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The basic helix-loop-helix transcription factor neurogenin1 is required for proper nervous system development in vertebrates. It is expressed in neuronal precursors during embryonic development and is thought to play a role in specifying neuronal fate. To investigate the regulation of neurogenin1 expression, the transcriptional start site of the gene was identified and a 2.7-kb fragment ending in the first exon was shown to possess basal promoter activity. This 2.7-kb fragment was able to promote expression of reporter genes in P19 cells under conditions in which expression of endogenous neurogenin1 was induced. Importantly, the 2.7-kb fragment was able to drive expression of a lacZ reporter gene in transgenic mice in most tissues in which neurogenin1 is normally expressed, including those peripheral ganglia that fail to develop in neurogenin1 "knockout" mice. These findings identify a regulatory region containing elements responsible for appropriate expression of a gene with a crucial role in generating the vertebrate nervous system.

Background: Impaired functional capacity is a common symptom in patients with heart failure. Standard measures of left ventricular (LV) function, such as ejection fraction (EF) and LV diastolic parameters, do not correlate with measures of functional capacity. The aim of this study is to determine if measures of global and regional LV strain better correlate with 6-minute walk distance than does EF or measures of LV diastolic function., Methods: 120 patients referred to a cardiology clinic for evaluation of known or suspected heart failure were approached for enrollment. Of those 120 patients, 58 had an echocardiogram within 3 months of enrollment with images adequate for regional and global strain assessment, had no contra-indication to exercise testing, and had no previously documented non-cardiac explanation for dyspnea on exertion. In those 58 patients, 6-minute walk distance was measured, LV EF was determined with Simpson's biplane method, and global and regional longitudinal strain were measured with TomTec Image Arena 4.5.1 software., Results: LV EF had no correlation with 6-minute walk distance (r = 0.22, p = 0.09) even when controlling for age, gender, and BMI (p = 0.07). No measures of LV diastolic function (including E velocity, Deceleration Time, e' annular velocities, or E/e') had a correlation with 6-minute walk distance. Multiple measures of global and regional LV longitudinal systolic function had a correlation with 6-minute walk distance. Longitudinal strain of the basal LV segments had the strongest correlation with 6-minute walk distance (r= -0.36, p = 0.005), and correlation persisted after controlling for age, gender, BMI, and systolic blood pressure (p = 0.004)., Conclusions: Longitudinal strain correlates with a measure of functional capacity, but LVEF and traditional measures of LV diastolic dysfunction do not. Measures of longitudinal strain, especially in basal LV segments, will likely be an important marker of clinically relevant LV function., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: While autoimmune rheumatic diseases (ARDs) have been linked with coronary microvascular dysfunction (CMD), the relationship between ARD and CMD in women with signs and symptoms of ischemia and no obstructive arteries (INOCA) are not well described. We hypothesized that among women with CMD, those with ARD history have greater angina, functional limitations, and myocardial perfusion compromise compared to those without ARD history., Methods: Women with INOCA and confirmed CMD by invasive coronary function testing were included from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project (NCT00832702). Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI), and cardiac magnetic resonance myocardial perfusion reserve index (MPRI) were collected at baseline. Chart review was performed to confirm self-reported ARD diagnosis., Results: Of the 207 women with CMD, 19 (9%) had a confirmed history of ARD. Compared to those without ARD, women with ARD were younger ( p  = 0.04). In addition, they had lower DASI-estimated metabolic equivalents ( p  = 0.03) and lower MPRI ( p  = 0.008) but similar SAQ scores. There was a trend towards increased nocturnal angina and stress-induced angina in those with ARD ( p  = 0.05 for both). Invasive coronary function variables were not significantly different between groups., Conclusions: Among women with CMD, women with a history of ARD had lower functional status and worse myocardial perfusion reserve compared to women without ARD. Angina-related health status and invasive coronary function were not significantly different between groups. Further studies are warranted to understand mechanisms contributing to CMD among women with ARDs with INOCA., Competing Interests: CB, serves as Board of Director for iRhythm, fees paid through CSMC from Abbott Diagnostics and Sanofi. JW served on an advisory board for Abbott Vascular. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chen, Chang, Manchanda, Cook-Wiens, Shufelt, Anderson, Petersen, Naik, Thomson, Berman, Handberg, Pepine, Bairey Merz and Wei.)

Study Objective: Cold Pressor Testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects., Design: Prospective cohort., Setting: Academic hospital., Participants: 107 women with suspected INOCA and 21-age-matched reference women., Interventions: CPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRI RPP ). Invasive coronary function testing in a subset of INOCA women (n=42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%., Main Outcome Measure: MPRI RPP ., Results: Compared to reference women, the INOCA group demonstrated higher resting RPP (p=0.005) and CPT MPRI RPP (1.09±0.36 vs 0.83±0.18, p=0.002). Furthermore, INOCA women with impaired ΔCBF (n=23) had higher CPT MPRI RPP (p=0.044) compared to reference women despite lower left ventricular ejection fraction (64±7 % vs 69±2 %, p=0.005) and mass-to-volume ratio (0.79±0.15 vs 0.62±0.09, p<0.0001). These differences in CPT MPRI RPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRI RPP among INOCA women did not differ based on defined acetylcholine responses., Conclusions: Myocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. CPT induced a higher MPRI RPP also in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Further investigation in a larger cohort is needed., Competing Interests: Disclosure/Conflict of Interest Statement: The authors have nothing to disclose.

Introduction: mRNA COVID-19 vaccines have emerged as a new form of vaccination that has proven to be highly safe and effective against COVID-19 vaccination. Rare adverse events including myocarditis have been reported in the literature., Methods: Data were gathered from the electronic medical record of four patients personally treated by the authors., Results: Four patients, ages 20 to 30, presented with myocarditis characterized by chest pain, elevations in troponin-I and C-reactive protein, and negative viral serologies two to four days following mRNA vaccine administration. One had a cardiac MRI showing delayed gadolinium enhancement in a subpericardial pattern. All experienced symptom resolution by the following day, and the two who have returned for follow-up had normal troponin-I and CRP values., Discussion: Along with previously reported instances, these cases raise suspicion for a possible link between mRNA vaccines and myocarditis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background: Women with suspected ischemia and no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD) as measured by impaired coronary flow reserve (CFR), which is associated with angina and adverse cardiovascular events. CFR is a ratio of hyperemic to baseline average peak velocity (bAPV), and the relation of baseline flow to angina is not understood., Methods: We evaluated 259 women enrolled in the WISE-Coronary Vascular Dysfunction (WISE-CVD) project with suspected CMD who underwent invasive coronary functional testing. We analyzed variables stratified by high (e.g. ≥22 cm/s) vs low (<22 cm/s) bAPV, using t-test or Wilcoxon rank; linear and multivariable regression was used with bAPV as a continuous variable., Results: Women with high bAPV had worse Seattle Angina Questionnaire (SAQ) angina frequency (58 ± 26 vs 67 ± 25, p = 0.005) and SAQ-7 scores (57 ± 22 vs 62 ± 21, p = 0.03), with higher nitrate (p = 0.02) and ranolazine use (p = 0.03). The high bAPV subgroup also had lower CFR (p < 0.001)). Linear regression related higher bAPV with lower SAQ-7 (p = 0.01) and lower angina frequency scores (p = 0.001). These results remained significant in multivariable modelling adjusting for baseline differences (p < 0.04). SAQ-7 was significantly predicted by bAPV., Conclusions: Among women with suspected INOCA, angina relates to high bAPV, a result supported by the concomitant greater use of anti-anginal drugs. These results suggest that high bAPV contributes to impaired CFR and may represent a specific pathophysiologic contributor to CMD and may be a treatment target in INOCA subjects., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To determine the relationship between coronary vascular dysfunction and history of migraines in women with suspected ischemia and no obstructive coronary arteries (INOCA)., Methods: In the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study, 402 women with suspected INOCA answered baseline angina questionnaires, including the Seattle Angina Questionnaire (SAQ). Coronary function testing (CFT) performed in a subgroup of 252 women evaluated for nonendothelial and endothelial-dependent coronary vascular function. Wilcoxon rank sum test, t -test, and linear regression models were performed., Results: Of the 252 women who underwent CFT, 126 (50%) women reported migraine history. Compared to women who reported no migraines, women with migraines were younger and more were premenopausal. They had more angina at rest, with strong emotions, and hot/cold temperatures, as well as angina that wakes them from sleep ( P < 0.05 for all). Women with migraines also scored worse on SAQ angina frequency and quality of life P < 0.01 for both). There was no difference in prevalence of coronary vascular dysfunction in the two groups. In addition, linear regression models demonstrated no significant age-adjusted differences in absolute CFT variables., Conclusion: Among women with suspected INOCA, migraine history is prevalent and women with migraines have worse angina compared to those without migraines. Coronary vascular dysfunction diagnosed by CFT does not appear to relate to migraine history., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.

A 67-year-old postmenopausal African American woman presented with biventricular takotsubo cardiomyopathy (TTC)-evidenced by transthoracic echocardiography (TTE) showing apical akinesis of both left and right ventricles in the absence of obstructive coronary artery disease on left heart catheterisation. On the 4th hospital day, she experienced acute left facial droop, dysarthria and dysphagia. CT of the head showed a wedge infarct of the right middle cerebral artery territory. Cardioembolism was presumed after intracranial and extracranial sources of thromboembolism were ruled out. Intravenous tissue plasminogen activator (tPA) was administered with resolution of symptoms. She was later discharged without neurological deficits. Crucially, repeat TTE after tPA infusion revealed a left ventricular mass concerning for thrombus. TTE 150 min prior to stroke onset was devoid of a mass. This case uniquely illustrates the potential for rapid thrombus formation and embolism in patients with TTC. As such, it emphasises the high index of suspicion required for management of these patients., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Declaration of competing interest Dr. Bairey Merz has received personal fees paid through CSMC from Abbott Diagnostics, Sanofi and serves as Board of Director at iRhythm. Dr. Pepine has received research grants from GE Healthcare, Merck, Sanofi, CLS Behring, Biocardia, McJunkin Family Foundation, Brigham & Women's Hospital, Gatorade Trust through the University of Florida Department of Medicine, Athersys Inc., AMI MultiStem, and Mesoblast, Inc.; has received consultant fees/honoraria from Verily Life Sciences LLC Project Baseline OSMB (Google), Ironwood, XyloCor, Slack Inc., Imbria Pharmaceuticals, Milestone Pharmaceuticals Inc., Ventrix, Inc., AstraZeneca Pharmaceuticals, and Sanofi-Aventis. Dr. Handberg receives research grants from Aastrom Biosciences, Amorcyte, Biocardia, Brigham and Women's Hospital, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Duke Clinical Research Institute, East Carolina University, Everyfit Inc., Medtronic, Merck & Co., Mesoblast, National Institutes of Health (NIH), NIH through University of Rochester, NIH through Brigham and Women's Health, NIH through University of Texas, PCORI, and Sanofi Aventis; Research grant and educational grant from Gilead Sciences; Unrestricted educational grants for the Vascular Biology Working Group from Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Ionis, and Relypsa; and Consultant fees from Bristol-Myers Squibb Company., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: We investigated the outcomes of patients who underwent Transcatheter Aortic Valve Replacement (TAVR) with and without Balloon Aortic Valvuloplasty (BAV) using the SAPIEN 3 (S3) valve., Methods: All patients who underwent TAVR using S3 valve were included. The primary outcomes were the incidence of stroke and significant paravalvular leak (PVL). Secondary outcomes were the incidence of mortality, balloon post dilation, and need for permanent pacemaker., Results: From July-2014 to April-2018, 34 (9%) patients underwent BAV prior to TAVR and 344 (91%) patients underwent direct TAVR without BAV using the S3 valve. The Society of Thoracic Surgeons (STS) risk score was similar between two groups; 5.8 ± 3.5 in no BAV group and 5.4 ± 3.3 in BAV group, p = 0.53. After TAVR, 6 (1.7%) patients in no BAV group but no patient in BAV group developed stroke (p = 1.0). No patient had severe PVL and only 5 patients (1.3%) had moderate PVL at 30-day; 4 (1.2%) in no BAV group and 1 (2.9%) in BAV group (p = 0.38). Forty-six patients (13.4%) in the no BAV group and 4 (11.8%) patients in the BAV group needed balloon post dilation (p = 1.0). Six (1.6%) patients died during hospitalization, all in the no BAV group (p = 1.0). Forty-five (11.9%) patients needed new pacemaker implantation; 44 (12.8%) patients in no BAV group and 1 (2.9%) patient in BAV group (p = 0.1). Two-year survival rate was 85% in no BAV group and 84% in BAV group (p = 0.46)., Conclusions: TAVR using S3 valves is associated with very low rates of post-TAVR stroke and significant PVL. Outcomes of direct TAVR are similar to the outcomes of TAVR with BAV, without an increased rate of stroke, significant PVL, or balloon post dilation., (Copyright © 2019. Published by Elsevier Inc.)

Commonly used in vitro fertilization protocols produce pregnancies without a corpus luteum (CL), a major source of reproductive hormones. In vitro fertilization pregnancies without a CL showed deficient gestational increases of central (aortic) arterial compliance during the first trimester and were at increased risk for developing preeclampsia. Here, we investigated whether there was generalized impairment of cardiovascular adaptation in in vitro fertilization pregnancies without a CL compared with pregnancies conceived spontaneously or through ovarian stimulation, which lead to 1 and >1 CL, respectively (n=19-26 participants per cohort). Prototypical maternal cardiovascular adaptations of gestation were serially evaluated noninvasively, initially during the follicular phase before conception, 6× in pregnancy, and then, on average, 1.6 years post-partum. The expected increases of cardiac output, left atrial dimension, peak left ventricular filling velocity in early diastole (E wave velocity), peripheral/central arterial pulse pressure ratio, and global AC, as well as decrease in augmentation index were significantly attenuated or absent during the first trimester in women who conceived without a CL, when compared with the 1 and >1 CL cohorts, which were comparable. Thereafter, these cardiovascular measures showed recovery in the 0 CL group except for E wave velocity, which remained depressed. These results provided strong support for a critical role of CL factor(s) in the transformation of the maternal cardiovascular system in early gestation. Regimens that lead to the development of a CL or replacement of missing CL factor(s) may be indicated to improve cardiovascular function and reduce preeclampsia risk in in vitro fertilization pregnancies.

Background: Sepsis survivors often develop chronic critical illness (CCI) and demonstrate the persistent inflammation, immunosuppression, and catabolism syndrome predisposing them to long-term functional limitations and higher mortality. There is a need to identify biomarkers that can predict long-term worsening of physical function to be able to act early and prevent mobility loss. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a well-accepted biomarker of cardiac overload, but it has also been shown to be associated with long-term physical function decline. We explored whether NT-proBNP blood levels in the acute phase of sepsis are associated with physical function and muscle strength impairment at 6 and 12 months after sepsis onset., Methods: This is a retrospective analysis conducted in 196 sepsis patients (aged 18-86 years old) as part of the University of Florida (UF) Sepsis and Critical Illness Research Center (SCIRC) who consented to participate in the 12-month follow-up study. NT-proBNP was measured at 24 h after sepsis onset. Patients were followed to determine physical function by short physical performance battery (SPPB) test score (scale 0 to12-higher score corresponds with better physical function) and upper limb muscle strength by hand grip strength test (kilograms) at 6 and 12 months. We used a multivariate linear regression model to test an association between NT-proBNP levels, SPPB, and hand grip strength scores. Missing follow-up data or absence due to death was accounted for by using inverse probability weighting based on concurrent health performance status scores. Statistical significance was set at p ≤ 0.05., Results: After adjusting for covariates (age, gender, race, Charlson comorbidity index, APACHE II score, and presence of CCI condition), higher levels of NT-proBNP at 24 h after sepsis onset were associated with lower SPPB scores at 12 months (p < 0.05) and lower hand grip strength at 6-month (p < 0.001) and 12-month follow-up (p < 0.05)., Conclusions: NT-proBNP levels during the acute phase of sepsis may be a useful indicator of higher risk of long-term impairments in physical function and muscle strength in sepsis survivors.

Objective: Limited data is available about the effect of implanted valve size on prosthesis-patient mismatch (PPM) incidence and aortic gradient (AG) after transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR). We compared PPM incidence and postprocedural AG between TAVR and SAVR patients considering the impact of implanted valve size., Methods: From March 20, 2012, to September 30, 2015, 563 consecutive patients underwent TAVR ( n = 419) or isolated SAVR ( n = 144). Postprocedural transthoracic echocardiography was obtained within 30 days; AG, effective orifice area (EOA), and EOA index were calculated., Results: A total of 381 patients in TAVR group and 82 patients in SAVR group were included. Mean preoperative AG and mean aortic valve area were not significantly different between the 2 groups. Postprocedural AG was significantly lower in TAVR than SAVR group, 7.74 ± 5.39 versus 14.27 ± 8.16 ( P < 0.001). Between patients who had TAVR and SAVR with a valve size ≤23 mm, SAVR patients were 3 times more likely to have greater than mild AG after the procedure, OR: 3.1 (95% CI, 1.1 to 8.9) ( P < 0.001). PPM incidence was significantly higher in SAVR group than TAVR group, 44 (53.7%) versus 112 (29.4%), OR = 2.8 (95% CI, 1.7 to 4.5) ( P < 0.001). The PPM incidence was also higher in SAVR group than TAVR group among those who had the procedures with a valve size ≤23 mm, 35 (64.8%) versus 56 (47.9%), OR = 2 (95% CI, 1.1 to 3.9) ( P = 0.048). Postprocedural outcomes were comparable between the 2 groups., Conclusions: In comparison to SAVR, TAVR is associated with less PPM and lower AG, especially in patients receiving a valve size ≤23 mm.

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., Competing Interests: There are no relevant conflicts of interest of any of the authors to disclose., (Copyright © 2019 R. David Anderson et al.)

Aging and diabetes are associated with decreased aerobic fitness, an independent predictor of mortality. Aerobic exercise is prescribed to improve aerobic fitness; however, middle-aged/older diabetic patients often suffer from mobility limitations which restrict walking. Non-weight-bearing/low-impact exercise is recommended but the optimal exercise prescription is uncertain. The goal of this randomized controlled trial was twofold: 1) to test if high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), implemented on a non-weight-bearing all-extremity ergometer, are feasible, well-tolerated and safe in middle-aged/older adults with type 2 diabetes; and 2) to test whether all-extremity HIIT is more effective in improving aerobic fitness than MICT. A total of 58 sedentary individuals with type 2 diabetes (46 to 78 years; 63 ± 1) were randomized to all-extremity HIIT (n = 23), MICT (n = 19) or non-exercise control (CONT; n = 16). All-extremity HIIT and MICT, performed 4×/week for 8 weeks under supervision, resulted in no adverse events requiring hospitalization or medical treatment. Aerobic fitness (VO 2peak ) improved by 10% in HIIT and 8% in MICT and maximal exercise tolerance increased by 1.8 and 1.3 min, respectively (P ≤ 0.002 vs. baseline; P ≥ 0.9 for HIIT vs. MICT). In conclusion, all-extremity HIIT and MICT are feasible, well-tolerated and safe and result in similar improvements in aerobic fitness in middle-aged/older individuals with type 2 diabetes. These findings have important implications for exercise prescription for diabetic patients; they indicate that all-extremity exercise is a feasible alternative to weight-bearing exercise and those who are unable or unwilling to engage in HIIT may receive similar benefits from MICT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing Interests: Puja K. Mehta has received research grants from Gilead and General Electric. Chrisandra Shufelt has received a research grant from Gilead. Daniel S. Berman has received research grants from Astellas Pharma US, Inc, Bayer Healthcare Pharmaceuticals, and Siemens Medical Solutions. C. Noel Bairey Merz would like to report funding from iRhythm, Abbott Diagnostics, and Sanofi.

Profound changes occur in the maternal circulation during pregnancy. Routine measures of arterial function - central systolic pressure (CSP) and augmentation index (AIx) - decline during normal human pregnancy. The objectives of this study were twofold: (1) explore wave reflection indices besides CSP and AIx that are not routinely reported, if at all, during normal human pregnancy; and (2) compare wave reflection indices and global arterial compliance (gAC) obtained from carotid artery pressure waveforms (CAPW) as a surrogate for aortic pressure waveforms (AOPW) versus AOPW synthesized from radial artery pressure waveforms (RAPW) using a generalized transfer function. To our knowledge, a comparison of these two methods has not been previously evaluated in the context of pregnancy. Ten healthy women with normal singleton pregnancies were studied using applanation tonometry (SphygmoCor) at pre-conception, and then during 10-12 and 33-35 gestational weeks. CSP and AIx declined, and gAC increased during pregnancy as previously reported. As a consequence of the rise in gAC, the return of reflected waves of lesser magnitude from peripheral reflection sites to the aorta was delayed that, in turn, reduced systolic duration of reflected waves, augmentation index, central systolic pressure, LV wasted energy due to reflected waves, and increased brachial-central pulse pressure. For several wave reflection indices, those derived from CAPW as a surrogate for AOPW versus RAPW using a generalized transfer function registered greater gestational increases of arterial compliance. This discordance may reflect imprecision of the generalized transfer function for some waveform parameters, though potential divergence of carotid artery and aortic pressure waveforms during pregnancy cannot be excluded., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Women represent approximately half of heart failure hospitalizations and are disproportionately affected by heart failure with preserved ejection fraction (HFpEF). Women with signs and symptoms of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive coronary artery disease (CAD) often have elevated left ventricular end-diastolic pressure (LVEDP). However, isolated elevated LVEDP in the absence of coronary microvascular dysfunction (CMD) is not understood., Methods: Among 244 women with signs and symptoms of ischemia, no obstructive CAD, and preserved LVEF who underwent invasive coronary reactivity testing (CRT), 43 (18%) women had no evidence of CMD. LVEDP was measured at time of CRT, and left ventricular (LV) volumes and mass were assessed by cardiac magnetic resonance (CMR) imaging., Results: Of the 43 women without CMD, 24 (56%) had elevated LVEDP [mean 18 mm Hg (SD = 3)] compared to 19 (44%) with normal LVEDP [11 mm Hg (SD = 3)]. The elevated LVEDP group had a comparatively higher systolic and diastolic blood pressure, lower LV end-diastolic volume index (EDVI), and higher mass-to-volume ratio. Other functional parameters were not significantly different., Conclusions: Among women with signs and symptoms of ischemia without obstructive CAD, absence of CMD, and preserved LVEF, isolated elevated LVEDP is associated with a significantly higher systolic and diastolic blood pressure, higher LV mass-to-volume ratio and lower LV EDVI. These results suggest these women have maladaptive remodeling to blood pressure. Given the relatively high prevalence of HFpEF in women, these hypothesis-generating results suggest that further study of ventricular remodeling is warranted., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Bicuspid aortic valve (BAV) stenosis has been considered a relative contraindication to transcatheter aortic valve replacement (TAVR). We compared the outcomes of TAVR in patients with BAV stenosis versus patients with trileaflet aortic valve stenosis., Methods: From March 2012 to September 2017, 727 patients underwent TAVR. Thirty-two patients with BAV were included in this study and compared to 96 patients with comparable risk factors (1:3) with a trileaflet aortic valve (TAV). Transesophageal echocardiography was used to estimate post-TAVR degree of paravalvular leak (PVL)., Results: Mean ± standard deviation Society of Thoracic Surgeons risk was 6.01 ± 3.42 in the BAV group and 6.08 ± 3.76 in the TAV group (P = 0.92). Thirty-day mortality was 4.2% (N = 4) in the TAV group and 6.25% (N = 2) in the BAV group (P = 0.63). Three (3.1%) patients in the TAV group and two (6.25%) patients in the BAV group developed a post operative stroke (P = 0.59). Following TAVR, mean aortic valve gradient significantly decreased in both TAV (42.56 ± 14.93 vs 9.27 ± 5.57, P < 0.001) and BAV (44.12 ± 11.82 vs 9.03 ± 7.29, P < 0.001) groups. No patient had a severe PVL after TAVR, and only two (2.08%) patients in the TAV group and one (3.12%) patient in the BAV group had moderate PVL (P = 1.0). Patient survival rate at 1 and 2 years was 86% in the BAV group and 90% at 1 and 2 years in the TAV group (P = 0.74)., Conclusions: TAVR in BAV disease is feasible with favorable valve performance. Immediate and mid-term outcomes of TAVR in patients with BAV are comparable to those with TAV., (© 2018 Wiley Periodicals, Inc.)

Background: Digital wearable devices provide a "real-world" assessment of physical activity and quantify intervention-related changes in clinical trials. However, the value of digital wearable device-recorded physical activity as a clinical trial outcome is unknown., Objective: Because late sodium channel inhibition (ranolazine) improves stress laboratory exercise duration among angina patients, we proposed that this benefit could be quantified and translated during daily life by measuring digital wearable device-determined step count in a clinical trial., Methods: We conducted a substudy in a randomized, double-blinded, placebo-controlled, crossover trial of participants with angina and coronary microvascular dysfunction (CMD) with no obstructive coronary artery disease to evaluate the value of digital wearable device monitoring. Ranolazine or placebo were administered (500-1000 mg twice a day) for 2 weeks with a subsequent 2-week washout followed by crossover to ranolazine or placebo (500-1000 mg twice a day) for an additional 2 weeks. The outcome of interest was within-subject difference in Fitbit Flex daily step count during week 2 of ranolazine versus placebo during each treatment period. Secondary outcomes included within-subject differences in angina, quality of life, myocardial perfusion reserve, and diastolic function., Results: A total of 43 participants were enrolled in the substudy and 30 successfully completed the substudy for analysis. Overall, late sodium channel inhibition reduced within-subject daily step count versus placebo (mean 5757 [SD 3076] vs mean 6593 [SD 339], P=.01) but did not improve angina (Seattle Angina Questionnaire-7 [SAQ-7]) (P=.83). Among the subgroup with improved angina (SAQ-7), a direct correlation with increased step count (r=.42, P=.02) was observed., Conclusions: We report one of the first studies to use digital wearable device-determined step count as an outcome variable in a placebo-controlled crossover trial of late sodium channel inhibition in participants with CMD. Our substudy demonstrates that late sodium channel inhibition was associated with a decreased step count overall, although the subgroup with angina improvement had a step count increase. Our findings suggest digital wearable device technology may provide new insights in clinical trial research., Trial Registration: Clinicaltrials.gov NCT01342029; https://clinicaltrials.gov/ct2/show/NCT01342029 (Archived by WebCite at http://www.webcitation.org/6uyd6B2PO)., (©Kade Birkeland, Raj M Khandwalla, Ilan Kedan, Chrisandra L Shufelt, Puja K Mehta, Margo B Minissian, Janet Wei, Eileen M Handberg, Louise EJ Thomson, Daniel S Berman, John W Petersen, R David Anderson, Galen Cook-Wiens, Carl J Pepine, C Noel Bairey Merz. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 20.12.2017.)

Background: We compared stroke occurrence and outcomes between Transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR), both periprocedural and at follow-up., Methods: From March 2012 to December 2014, 391 consecutive patients underwent TAVR (N.=290) or isolated SAVR (N.=101), concomitantly. Patients' data were prospectively collected., Results: TAVR patients had more comorbidities. One (0.34%) TIA and 9 (3.11%) strokes occurred in-hospital following TAVR, but no cerebrovascular event occurred after SAVR (P=0.11). One stroke (0.99%) and one TIA (0.99%) were detected in SAVR group within 30 days. Among TAVR patients, one (0.75%) stroke at 6 months, 2 (1.9%) strokes and 2 (1.9%) TIAs at 12 months were diagnosed. Kaplan-Meier analysis revealed that 96% and 99% 12-month CVA free survival following TAVR and SAVR, respectively (P=0.67). Preoperative mean trans-aortic valve systolic pressure gradient higher than 40 mmHg remained as risk factor for stroke in TAVR patients only, OR: 4.48 (CI: 1.2-16.54, P=0.02). One intraoperative death, and 5 (4 with CVA) in-hospital deaths occurred after TAVR; whereas only one patient died in SAVR group (P=0.49). Thirty-day mortality was 3.8% (11/290) for TAVR and 0.99% (1/101) for SAVR patients. SAVR patients' survival was 99% at 6 months, 97.9% at 12, and 96.4% at 24 months, whereas survival in TAVR was 97.5% at 6, 92% at 12, and 73.6% at 24 months (HR: 8.43 (CI: 2.47-28.73), P<0.001)., Conclusions: Even with significant differences in patients' baseline characteristics; in-hospital and mid-term stroke rates are not significantly higher following TAVR than SAVR. Although periprocedural stroke is not uncommon in TAVR, mid-term stroke rate is low.

Large elastic arteries stiffen with age, which predisposes older adults to increased risk for cardiovascular disease. Aerobic exercise training is known to reduce the risk for cardiovascular disease, but the optimal exercise prescription for attenuating large elastic arterial stiffening in older adults is not known., Purpose: The purpose of this randomized controlled trial was to compare the effect of all-extremity high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on aortic pulse wave velocity (PWV) and carotid artery compliance in older adults., Methods: Forty-nine sedentary older adults (age = 64 ± 1 yr), free of overt major clinical disease, were randomized to HIIT (n = 17), MICT (n = 18), or nonexercise controls (CONT; n = 14). HIIT (4 × 4 min at 90% HRpeak interspersed with 3 × 3 min active recovery at 70% HRpeak) and isocaloric MICT (70% HRpeak) were performed on an all-extremity non-weight-bearing ergometer, 4 d·wk for 8 wk under supervision. Aortic (carotid to femoral PWV [cfPWV]) and common carotid artery compliance were assessed at pre- and postintervention., Results: cfPWV improved by 0.5 m·s in MICT (P = 0.04) but did not significantly change in HIIT and CONT (P > 0.05). Carotid artery compliance improved by 0.03 mm·mm Hg in MICT (P = 0.001), but it remained unchanged in HIIT and CONT (P > 0.05). Improvements in arterial stiffness in response to MICT were not confounded by changes in aortic or brachial blood pressure, HR, body weight, total and abdominal adiposity, blood lipids, or aerobic fitness., Conclusion: All-extremity MICT, but not HIIT, improved central arterial stiffness in previously sedentary older adults free of major clinical disease. Our findings have important implications for aerobic exercise prescription in older adults.

Various non-invasive methods are available to measure cardiac output (CO) during pregnancy. We compared serial measures of CO using various methods to determine which provided the least variability. Ten patients with spontaneous pregnancy had estimation of CO at baseline prior to becoming pregnant and at the end of the first and third trimesters. Echocardiographic data were used to estimate CO using the Teichholz method, Simpson's biplane method, and the Doppler determined velocity time integral (VTI) method. In addition, a Bioz Dx device was used to estimate CO by impedance cardiography. CO estimated with the VTI method had the lowest beat-to-beat variability. CO estimated with the VTI method was higher than CO estimated with the 2D-Teichholz method and Simpson's method. The percent change in CO during pregnancy was similar for all echo methods (VTI, Teichholz, and Simpson's biplane). Baseline CO determined with impedance cardiography was higher than CO determined with the VTI method. However, change in CO during pregnancy was significantly lower when measured with impedance cardiography. There was marked heterogeneity in the degree of rise in CO during the first trimester (-3 to 55%). The wide variation in the gestational rise in CO was unexpected, and at least in part secondary to variable increase in heart rate. We recommend the use of the Doppler determined VTI method for the estimation of CO in pregnancy., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Assessment of coronary endothelial function with intracoronary acetylcholine (IC-Ach) provides diagnostic and prognostic data in patients with suspected coronary microvascular dysfunction (CMD), but is often not feasible due in part to the time and expertise needed for pharmacologic mixing. Cold pressor testing (CPT) is a simple and safe stimulus useful for either invasive or non-invasive endothelial function testing and myocardial perfusion imaging but has not been specifically evaluated among symptomatic women with signs of ischemic heart disease (IHD) who have no obstructive coronary artery disease (CAD)., Methods: 163 women with signs and symptoms of IHD and no obstructive CAD from the NHLBI- Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study underwent coronary reactivity testing with a Doppler flow wire (FloWire® Volcano, San Diego, CA) in the proximal left anterior descending artery. Coronary artery diameter and coronary blood flow (CBF) assessed by core lab using QCA before and after IC-Ach (18.2 μg/ml infused over 3 minutes) and during CPT., Results: Mean age was 55 ± 12 years. Rate pressure product (RPP) in response to IC-Ach did not change (baseline to peak, P = 0.26), but increased during CPT (363±1457; P = 0.0028). CBF in response to CPT was poorly correlated to IC-Ach CBF. Change in coronary artery diameter after IC-Ach correlated with change after CPT (r = 0.59, P<0.001). The correlation coefficient was stronger in subjects with coronary dilation to IC-Ach (r = 0.628, P<0.001) versus those without dilation (r = 0.353, P = 0.002), suggesting that other factors may be important to this relationship when endothelium is abnormal., Conclusions: In women with no obstructive CAD and suspected CMD, coronary diameter changes with IC-Ach and CPT are moderately-well correlated suggesting that CPT testing may be of some use, particularly among patients with normal endothelial function, however, not an alternative to IC-Ach for diagnosis of coronary endothelial dysfunction.

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., Competing Interests: This study was funded in part by QMED, Inc., Laurence Harbor, NJ. Puja Mehta received a significant research support from Gilead and General Electric. Louise E. Thomson received research funds from Gilead Science Inc and grants from NIH/NHLBI. R. David Anderson is a consultant for BioSense Webster and subsidiary of Johnson and Johnson. Carl J. Pepine reports grants from NIH/NHLBI, during the conduct of the study; grants from Amarin, Amgen, AstraZeneca, Baxter, Boehringer Ingleheim, Catadasis, Cytori, Daiichi Sankyo, Esperion, Genentech, ISIS Pharmaceuticals, Neostem, Sanofi/Aventis, and Unified Therapeutics. Daniel S. Berman reports CSMC royalties, Molecular Dynamics consulting fees, and a Bayer research grant. C. Noel Bairey Merz reports consulting revenue paid to CSMC from Gilead, Medscape, Research Triangle Institute, research money from Gilead, Erika Glazer, payments for lectures from Beaumont Hospital, European Horizon, Florida Hospital, INOVA, Korean Cardiology Society, Practice Point Communications, Pri-Med, University of Chicago, VBWG, University of Colorado, University of Utah, WomenHeart, Harold Buchwald Heart-Health, Tufts. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Background: A new post-myocardial infarction (MI) therapy is injection of high-water-content polymeric biomaterial gels (hydrogels) into damaged myocardium to modulate cardiac negative remodeling and preserve heart function., Methods: We investigated the therapeutic potential of a novel gelatinized alginate hydrogel with a unique microstructure of uniform capillary-like channels (termed Capgel). Shortly (48h) after induced anterior MI, Sprague Dawley rats received intramyocardial injection of Capgel directly into the antero-septal wall at the infarct border zone (n=12) or no injection (n=10, controls). Echocardiograms were performed at 48h (week 0) and 4weeks (week 4) to evaluate left ventricular function., Results: Echocardiograms showed 27% improvement of left ventricular systolic function over time with gel injection: fractional shortening increased from 26±3% at week 0 to 33±2% at week 4 (p=0.001). Capgel was present at the injection site after 4weeks, but was minimal at 8weeks. The remaining gel was heavily populated by CD68(+) macrophages with CD206(+) clusters and blood vessels. An in vitro experiment was performed to assess Angiotensin-(1-7) released from Capgel. Angiotensin-(1-7) was released from the Capgel in a sustained manner for 90days., Conclusions: Use of Capgel, a degradable, bioactive hydrogel composed of gelatinized capillary-alginate gel, appears safe for intramyocardial injection, is associated with improved left ventricular function after MI in rats, and may provide a long-term supply of Angiotensin-(1-7)., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Ischemia stimulates a reparative response resulting in mobilization of circulating progenitor cells (CPCs). We hypothesized that women with chronic myocardial ischemia from coronary microvascular disease (CMD) will mobilize CPCs., Methods: In 123 women with ischemic symptoms and signs but no obstructive coronary artery disease (CAD) enrolled in the Women's Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction Study (WISE-CVD), we measured coronary flow reserve (CFR) in response to intracoronary adenosine. Peripheral blood CPCs were measured using flow cytometry for expression of CD34, CD133, CXCR4, and VEGFR2., Results: Subjects were 53 ± 11 years, BMI 30 ± 8; 44% hypertensive, 11% diabetic, 23% hyperlipidemic and 7% smokers. Lower CFR correlated inversely with higher levels of hematopoietic-enriched CD34+ (r = -0.23, p = 0.011), CD34+/CD133+ (r = -0.24, p = 0.008), and CD34+/CXCR4+ (r = -0.19, p = 0.036) cells. In multivariable regression analyses, after adjusting for traditional cardiovascular risk factors, lower CFR remained significantly associated with elevated levels of CD34+ (β -0.18, p = 0.042), CD34+/CD133+ (β -0.24, p = 0.036), and CD34+/CXCR4+ (β -0.22, p = 0.050) cells. We found no association between CFR and CD34+/VEGFR2+ cells., Conclusions: In women with non-obstructive CAD, impaired CFR is associated with higher levels of CPCs, suggesting that chronic myocardial ischemia from CMD stimulates CPC mobilization. The functional significance of elevated CPCs in these subjects requires further investigation as a potential biomarker and treatment target., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aging is associated with decreased aerobic fitness and cardiac remodeling leading to increased risk for cardiovascular disease. High-intensity interval training (HIIT) on the treadmill has been reported to be more effective in ameliorating these risk factors compared with moderate-intensity continuous training (MICT) in patients with cardiometabolic disease. In older adults, however, weight-bearing activities are frequently limited due to musculoskeletal and balance problems. The purpose of this study was to examine the feasibility and safety of non-weight-bearing all-extremity HIIT in older adults. In addition, we tested the hypothesis that all-extremity HIIT will be more effective in improving aerobic fitness, cardiac function, and metabolic risk factors compared with all-extremity MICT. Fifty-one healthy sedentary older adults (age: 65±1years) were randomized to HIIT (n=17), MICT (n=18) or non-exercise control (CONT; n=16). HIIT (4×4min 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on a non-weight-bearing all-extremity ergometer, 4×/week for 8weeks under supervision. All-extremity HIIT was feasible in older adults and resulted in no adverse events. Aerobic fitness (peak oxygen consumption; VO2peak) and ejection fraction (echocardiography) improved by 11% (P<0.0001) and 4% (P=0.001), respectively in HIIT, while no changes were observed in MICT and CONT (P≥0.1). Greater improvements in ejection fraction were associated with greater improvements in VO2peak (r=0.57; P<0.0001). Insulin resistance (homeostatic model assessment) decreased only in HIIT by 26% (P=0.016). Diastolic function, body composition, glucose and lipids were unaffected (P≥0.1). In conclusion, all-extremity HIIT is feasible and safe in older adults. HIIT, but not MICT, improved aerobic fitness, ejection fraction, and insulin resistance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Acute kidney injury (AKI) during transcatheter aortic valve replacement (TAVR) increases morbidity and mortality. In this study, we investigated the incidence and risk factors for AKI in patients undergoing TAVR., Methods: Two hundred ninety consecutive patients underwent TAVR. Valve Academic Research Consortium (VARC)-I criteria for AKI diagnosis at 72 hours, and VARC-II criteria at seven days were employed., Results: Overall AKI incidence was 24.62% (65/264): 50 patients at 72 hours and 15 patients at seven days. Multivariate logistic regression determined transapical (TA) approach (OR: 4.46 [1.37-7.63]), preprocedural glomerular filtration rate less than 45 mL/min (OR: 3.47 [1.35-14.70]), and blood transfusion (OR: 3.34 [1.58-11.09]) as independent predictors for AKI at 72 hours; and prior coronary artery bypass grafting (OR: 3.02 [1.007-9.09]) and peripheral artery disease (PAD) (OR: 3.53 [1.06-11.62]) for AKI at seven days. In-hospital and 30-day mortality was higher in AKI patients. Non-AKI patients' survival was 93% at six months, 89% at 12 months, and 86% at 24 months, whereas survival in AKI at 72 hours was 66% at 6, 12, and 24 months (HR AKI vs. non-AKI: 3.9 [CI: 2.0-7.6]), and survival in AKI at seven days was 64% at 6, 12, and 24 months, HR: 3.13 (CI: 1.42-6.92). For the 12 dialysis patients survival was 82% at 6, 12, and 24 months., Conclusions: AKI after TAVR is associated with worse outcomes. Blood transfusion should be administered restrictively in TAVR. Patients with CKD, PAD, prior CABG, and TA approach require close surveillance as they are at risk for AKI through seven days after TAVR. doi: 10.1111/jocs.12768 (J Card Surg 2016;31:416-422)., (© 2016 Wiley Periodicals, Inc.)

Aims: The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling., Materials and Results: Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041)., Conclusions: In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects., Trial Registration: clinicaltrials.gov Identifier: NCT01342029., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Stress-induced cardiomyopathy (SCM) after subarachnoid hemorrhage (SAH) includes predominant apical or basal regional left ventricular dysfunction (RLVD) with concomitant changes in electrocardiogram or increase in cardiac enzymes. We hypothesized that difference in outcome is associated with the type of RLVD after SAH., Methods: We studied a single-center retrospective cohort of SAH patients hospitalized between 2000 and 2010 with follow-up until 2013. We classified patients who had an echocardiogram for clinically indicated reasons according to the predominate location of RLVD as classic SCM-apical form and variant SCM-basal form. A Cox proportional hazard model and logistic regression were used to estimate the risk for death and hospital complications associated with different RLVD after adjustment for propensity to undergo echocardiography given clinical characteristics on admission., Results: Among 715 SAH patients, 28% (200/715) had an echocardiogram for clinical evidence of cardiac dysfunction during hospitalization, the most common being acute left ventricular dysfunction, suspected acute ischemic event, changes in electrocardiogram and cardiac enzymes, and arrhythmia. SCM was present in 59 patients (8% of all cohort and 30% of patients with echocardiogram, respectively) with similar distribution of SCM-basal (25/59) and SCM-apical forms (34/59). SAH patients who had an echocardiogram for clinically indicated reasons had a significantly decreased risk-adjusted long-term survival compared with those without an echocardiogram, regardless of the presence of RLVD. SCM-basal form was associated with cardiac complications (odds ratio, 6.1; 99% confidence interval, 1.8-20.2) and severe sepsis (odds ratio, 5.3; 99% confidence interval, 1.6-17.2)., Conclusions: SAH patients with echocardiogram for a clinically indicated reason have a decreased long-term survival, regardless of the presence of RLVD. The association between severe sepsis and SCM-basal warrants future studies to determine their potential synergistic effect on left ventricular systolic dysfunction among SAH patients., Competing Interests: The authors declare no conflicts of interest.

Neurogenic stunned myocardium is a significant complication of subarachnoid hemorrhage. Diagnosis of neurogenic stunned myocardium is complicated by variable presentation. We present a case of a 23-year-old woman admitted with a subarachnoid hemorrhage from an arteriovenous malformation and associated aneurysm. Postoperatively, she developed pulmonary edema and mildly elevated cardiac biomarkers. Echocardiography showed hypokinesis of the basal left ventricular segments and normal contraction of the apical left ventricular segments consistent with a variant form of neurogenic stunned myocardium. We describe characteristics and outcomes of neurogenic stunned myocardium in this young patient with arteriovenous malformation-associated aneurysmal subarachnoid hemorrhage.

Objectives: Chronic kidney disease (CKD) is more prevalent among women and is associated with adverse cardiovascular events. Among women with symptoms and signs of ischemia enrolled in the Women's Ischemia Syndrome Evaluation (WISE), a relatively high mortality rate was observed in those with no obstructive coronary artery disease. Coronary microvascular dysfunction or reduced coronary flow reserve (CFR) was a strong and independent predictor of adverse outcomes. The objective of this analysis was to determine if renal function was associated with coronary microvascular dysfunction in women with signs and symptoms of ischemia., Methods: The WISE was a multicenter, prospective, cohort study of women undergoing coronary angiography for suspected ischemia. Among 198 women with additional measurements of CFR, we determined the estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. We tested the association between eGFR and CFR with regression analysis., Results: The median eGFR was 89 ml/min. The eGFR correlated with CFR (r = 0.22; P = 0.002). This association persisted even after covariate adjustment. Each 10-unit decrease in eGFR was associated with a 0.04-unit decrease in CFR (P = 0.04).There was a strong interaction between eGFR and age (P = 0.006): in those ≥60 years old, GFR was strongly correlated with CFR (r = 0.55; P<0.0001). No significant correlation was noted in those <60 years old., Conclusions: Reduced renal function was significantly associated with lower CFR in women with symptoms and signs of ischemia. Coronary microvascular dysfunction warrants additional study as a mechanism contributing to increased risk of cardiovascular events in CKD.

Background: Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). Although traditional noninvasive stress imaging is often normal in CMD, cardiac MRI may be able to detect CMD in this population., Methods and Results: Vasodilator stress cardiac MRI was performed in 118 women with suspected CMD who had undergone CRT and 21 asymptomatic reference subjects. Semi-quantitative evaluation of the first-pass perfusion images was completed to determine myocardial perfusion reserve index (MPRI). The relationship between CRT findings and MPRI was examined by Pearson correlations, logistic regression, and sensitivity/specificity. Symptomatic women had lower mean pharmacological stress MPRI compared with reference subjects (1.71±0.43 versus 2.23±0.37; P<0.0001). Lower MPRI was predictive of ≥1 abnormal CRT variables (odds ratio =0.78 [0.70, 0.88], P<0.0001, c-statistic 0.78 [0.68, 0.88]). An MPRI threshold of 1.84 predicted CRT abnormality with sensitivity 73% and specificity 74%., Conclusions: Noninvasive cardiac MRI MPRI can detect CMD defined by invasive CRT. Further work is aimed to optimize the noninvasive identification and management of CMD patients., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00832702., (© 2015 American Heart Association, Inc.)

Background: Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and adverse cardiovascular outcomes, but mechanisms are unclear. We hypothesized that mild CKD independently predicts adverse outcomes in women with symptoms and signs of ischemia., Methods: We categorized 876 women from the Women's Ischemia Syndrome Evaluation cohort according to estimated glomerular filtration rate (eGFR) (eGFR ≥90 mL/min per 1.73 m(2) [normal], 60-89 mL/min per 1.73 m(2) [mild CKD], ≤59 mL/min per 1.73 m(2) [severe CKD]). Time to death from all-cause and cardiovascular causes and major adverse outcomes were assessed by multivariate regression adjusted for baseline covariates., Results: Obstructive coronary artery disease (CAD) was present only in few patients (39%). Even after adjusting for CAD severity, renal function remained a strong independent predictor of all-cause and cardiac mortality (P < .001). Every 10-unit decrease in eGFR was associated with a 14% increased risk of all-cause mortality (adjusted hazard ratio [AHR] 1.14 [1.08-1.20], P < .0001), 16% increased risk of cardiovascular mortality (AHR 1.16 [1.09-1.23], P < .0001), and 9% increased risk of adverse cardiovascular events (AHR 1.09 [1.03-1.15], P = .002)., Conclusions: Even mild CKD is a strong independent predictor of all-cause and cardiac mortality in women with symptoms/signs of ischemia, regardless of underlying obstructive CAD severity, underscoring the need to better understand the interactions between ischemic heart disease and CKD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Many patients with angina and signs of myocardial ischemia on stress testing have no significant obstructive epicardial coronary disease. There are many potential coronary and non-coronary mechanisms for ischemia without obstructive epicardial coronary disease, and prominent among these is coronary microvascular and/or endothelial dysfunction. Patients with coronary microvascular and/or endothelial dysfunction are often at increased risk of adverse cardiovascular events, including ischemic events and heart failure despite preserved ventricular systolic function. In this article, we will review the diagnosis and treatment of coronary microvascular and endothelial dysfunction, discuss their potential contribution to heart failure with preserved ejection fraction, and highlight recent advances in the evaluation of atherosclerotic morphology in these patients, many of whom have non-obstructive epicardial disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Deferral of revascularization for abnormal but nonischemic lesions is usually recommended; however, the long-term outcome of this approach is not well known., Hypothesis: Deferral of nonischemic lesions will be associated with a low frequency of adverse events., Methods: A PubMed search of the MEDLINE database identified studies that reported clinical outcomes among patients who had fractional flow reserve-guided revascularization. We further categorized studies into 2 subgroups: left main and non-left main coronary artery lesions. Baseline demographics and clinical outcome data were extracted by 3 independent reviewers. Fixed and random effects summary risk ratios were constructed using Mantel-Haenszel and DerSimonian-Laird models, respectively. The primary outcome was the composite of death, myocardial infarction, and revascularization., Results: From 741 potential studies, 17 were included in the meta-analysis (n = 2975 participants), 8 in the left main subgroup (n = 595) and 9 studies (n = 2380) in non-left main subgroup. In the left main subgroup, the incidence of the composite outcome was 15.3% in the no-ischemia/deferral group vs 14.3% in the ischemia/revascularization group (risk ratio [RR] = 1.13, 95% confidence interval [CI]: 0.76-1.68, P = 0.54, I(2) = 3.7%). In the non-left main subgroup, the incidence of the composite outcome was 9.2% in the no-ischemia/deferral group vs 18.8% in the ischemia/revascularization group (RR = 0.42, 95% CI: 0.34-0.52, P < 0.0001, I(2) = 20.7%)., Conclusions: Patients with left main coronary disease had a relatively high incidence of adverse cardiovascular events, which was similar in both the deferral and revascularization groups. In patients with non-left main disease, ischemia was associated with worse outcomes despite revascularization., (© 2014 Wiley Periodicals, Inc.)

Background: TIMI frame count (TFC) predicts outcomes in patients with obstructive coronary artery disease (CAD); it remains unclear whether TFC predicts outcomes in patients without obstructive CAD., Methods: TFC was determined in a sample of women with no obstructive CAD enrolled in the Women's Ischemia Syndrome Evaluation (WISE) study. Because TFC is known to be higher in the left anterior descending artery (LAD), TFC determined in the LAD was divided by 1.7 to provide a corrected TFC (cTFC)., Results: A total of 298 women, with angiograms suitable for TFC analysis and long-term (6-10 year) follow up data, were included in this sub-study. Their age was 55±11 years, most were white (86%), half had a history of smoking, and half had a history of hypertension. Higher resting cTFC was associated with a higher rate of hospitalization for angina (34% in women with a cTFC >35, 15% in women with a cTFC ≤35, P<0.001). cTFC provided independent prediction of hospitalization for angina after adjusting for many baseline characteristics. In this cohort, resting cTFC was not predictive of major events (myocardial infarction, heart failure, stroke, or all-cause death), cardiovascular events, all-cause mortality, or cardiovascular mortality., Conclusions: In women with signs and symptoms of ischemia but no obstructive CAD, resting cTFC provides independent prediction of hospitalization for angina. Larger studies are required to determine if resting TFC is predictive of major events in patients without obstructive coronary artery disease.