Left ventricular global longitudinal strain is worse in BRCA mutation positive breast cancer patients prior to cancer treatment and premature menopause.

PURPOSE: Breast cancer patients with mutations in human tumor suppressor genes BRCA1 and BRCA2 are at higher risk of cardiovascular disease (CVD) than the general population, as they are frequently exposed to cardiotoxic chemotherapy, anti-estrogen therapy, radiation, and/or oophorectomy for cancer-related treatment and prophylaxis. Animal and cell culture models suggest that BRCA mutations may play an independent role in heart failure. We sought to evaluate cardiac structure and function in female BRCA1 and BRCA2 mutation carriers with breast cancer compared to BRCA wildtype women with breast cancer. METHODS: We performed a 1:2 age- and hypertension-matched retrospective cohort study comparing BRCA1 and BRCA2 mutation carriers (n = 38) versus BRCA wildtype controls (n = 76) with a new diagnosis of breast cancer. Echocardiographic data were obtained within 6 months of breast cancer diagnosis and prior to chemotherapy, anti-estrogen therapy, radiation, or oophorectomy. Left ventricular global longitudinal strain (LV-GLS), a highly sensitive marker of LV function, was measured using QLab 15 (Philips Healthcare). RESULTS: In the total cohort of 114 patients with a new diagnosis of breast cancer, the median age was 45 ± 11 years and the prevalence of hypertension was 8%. There were no differences in traditional cardiovascular disease risk factors between cases and controls. BRCA carriers had lower LV-GLS (- 18.1% ± 4.7% vs. - 20.1% ± 3.8%, p = 0.02) and greater right atrial area (12.9 cm2 ± 2.7 cm2 vs. 11.8 cm2 ± 2.0 cm2, p = 0.04) compared to controls; however, both LV-GLS and right atrial area were within the normal range. Compared to controls, BRCA carriers had a trend toward worse LV posterior wall thickness (0.89 cm ± 0.15 cm vs. 0.83 cm ± 0.16 cm, p = 0.06) although not statistically significant. CONCLUSION: In women with newly diagnosed breast cancer and prior to treatment, LV-GLS was worse in BRCA1 and BRCA2 mutation carriers compared to those with BRCA wildtype. These findings suggest that BRCA mutations may be associated with subtle changes in cardiac function. Whether differences in GLS translate to increased cardiovascular risk in women with BRCA mutations needs to be further characterized.

Pericardial fat volume is related to endothelial-mediated coronary blood flow in women with suspected coronary microvascular dysfunction. A report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

Background: Coronary microvascular dysfunction is prevalent in women with signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) and is associated with an adverse prognosis. Elevated pericardial fat volume predicts adverse cardiac events, but mechanistic pathways of the association are not well understood. Methods: 118 women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study with suspected coronary microvascular dysfunction but no obstructive CAD underwent adenosine stress 1.5 T cardiovascular magnetic resonance imaging (CMR) imaging and invasive coronary reactivity testing. Semi-quantitative myocardial perfusion reserve index (MPR) index was derived from perfusion images. Pericardial fat volume was measured by manually contouring the cardiac margins and adjacent adipose tissue on a single trans-axial HASTE slice at the level of the left main coronary artery origin and indexed to body surface-area. Simple standard deviation analysis obtained for continuous variables and frequency (percent) for categorical variables. The relationships between pericardial fat volume and coronary reactivity testing parameters were examined by correlation and multivariable regression analyses. Results: Women with suspected coronary microvascular dysfunction had a mean age of 55 ± 10 years, body mass index (BMI) of 28 ± 7 kg/m2, 44 % had a history of smoking, 63 % hypertension, 8 % diabetes, and 20 % dyslipidemia. CMR imaging-derived pericardial fat volume and coronary blood flow response to intracoronary acetylcholine (Δ CBF) were negatively correlated (r = -0.32, p = 0.0013). After adjustment for age, number of risk factors, high-density lipoprotein (HDL), and cold pressor diameter response, pericardial fat volume remained a significant predictor of Δ coronary blood flow (p = 0.04). There was no association with other coronary reactivity testing measures or CMRI derived MPR index. Conclusions: Among women with suspected coronary microvascular dysfunction but no obstructive CAD, pericardial fat volume appears to be related in a hypothesized adverse direction to coronary microvascular endothelial function. These results support further work confirming and extending these results to investigate pericardial fat volume as mechanistic pathway and potential treatment target for coronary microvascular dysfunction-related adverse events.Trial registration: clinicaltrials.govNCT00832702.

Reduced myocardial perfusion is common among subjects with ischemia and no obstructive coronary artery disease and heart failure with preserved ejection fraction: a report from the WISE-CVD continuation study.

Aim: Women with evidence of ischemia and no obstructive coronary artery disease (INOCA) have an increased risk of major adverse cardiac events, including heart failure with preserved ejection fraction (HFpEF). To investigate potential links between INOCA and HFpEF, we examined pathophysiological findings present in both INOCA and HFpEF. Methods: We performed adenosine stress cardiac magnetic resonance imaging (CMRI) in 56 participants, including 35 women with suspected INOCA, 13 women with HFpEF, and 8 reference control women. Myocardial perfusion imaging was performed at rest and with vasodilator stress with intravenous adenosine. Myocardial perfusion reserve index was quantified as the ratio of the upslope of increase in myocardial contrast at stress vs. rest. All CMRI measures were quantified using CVI42 software (Circle Cardiovascular Imaging Inc). Statistical analysis was performed using linear regression models, Fisher's exact tests, ANOVA, or Kruskal-Wallis tests. Results: Age (P = 0.007), Body surface area (0.05) were higher in the HFpEF group. Left ventricular ejection fraction (P = 0.02) was lower among the INOCA and HFpEF groups than reference controls after age adjustment. In addition, there was a graded reduction in myocardial perfusion reserve index in HFpEF vs. INOCA vs. reference controls (1.5 ± 0.3, 1.8 ± 0.3, 1.9 ± 0.3, P = 0.02), which was attenuated with age-adjustment. Conclusion: Reduced myocardial perfusion reserve appears to be a common pathophysiologic feature in INOCA and HFpEF patients.

Association of coronary microvascular dysfunction and cardiac bridge integrator 1, a cardiomyocyte dysfunction biomarker.

BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with heart failure with preserved ejection fraction (HFpEF); however, pathophysiology is not well described. HYPOTHESIS: We hypothesized that CMD in women with suspected ischemia with no obstructive coronary artery disease (INOCA) is associated with cardiomyocyte dysfunction reflected by plasma levels of a cardiomyocyte calcium handling protein, cardiac bridge integrator 1 (cBIN1). METHODS: Women with suspected INOCA undergoing coronary function testing were included. Coronary flow reserve, vasodilation to nitroglycerin, change in coronary blood flow (ΔCBF), and vasodilation to acetylcholine (ΔAch) were evaluated. cBIN1 score (CS) levels in these women (n = 39) were compared to women with HFpEF (n = 20), heart failure with reduced ejection fraction (HFrEF) (n = 36), and reference controls (RC) (n = 50). Higher CS indicates cardiomyocyte tubule dysfunction. RESULTS: INOCA, HFpEF, and HFrEF women were older than RC (p < .05). Higher CS was associated with vasoconstriction to acetylcholine (r = -0.43, p = .011) with a trend towards lower ΔCBF (r = 0.30, p = .086). Higher CS was specific for ΔAch and ΔCBF but had limited sensitivity. INOCA women had higher CS than RC, but lower CS than HFpEF/HFrEF groups (p < .001). CONCLUSIONS: CS, a plasma biomarker indicating poor cardiomyocyte health, was higher in women with suspected INOCA as compared to RC, but lower than in women with HFpEF. Elevated CS in suspected INOCA patients represents an intermediate group between health and disease, supporting the hypothesis that CMD may progress to HFpEF. Larger prospective cohort studies are needed to confirm the pathophysiological relationship between cBIN1, CMD, and HFpEF.

Left ventricular circumferential strain and coronary microvascular dysfunction: A report from the Women's Ischemia Syndrome Evaluation Coronary Vascular Dysfunction (WISE-CVD) Project.

AIMS: Women with ischemia but no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical dysfunction. METHODS AND RESULTS: Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) <1.84 during adenosine-stress perfusion cMR, was compared with CS in women without CMD. In a subset who had invasive coronary function testing (CFT), the relationship between CS and CFT metrics, LV ejection fraction (LVEF) and cardiovascular risk factors was investigated. Among 317 women with INOCA, 174 (55%) had CMD measured by MPRI. CS was greater in women with CMD compared to those without CMD (23.2 ± 2.5% vs. 22.1 ± 3.0%, respectively, P = 0.001). In the subset with CFT (n = 153), greater CS was associated with increased likelihood of reduced vasodilator capacity (OR = 1.33, 95%CI = 1.02-1.72, p = 0.03) and discriminated abnormal vs. normal coronary vascular function compared to CAD risk factors, LVEF and LV concentricity (AUC: 0.82 [0.73-0.96 95%CI] vs. 0.65 [0.60-0.71 95%CI], respectively, P = 0.007). CONCLUSION: The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical dysfunction in CMD.

Risk factors for heart failure in women with ischemia and no obstructive coronary artery disease.

Study objective: Women with ischemia and no obstructive coronary artery disease (INOCA) are at increased risk for heart failure (HF) hospitalizations, which is predominantly HF with preserved ejection fraction (HFpEF). We aimed to identify predictors for the development of heart failure HF in a deeply phenotyped cohort of women with INOCA and long-term prospective follow-up. Design setting and participants: Women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) were evaluated for baseline characteristics including clinical history, medications, physical exam, laboratory data and angiographic data. Using a multivariate Cox analysis, we assessed the association between baseline characteristics and the occurrence of HF hospitalizations in 493 women with evidence of ischemia but no obstructive coronary disease, no prior history of HF, and available follow-up data. Results: During a median follow-up of 6-years, 18 (3.7%) women were hospitalized for HF. Diabetes mellitus and tobacco use were associated with HF hospitalization. In a multivariate analysis adjusting for known HFpEF predictors including age, diabetes, hypertension, tobacco use, and statin use, novel predictive variables included higher resting heart rate, parity and IL-6 levels and lower coronary flow reserve (CFR) and poor functional status. Conclusions: There is a considerable incidence of HF hospitalization at longer term follow-up in women with INOCA. In addition to traditional risk factors, novel risk variables that independently predict HF hospitalization include multi-parity, high IL-6, low CFR, and poor functional status. These novel risk factors may be useful to understand mechanistic pathways and future treatment targets for prevention of HFpEF.

Oxidative Stress Is Associated With Diastolic Dysfunction in Women With Ischemia With No Obstructive Coronary Artery Disease.

Background Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have evidence of diastolic dysfunction. Oxidative stress (OS) is associated with cardiovascular risk factors and adverse outcomes. The relationship between systemic OS and diastolic dysfunction is unknown. Methods and Results A subgroup of women (n=75) with suspected ischemia and no obstructive coronary artery disease who had both cardiac magnetic resonance imaging and OS measurements were enrolled in the WISE-CVD (Women Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction) study. Left ventricular end-diastolic pressure was measured invasively. Left ventricular end-diastolic volume and peak filling rate were assessed using cardiac magnetic resonance imaging. Aminothiol levels of plasma cystine and glutathione were measured as markers of OS. Spearman correlation and linear regression analyses were conducted. The group mean age was 54±11 years, and 61% had a resting left ventricular end-diastolic pressure >12 mm Hg. Cystine levels correlated negatively with the peak filling rate (r=-0.31, P=0.007) and positively with left ventricular end-diastolic pressure (r=0.25; P=0.038), indicating that increased OS was associated with diastolic dysfunction. After multivariate adjustment including multiple known risk factors for diastolic dysfunction and cardiovascular medications, cystine levels continued to be associated with peak filling rate (ß=-0.27, P=0.049) and left ventricular end-diastolic pressure (ß=0.25; P=0.035). Glutathione levels were not associated with indices of diastolic function. Conclusions OS, measured by elevated levels of cystine, is associated with diastolic dysfunction in women with evidence of ischemia and no obstructive coronary artery disease, indicating the role of OS in patients with ischemia and no obstructive coronary artery disease. Its role in the progression of heart failure with preserved ejection fraction should be explored further.

Resting coronary velocity and myocardial performance in women with impaired coronary flow reserve: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

BACKGROUND: Women with evidence of ischemia and no obstructive coronary arteries (INOCA) often have coronary microvascular dysfunction (CMD) indicated by impaired coronary flow reserve (CFR) to adenosine. Low CFR is associated with an adverse prognosis, including incident heart failure. Because the CFR calculation relies on the baseline intrinsic coronary vasomotor flow velocity, a major determinate of CFR and the degree of variation in baseline flow alone may be an important contributor to risk of adverse outcomes in women with CMD. A better understanding of baseline blood flow in the setting of low CFR and its association with myocardial performance would be helpful. METHODS: We evaluated 74 women who underwent invasive coronary reactivity testing in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study and had impaired CFR (<2.32). We assessed the relationship between coronary artery baseline average peak velocity (bAPV) at rest and cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function. RESULTS: When stratified as low (<22 cm/s) versus high (≥22 cm/s) bAPV, there were no differences in cardiovascular risk factors, coronary plaque burden, or LV structure. However, low bAPV was associated with higher LV end-diastolic filling pressure (P = 0.04), lower LV ejection fraction (P = 0.001), and differences in late systolic and diastolic strain rates (P = 0.01 to 0.05). CONCLUSIONS: In women with impaired CFR, low resting coronary flow velocity is associated with more adverse myocardial performance, which may contribute to risk for adverse outcomes and particularly heart failure in women with CMD.

KPT-9274, an Inhibitor of PAK4 and NAMPT, Leads to Downregulation of mTORC2 in Triple Negative Breast Cancer Cells.

Triple negative breast cancer (TNBC) is difficult to treat due to lack of druggable targets. We have found that treatment with the small molecule inhibitor KPT-9274 inhibits growth of TNBC cells and eventually leads to cell death. KPT-9274 is a dual specific inhibitor of PAK4 and Nicotinamide Phosphoribosyltransferase (NAMPT). The PAK4 protein kinase is often highly expressed in TNBC cells and has important roles in cell growth, survival, and migration. Previously we have found that inhibition of PAK4 leads to growth inhibition of TNBC cells both in vitro and in vivo. Likewise, NAMPT has been shown to be dysregulated in cancer due to its role in cell metabolism. In order to understand better how treating cells with KPT-9274 abrogates TNBC cell growth, we carried out an RNA sequencing of TNBC cells treated with KPT-9274. As a result, we identified Rictor as an important target that is inhibited in the KPT-9274 treated cells. Conversely, we found that Rictor is predicted to be activated when PAK4 is overexpressed in cells, which suggests a role for PAK4 in the regulation of Rictor. Rictor is a component of mTORC2, one of the complexes formed by the serine/threonine kinase mTOR. mTOR is important for the control of cell growth and metabolism. Our results suggest a new mechanism by which the KPT-9274 compound may block the growth of breast cancer cells, which is via inhibition of mTORC2 signaling. Consistent with this, sequencing analysis of PAK4 overexpressing cells indicates that PAK4 has a role in activation of the mTOR pathway.

Prevalence of Coronary Endothelial and Microvascular Dysfunction in Women with Symptoms of Ischemia and No Obstructive Coronary Artery Disease Is Confirmed by a New Cohort: The NHLBI-Sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD).

OBJECTIVE: In a separate, contemporary cohort, we sought to confirm findings of the original Women's Ischemia Syndrome Evaluation (WISE). BACKGROUND: The original WISE observed a high prevalence of both invasively determined coronary endothelial and coronary microvascular dysfunction (CMD) that predicted adverse events in follow-up. METHODS: We comparatively studied the WISE-Coronary Vascular Dysfunction (CVD) cohort (2009-2011), with signs and symptoms of ischemia but without significant CAD, to the original WISE (1997-2001) cohort. CMD was defined as coronary flow reserve (CFR) ≤2.5, or endothelial dysfunction as epicardial coronary artery constriction to acetylcholine (ACH), or <20% epicardial coronary dilation to nitroglycerin (NTG). RESULTS: In WISE (n=181) and WISE-CVD (n=235) women, mean age in both was 54 years, and 83% were white (WISE) vs 74% (WISE-CVD, p=0.04). Use of hormone replacement therapy was less frequent in WISE-CVD vs WISE (46% vs 57%, p=0.026) as was presence of hypertension (40% vs 52%, p=0.013), hyperlipidemia (20% vs 46%, p<0.0001), and smoking (46% vs 56%, p=0.036). Similar rates were observed in WISE-CVD and WISE cohorts for CMD (mean CFR 2.7±0.6 vs 2.6±0.8, p=0.35), mean change in diameter with intracoronary ACH (0.2±10.0 vs 1.6±12.8 mm, p=0.34), and mean change in diameter with intracoronary NTG (9.7±13.0 vs 9.8±13.5 mm, p=0.94), respectively. CONCLUSIONS: This study confirms prevalence of CMD in the contemporary WISE-CVD cohort similar to that of the original WISE cohort, despite a lower risk factor burden in WISE-CVD. Because these coronary functional abnormalities predict major adverse cardiac events, clinical trials of therapies targeting these abnormalities are indicated.

Cardiovascular and pregnancy outcomes in women with coronary microvascular dysfunction: a case series.

BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with adverse cardiovascular outcomes. Coronary microvascular dysfunction is observed in women of childbearing age, however, the frequency of adverse pregnancy outcomes (APO) is unknown. CASE SUMMARY: Women previously enrolled in a single centre prospective CMD registry diagnosed using invasive coronary reactivity testing were included. Among 279 women enrolled, 5 of 47 (10.6%) of childbearing age (18-44 years) subsequently became pregnant, representing a fertility rate of 36.8 births per 1000 women-years. None had history of hypertension, diabetes, or smoking. Four (80%) had a history of prior spontaneous miscarriage. Median age at CMD diagnosis was 32 years (IQR: 32-35). During pregnancy, most reported stable or improved angina, while one reported increased angina frequency, an emergency room visit and accelerated anti-anginal therapy. None experienced gestational hypertension, diabetes, pre-eclampsia, myocardial infarction, or death. Two (40%) experienced APO of preterm delivery and small neonate for gestational age. Following pregnancy, angina severity scores, and/or functional capacity decreased in three women (60%). DISCUSSION: In this first case-series of five women with CMD who became pregnant, increased angina and accelerated care during pregnancy and post-partum was not commonly observed. Fertility rates were lower than the national average, while prior spontaneous miscarriage and subsequent APO were higher. Further studies are warranted to understand and manage pregnancy in women with CMD, as well as the impact of pregnancy on longer term angina, functional capacity, and outcomes.

Adenosine vs Regadenoson Pharmacologic Stress Differs in Women with Suspected Coronary Microvascular Dysfunction: A Report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) Study.

Background: Stress cardiac magnetic resonance (CMR) imaging with myocardial perfusion reserve index (MPRI) measurement has emerged as a noninvasive method for assessing coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease (CAD). Pharmacologic stress with adenosine or regadenoson is typically used with comparable coronary vasodilation, but higher unadjusted MPRI has been reported with regadenoson in healthy men. This difference has not been assessed in symptomatic or healthy women. Methods: In a prospective cohort study, 139 symptomatic women with suspected CMD and no obstructive CAD underwent stress CMR and invasive coronary flow reserve (CFR) testing. Adenosine was the default vasodilator (n=99), while regadenoson was used if history of asthma or prior adenosine intolerance (n=40). Stress CMR was also performed in 40 age-matched healthy controls using adenosine (n=20) and regadenoson (n=20). Unpaired t-tests and analysis of covariance were performed to compare MPRI with adenosine and regadenoson in the symptomatic women and healthy controls. Results: Compared to regadenoson cases, adenosine cases had lower invasive CFR (2.64±0.62 vs 2.94±0.68, p=0.01) and pharmacologic heart rate change (28±16 vs 38±15 bpm, p=0.0008). Unadjusted MPRI was lower in the adenosine compared to regadenoson cases (1.73±0.38 vs 2.27±0.59, p<0.0001). When adjusted for heart rate, rate-pressure-product, and invasive CFR, MPRI remained lower in the adenosine cases (p<0.0001). Invasive CFR to adenosine correlated with adenosine MPRI (r 0.17, p=0.02) but not regadenoson MPRI (r -0.14, p=0.19). There was no significant difference in MPRI in the controls who received adenosine vs regadenoson (2.27±0.33 vs 2.38±0.44, p=0.36). Conclusion: In women undergoing stress CMR for suspected CMD, those who received adenosine had lower MPRI than those who received regadenoson. However, there were no differences in MPRI in the healthy controls. These findings suggest there may be physiologic differences in adenosine and regadenoson response in the coronary microcirculation of symptomatic women.

Vascular Aging Is Accelerated in Flight Attendants With Occupational Secondhand Smoke Exposure.

OBJECTIVE: To determine whether early vascular aging may be present in flight attendants with remote in-cabin secondhand smoke (SHS) exposure. METHODS: Twenty-six flight attendants with a history of in-cabin SHS exposure prior to the airline smoking bans were recruited. Pulse wave analysis, peripheral arterial tonometry, and brachial artery reactivity testing evaluated their arterial compliance and endothelial function. RESULTS: Flight attendants with remote in-cabin SHS exposure have normal blood pressure, pulse wave velocity, and reactive hyperemia index, but abnormal pulse pressure, augmentation index, flow-mediated dilation, and hyperemic mean flow ratio. CONCLUSION: These preliminary findings suggest that flight attendants with remote in-cabin SHS exposure have preclinical signs of accelerated vascular aging and raise new questions about the relationship between remote SHS exposure and vascular health.

Inter-scan Reproducibility of Cardiovascular Magnetic Resonance Imaging-Derived Myocardial Perfusion Reserve Index in Women with no Obstructive Coronary Artery Disease.

BACKGROUND: Cardiovascular magnetic resonance imaging (CMRI) derived myocardial perfusion reserve index (MPRI) has recently been shown to detect coronary microvascular dysfunction (CMD) in women with signs and symptoms of ischemia and no obstructive coronary artery disease (CAD). The aim of this study was to determine the inter-scan reproducibility of MPRI in this patient group in order to assess its diagnostic robustness in serial scans and assess its utility as a marker of potential therapies for CMD. METHODS: Rest/stress perfusion CMR was performed at 1.5T using a standardized protocol in 17 women with signs and symptoms of ischemia and no obstructive CAD on two separate days (within 90 days of each other). The same pharmacological stress agent (adenosine/regadenoson) was used for both scans. MPRI was calculated from time-intensity curves of the whole myocardium and blood pool at stress and rest. One experienced observer, blinded to clinical data, performed all measurements. Intra-class correlation coefficients (ICC), coefficient of variation (CoV), and Bland-Altman plots were determined. RESULTS: Mean age was 53±10 years old and BMI 28±7 kg/m2; 47% had hypertension, 4% diabetes, 9% hyperlipidemia and 10% family history of CAD. Mean MPRI for the 17 women was higher for scan 2 compared to scan 1 (1.98±0.3 vs. 1.65±0.78, respectively, p<0.001); and this relationship persisted even when corrected for resting rate pressure product (RPP) (2.42±0.81 vs. 1.97±0.92, respectively, 0.002), The mean bias for MPRI between sequential scans was 0.34 (95% CI: 0.18 to 0.49, limits of agreement: -0.31, 0.98 and when corrected for resting RPP it was 0.45 (95% CI: 0.21 to 0.68, limits of agreement: -0.52, 1.41), ICC and CoV also indicated modest inter-scan reproducibility (ICC 0.57; CoV 20.3%), but both measures were comparable to values seen in prior studies in CAD populations and healthy volunteers. CONCLUSION: Inter-scan reproducibility of CMRI-derived MPRI in women with suspected CMD is modest, with relatively wide limits of agreement. This variability is similar to that seen in other populations, suggesting that some caution must be exercised when using absolute MPRI cut-offs in isolation for the diagnosis of CMD or repeated measures of MPRI to track response to therapy. Additional work is ongoing to improve reproducibility from both biological and technological standpoints.

Angiogenesis on coronary angiography is a marker for accelerated cardiac allograft vasculopathy as assessed by intravascular ultrasound.

BACKGROUND: Errant neovascularization and coronary artery fistulae (CAF) are frequently observed after cardiac transplantation. The relationship between angiographic neovascularization/CAF and coronary plaque progression is unknown. METHODS: Angiography and intravascular ultrasound were routinely performed at 4-6 weeks and 1-year post-transplant. Pts were divided into three groups: no angiographic angiogenesis (Group 1), neovascularization only (Group 2), and CAF (Group 3). First-year changes in maximal intimal thickness (MIT), maximal intimal area (MIA), and percent atheroma volume (PAV) were compared between groups. RESULTS: The 106 pts were included, 40/106 in Group 1, 42/106 in Group 2, and 24/106 in Group 3. Respectively, first-year ΔMIT was 0.14 ± 0.13 mm, 0.32 ± 0.26 mm, and 0.50 ± 0.34 mm, P < .001. ΔMIA was 0.6 ± 0.6 mm2 , 1.7 ± 1.8 mm2 , and 3.0 ± 2.6 mm2 , P < .001. ΔPAV was 2.3 ± 2.5%, 6.0 ± 5.1%, and 9.6 ± 9.0%, P < .001. Rapid plaque progression occurred in 1/40 (2.5%) pts in Group 1, 12/42 (28.6%) in Group 2, and 12/24 (50%) in Group 3, P < .001. Multivariate analysis identified both antithymocyte globulin and presence of CAF as independently associated with rapid plaque progression: OR 0.29 (P = .038) and 4.04 (P = .014). CONCLUSION: Neovascularization and CAF are commonly present on surveillance angiography after cardiac transplantation and may signify amplified angiogenesis. Their presence is associated with accelerated coronary plaque progression by IVUS.

Typical angina is associated with greater coronary endothelial dysfunction but not abnormal vasodilatory reserve.

BACKGROUND: Typical angina (TA) is defined as substernal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin. Women and elderly patients are usually have atypical symptoms both at rest and during stress, often in the setting of nonobstructive coronary artery disease (CAD). HYPOTHESIS: To further understand this, we performed subgroup analysis comparing subjects who presented with TA vs nontypical angina (NTA) using baseline data of patients with nonobstructive CAD and coronary microvascular dysfunction (CMD) enrolled in a clinical trial. METHODS: 155 subjects from the RWISE study were divided into 2 groups based on angina characteristics: TA (defined as above) and NTA (angina that does not meet criteria for TA). Coronary reactivity testing (responses to adenosine, acetylcholine, and nitroglycerin), cardiac magnetic resonance-determined myocardial perfusion reserve index (MPRI), baseline Seattle Angina Questionnaire (SAQ), and Duke Activity Status Index (DASI) scores were evaluated. RESULTS: The mean age was 55 ± 10 years; Overall, 30% of subjects had TA. Baseline shortness of breath, invasively assessed acetylcholine-mediated coronary endothelial function, and SAQ score were worse in the TA group (all P < 0.05), whereas adenosine-mediated coronary flow reserve, MPRI, and DASI score were similar to the NTA group. CONCLUSIONS: Among subjects with CMD and no obstructive CAD, those with TA had more angina pectoris, shortness of breath, and worse quality of life, as well as more severe coronary endothelial dysfunction. Typical angina in the setting of CMD is associated with worse symptom burden and coronary endothelial dysfunction. These results indicate that TA CMD subjects represent a relatively new CAD phenotype for future study and treatment trials.

Cold Pressor Stress Cardiac Magnetic Resonance Myocardial Flow Reserve Is Not Useful for Detection of Coronary Endothelial Dysfunction in Women with Signs and Symptoms of Ischemia and No Obstructive CAD.

BACKGROUND: Coronary endothelial function testing using acetylcholine is not routinely available, while non-pharmacological cold pressor testing (CPT) is considered an endothelial stressor. Noninvasive cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index (MPRI) can detect coronary microvascular dysfunction (CMD). We evaluated if CPT stress CMRI MPRI could detect invasive coronary endothelial dysfunction. METHODS: Coronary reactivity testing was performed in 189 women with symptoms and signs of ischemic but no obstructive coronary artery disease as previously described plus CPT stress. Subjects also underwent pharmacologic and CPT stress during CMRI (1.5 T). Statistical analysis comparing CPT MPRI between groups was performed by Welch`s t-test and Mann-Whitney where appropriate. Anderson-Darling test and Levene test were considered to verify the normality and homogeneity of variances assumptions. Correlation analyses between CPT MPRI and both invasive and noninvasive measures of CMD were performed using Spearman correlation. RESULTS: While CPT MPRI correlated with pharmacological stress MPRI, it did not correlate with invasive measures of CMD including invasively measured responses to intracoronary (IC) adenosine, IC acetylcholine, CPT, or IC nitroglycerin. Additionally CPT MPRI was not significantly different between subjects with normal compared to abnormal pharm stress MPRI or normal compared to abnormal invasive CMD parameters. CONCLUSION: Despite correlation with pharmacological stress MPRI, non-invasive CPT MPRI does not appear to be useful for detecting CMD in symptomatic women.

Cardiac magnetic resonance imaging for myocardial perfusion and diastolic function-reference control values for women.

Angina, heart failure with preserved ejection fraction (HFpEF) and coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease (CAD) are more common in women and are associated with adverse cardiovascular prognosis. Cardiac magnetic resonance imaging (CMRI) is established for assessment of left ventricular (LV) morphology and systolic function and is increasingly used to assess myocardial perfusion and diastolic function. Indeed, stress CMRI allows measurement of myocardial perfusion reserve index (MPRI) using semi-quantitative techniques, and quantification of LV volumetric filling patterns provides valuable insight into LV diastolic function. The utility of these two techniques remains limited, because reference control values for MPRI and LV diastolic function in asymptomatic middle-aged, women have not previously been established. To address this limitation, we recruited twenty women, without clinical cardiovascular disease or cardiovascular risk factors, with normal maximal Bruce protocol exercise treadmill testing. Subjects underwent CMRI (1.5 tesla) using a standardized protocol of adenosine stress and rest perfusion and LV cinematic imaging. Commercially available with automated CMRI segmentation was used for calculation of MPRI, LV filling profiles, and ejection fraction. Mean age was 54±9 years and mean body mass index was 25±4 kg/m(3). The exercise treadmill testing results demonstrated a normotensive group with normal functional capacity and hemodynamic response. We report reference control values for semi-quantitative MPRI as well as measures of LV systolic and diastolic function including ejection fraction, stroke volume, peak filling rate (PFR), PFR adjusted for end-diastolic volume (EDV) and stroke volume, time to PFR, and EDV index. The data herein provide reference values for MPRI and diastolic function in a cohort of healthy, middle-aged of women. These reference values may be used for comparison with a variety of patient populations, including women with CMD and HFpEF.