence and patient awareness of cardiovascular risk factors, and the association between history of adverse pregnancy outcomes (APO­including gestational hypertension, gestational diabetes, and preeclampsia) and prevalence of cardiovascular risks among women presenting to outpatient obstetrics/gynecology (OB/GYN) clinics. Materials and Methods: We surveyed 2,946 female patients attending 16 outpatient OB/GYN clinics across the United States between January 2010 and January 2012. Main outcome measures were self-reported cardiovascular risk factors and symptoms such as angina and dyspnea. Results: Mean age of the patients was 51 ± 13.6 years. Cardiovascular risks and symptoms were highly prevalent (86.0% and 40.1%, respectively). Many patients did not know if they had common risk factors such as hypertension, hypercholesterolemia, or diabetes (18.4%, 32.0%, and 17.9%, respectively). Women with a history of APO were slightly more likely to be aware of common risk factors, including abnormal blood pressure (17% vs. 18.6%), high cholesterol (31.7% vs. 32%), and obesity/elevated body mass index (43.9% vs. 49.7%). Compared with patients with no history of APO, patients with APO (n = 380, 12.9%) were more likely to have risk factors (89.5% vs. 83.9%, p = 0.002) and symptoms (45.5% vs. 39.3%, p = 0.02). Conclusions: Awareness of cardiovascular risk factors and symptoms among all women surveyed in this study was poor, although awareness for some risk factors was relatively higher among patients with APO. This study demonstrates the feasibility of cardiovascular assessment in OB/GYN clinics using a simple questionnaire and its potential role for early recognition and timely intervention.

Impact of Abnormal Coronary Reactivity on Long-Term Clinical Outcomes in Women.

BACKGROUND: Currently as many as one-half of women with suspected myocardial ischemia have no obstructive coronary artery disease (CAD), and abnormal coronary reactivity (CR) is commonly found. OBJECTIVES: The authors prospectively investigated CR and longer-term adverse cardiovascular outcomes in women with and with no obstructive CAD in the National Heart, Lung, and Blood Institute-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. METHODS: Women (n = 224) with signs and symptoms of ischemia underwent CR testing. Coronary flow reserve and coronary blood flow were obtained to test microvascular function, whereas epicardial CR was tested by coronary dilation response to intracoronary (IC) acetylcholine and IC nitroglycerin. All-cause mortality, major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke, and heart failure), and angina hospitalizations served as clinical outcomes over a median follow-up of 9.7 years. RESULTS: The authors identified 129 events during the follow-up period. Low coronary flow reserve was a predictor of increased MACE rate (hazard ratio [HR]: 1.06; 95% confidence interval [CI]: 1.01 to 1.12; p = 0.021), whereas low coronary blood flow was associated with increased risk of mortality (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.038) and MACE (HR: 1.11; 95% CI: 1.03 to 1.20; p = 0.006) after adjusting for cardiovascular risk factors. In addition, a decrease in cross-sectional area in response to IC acetylcholine was associated with higher hazard of angina hospitalization (HR: 1.05; 95% CI: 1.02 to 1.07; p < 0.0001). There was no association between epicardial IC-nitroglycerin dilation and outcomes. CONCLUSIONS: On longer-term follow-up, impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of ischemia. Evaluation of CR abnormality can identify those at higher risk of adverse outcomes in the absence of significant CAD. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00000554).

Diabetes mellitus, hypothalamic hypoestrogenemia, and coronary artery disease in premenopausal women (from the National Heart, Lung, and Blood Institute sponsored WISE study).

Diabetes mellitus (DM) portends a higher risk of coronary heart disease mortality in women compared with men. This relationship appears to be independent of traditional cardiac risk factors, and the role of reproductive hormones has been postulated. We assessed the relationship between DM, hypothalamic hypoestrogenemia (HHE), angiographic coronary artery disease (CAD), and major adverse cardiovascular events (MACE) during a median of 5.9 years in premenopausal women enrolled in the WISE Study. We evaluated 95 premenopausal women from WISE who underwent coronary angiography for suspected ischemia and were not using exogenous reproductive hormones. Results showed no difference in age between women with (n = 30) and without (n = 65) DM (43 +/- 6 years). DM was associated with hypertension, HHE, angiographic CAD, and coronary artery severity score (all p <0.05). Women with DM were twice as likely to have HHE (50% vs 26%; p = 0.02) compared with women without DM. The presence of both DM and HHE was associated with increased prevalence (40% vs 12% or 13%; p = 0.006) and severity of angiographic CAD (coronary artery severity score 19.9 +/- 19.2 vs 7.7 +/- 4.6 or 12.3 +/- 18.8; p = 0.008) compared with either HHE or DM alone, respectively. DM was moderately predictive of MACE. In conclusion, in premenopausal women undergoing coronary angiography for suspected myocardial ischemia, DM was associated with HHE. The presence of both DM and HHE predicted a greater burden of angiographic CAD. Prospective research is warranted to better understand causal relations between DM, endogenous hormones, and MACE in premenopausal women.

Impact of ranolazine on coronary microvascular dysfunction (MICRO) study.

BACKGROUND: Patients with angina and coronary microvascular dysfunction, without evidence of structural or epicardial coronary disease (Type I CMVD) remain without evidence based treatment options. Previous work has demonstrated that ranolazine can improve angina frequency and stability among patients with Type 1 CMVD; however, the mechanism remains unclear. Therefore, the objective of this pilot project was to assess the impact of ranolazine on Type I CMVD as measured using an invasive tool to measure global resistance (index of microcirculatory resistance (IMR)). METHODS: Patients with Type 1 CMVD diagnosed using IMR were enrolled and treated with ranolazine 1000mg BID. Coronary angiography and IMR were performed at baseline and on treatment after four weeks. The primary outcome measure was change in IMR pre- and post-treatment. Secondary outcome measures, improvement in angina and activity level, were assessed using the Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI) and Metabolic equivalent for Task (MET) scores. RESULTS: A total of 7 patient were enrolled and completed the study. Mean age was 57.6±7.5, 43% were female and 43% were Hispanic. Mean baseline IMR was 37.25±16.27 which decreased to 19.48±5.69 (p=0.02; (-48% Δ) after treatment with ranolazine. Four of the five SAQ domains improved on treatment with significant improvement in physical limitation (p=0.001), angina frequency (p=0.04), angina stability (p=0.05) and disease perception (p=0.001). Non-significant improvements in activity were also seen in both the DASI and MET scores. CONCLUSION: Among patients with Type 1 CMVD, our pilot data suggest favorable changes in IMR, anginal symptoms and activity status with ranolazine treatment. These findings support further evaluation of the effects of ranolazine on microcirculatory function and angina symptoms in a larger cohort of patients with Type 1 CMVD.

Premature atherosclerosis in premenopausal women: Does cytokine balance play a role?

Contributory risk factors to premature coronary artery disease (CAD) in premenopausal women are poorly understood and data on this subset of women is lacking. There is growing evidence that the process of inflammation is a part of the atherosclerotic process. Mechanistic insights from animal work suggest that the profile of circulating cytokines reflects both endothelial integrity and the presence of immune and progenitor cells. Significant differences in pro- and anti-inflammatory cytokine concentrations between patients with and without CAD exist. Young women with obstructive CAD may experience differences in pro-inflammatory cytokines and the recruitment of reparative cells that secrete T-Helper (Th2 cytokines compared to women without CAD. Thus, cytokine balance may play a role in obstructive CAD in young women. In this pilot study we set out to identify an array of circulating inflammatory marker profiles which could be useful for the development of risk assessment and preventive strategies. We tested the hypothesis that an increase in serologic Th1 cytokines relative to Th2)/hematopoietic regulatory (HR) cytokines is related to premature coronary atherosclerosis in premenopausal women.

Migraine Headache and Long-Term Cardiovascular Outcomes: An Extended Follow-Up of the Women's Ischemia Syndrome Evaluation.

BACKGROUND: The association between migraine headache and cardiovascular events has been inconsistent. This study determines the long-term risk of cardiovascular events among women with and without a history of migraine headache who were under evaluation for suspected myocardial ischemia in the Women's Ischemia Syndrome Evaluation (WISE). METHODS: The WISE is a National Heart, Lung and Blood Institute-sponsored prospective, multicenter study that aims to improve myocardial ischemia evaluation in women. A total of 936 women presenting with symptoms of myocardial ischemia underwent structured data collection and coronary angiography. Information pertaining to migraine headache was available in 917 women. All-cause mortality data were available on all women for a median of 9.5 years, and nonfatal cardiovascular event data were available on 888 women for a median of 6.5 years. RESULTS: A total of 224 (24.4%) women reported a history of migraine headache. Compared with women who did not report a history of migraine headache, women with a history of migraine headache had an increased adjusted risk of cardiovascular event (cardiovascular death, nonfatal myocardial infarction, heart failure, or stroke) (hazard ratio 1.83; 95% confidence interval, 1.22-2.75) at a median follow-up of 6.5 years. This result was driven mainly by a twofold increase in the risk of stroke (hazard ratio 2.33; 95% confidence interval, 1.16-4.68). CONCLUSION: Among women being evaluated for ischemic heart disease, those reporting a history of migraine headache had increased risk of future cardiovascular events on long-term follow-up. This risk was primarily driven by a more-than twofold increase in the risk of stroke.

New insights into the pathophysiology, classification, and diagnosis of coronary microvascular dysfunction.

The coronary microvasculature plays a key role in determining and modulating coronary blood flow across the spectrum of myocardial demand. Our understanding of this complex system has been limited partly due to our inability to visualize the anatomy of an extensive microvascular bed and its complicated functional pathways. Nonetheless, research has led to the current belief that coronary microvascular dysfunction (CMVD) is a clinical entity that is an independent predictor of poor long-term outcomes in patients across a broad spectrum of cardiac diseases. CMVD exists in many clinical forms, in the presence and absence of epicardial coronary artery disease and structural heart disease. Both invasive and noninvasive tools have been used to assess the functional aspects of CMVD and both come with limitations. To date, invasive testing to assess coronary blood flow and microvascular resistance in response to provocative and hyperemic stimuli remains the gold standard. A recent clinical classification has been put forth to correctly categorize patients with CMVD. Despite the adverse outcomes associated with CMVD, proven targeted therapies remain elusive. Symptom relief and cardiovascular risk factor modification are the goals of current recommendations. There is a strong need for adequately powered trials to test specific management strategies and their effect on outcomes among patients with CMVD.

In-hospital mortality among patients with type 2 diabetes mellitus and acute myocardial infarction: results from the national inpatient sample, 2000-2010.

BACKGROUND: Case-fatality rates in acute myocardial infarction (AMI) have significantly decreased; however, the prevalence of diabetes mellitus (DM), a risk factor for AMI, has increased. The purposes of the present study were to assess the prevalence and clinical impact of DM among patients hospitalized with AMI and to estimate the impact of important clinical characteristics associated with in-hospital mortality in patients with AMI and DM. METHODS AND RESULTS: We used the National Inpatient Sample to estimate trends in DM prevalence and in-hospital mortality among 1.5 million patients with AMI from 2000 to 2010, using survey data-analysis methods. Clinical characteristics associated with in-hospital mortality were identified using multivariable logistic regression. There was a significant increase in DM prevalence among AMI patients (year 2000, 22.2%; year 2010, 29.6%, Ptrend<0.0001). AMI patients with DM tended to be older and female and to have more cardiovascular risk factors. However, age-standardized mortality decreased significantly from 2000 (8.48%) to 2010 (4.95%) (Ptrend<0.0001). DM remained independently associated with mortality (adjusted odds ratio 1.069, 95% CI 1.051 to 1.087; P<0.0001). The adverse impact of DM on in-hospital mortality was unchanged over time. Decreased death risk over time was greatest among women and elderly patients. Among younger patients of both sexes, there was a leveling off of this decrease in more recent years. CONCLUSIONS: Despite increasing DM prevalence and disease burden among AMI patients, in-hospital mortality declined significantly from 2000 to 2010. The adverse impact of DM on mortality remained unchanged overall over time but was age and sex dependent.

Entrapped devices after PCI.

In contemporary practice, entrapped devices are rarely encountered during percutaneous coronary intervention (PCI) but can be associated with serious morbidity and mortality. We present a case of a 62 y/o male who presented with an acute coronary syndrome. Revascularization was performed and complicated by guide wire entrapment and fracture. Cardiologists should be aware of this complication and the treatment options available.

Appropriate timing of nitroglycerin prior to intravascular ultrasound.

OBJECTIVES: To determine the time to maximal coronary dilation following intracoronary (IC) nitroglycerin (NTG) and whether the decrease in aortic pressure (AoP) is a surrogate marker for coronary vasodilatation. BACKGROUND: Intravascular ultrasound (IVUS) facilitates assessment of coronary plaque severity and morphology and aids in stent sizing. NTG is often administered prior to IVUS to prevent catheter-induced spasm and to facilitate standardized and accurate vessel size measurements. The impact of dose, timing, and route of delivering NTG on vessel size remains undefined. METHODS: Twelve patients undergoing IVUS-guided stent placement were studied. An IVUS catheter was positioned proximal to the target lesion and the following measurements made at baseline and 30 second (sec) intervals for 180 sec following 200 mcg IC NTG: AoP, IVUS-derived lumen diameter (Ld), lumen cross-sectional area (La), external elastic membrane diameter (EEMd) and EEM area (EEMa). Lumen and EEM measurements were compared at different time intervals and the relationship between time to max Ld and nadir AoP was analyzed. RESULTS: All patients had a vasodilatory response to IC NTG. Increase from baseline to max Ld following IC NTG was statistically significant (mean change 0.31 ± 0.18 mm, P=.0001). Mean time to max Ld following IC NTG was 117 sec (range, 60-180 sec). No correlation between time to max Ld and AoP nadir was observed (r = 0.19). CONCLUSIONS: Our study suggests that administration of 200 mcg IC NTG results in a significant change in lumen diameter and area with maximal vasodilation occurring on average approximately 2 minutes following IC NTG administration. There was no significant correlation between AoP change and maximal NTG-induced coronary vasodilation.