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Cardiac Syndrome X (CSX), characterized by angina-like chest discomfort, ST segment depression during exercise, and normal epicardial coronary arteries at angiography, is highly prevalent in women. CSX is not benign, and linked to adverse cardiovascular outcomes and a poor quality of life. Coronary microvascular and endothelial dysfunction and abnormal cardiac nociception have been implicated in the pathogenesis of CSX. Treatment includes life-style modification, anti-anginal, anti-atherosclerotic, and anti-ischemic medications. Non-pharmacological options include cognitive behavioral therapy, enhanced external counterpulsation, neurostimulation, and stellate ganglionectomy. Studies have shown the efficacy of individual treatments but guidelines outlining the best course of therapy are lacking., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: We sought to comparatively assess cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index (MPRI) in women with confirmed microvascular coronary dysfunction (MCD) cases and reference control women., Background: Women with signs or symptoms of myocardial ischemia in the absence of obstructive coronary artery disease (CAD) frequently have MCD which carries an adverse prognosis. Diagnosis involves invasive coronary reactivity testing (CRT). Adenosine CMRI is a non-invasive test that may be useful for the detection of MCD., Methods: Fifty-three women with MCD confirmed by CRT and 12 age- and estrogen-use matched reference controls underwent adenosine CMRI. CMRI was assessed for MPRI, calculated using the ratio of myocardial blood flow at hyperemia/rest for the whole myocardium and separately for the 16 segments as defined by the American Heart Association. Statistical analysis was performed using repeated measures ANOVA models., Results: Compared to reference controls, MCD cases had lower MPRI values globally and in subendocardial and subepicardial regions (1.63±0.39 vs. 1.98±0.38, P=0.007, 1.51±0.35 vs. 1.84±0.34, P=0.0045, 1.68±0.38 vs. 2.04±0.41, P=0.005, respectively). A perfusion gradient across the myocardium with lower MPRI in the subendocardium compared to the subepicardium was observed for both groups., Conclusions: Women with MCD have lower MPRI measured by perfusion CMRI compared to reference controls. CMRI may be a useful diagnostic modality for MCD. Prospective validation of a diagnostic threshold for MPRI in patients with MCD is needed.

Unlabelled: Women with myocardial ischemia without obstructive coronary artery disease (CAD) often have microvascular coronary dysfunction (MCD). Traditional cardiac risk factors (RFs) contribute modestly to MCD detected by invasive coronary reactivity testing (CRT). Cardiac magnetic resonance imaging (CMRI) is an emerging noninvasive technique used to evaluate MCD. We evaluated RFs related to CMRI myocardial perfusion in women with MCD. 53 women with CRT confirmed MCD underwent adenosine stress and rest CMRI (1.5 Tesla). The myocardial perfusion reserve index (MPRI) was calculated (Pie Medical) with lower MPRI meaning less perfusion reserve. Relationships between RFs and MPRI were examined. The mean age was 54±10 years with a mean body mass index (BMI) of 26.2±4.2. The mean MPRI was 1.63±0.39. Hypertension, dyslipidemia, elevated BMI, and post-menopausal status were inversely related to MPRI, while ever smoking, age, family history of CAD, history of irregular menses, and history of menopausal hormone therapy (MHT) or oral contraceptive (OC) use were not. Dyslipidemia and BMI remained significant independent predictors of MPRI. Regression modeling demonstrated that the RFs of dyslipidemia, obesity, hypertension, family history of CAD, and history of irregular menses explained 27% of the observed MCD variance., Conclusions: In conclusion, impaired MPRI measured by CMRI is related to dyslipidemia and elevated BMI in women with MCD. These results suggest traditional RFs contribute modestly to MCD; a larger cohort of women with MCD should be examined to confirm and extend these observations. The impact of traditional CAD RF modification strategies, including optimal medical therapy, should be explored as MCD treatment targets.

Purpose: Adenosine stress first pass cardiac magnetic resonance imaging (CMRI) is a rapidly evolving tool in the diagnosis of ischemic heart disease (IHD). The rest and stress first pass myocardial perfusion data may be interpreted using commercially available software for calculation of time intensity curves in order to generate a numeric value of the segmental or whole heart myocardial perfusion reserve index (MPRI). The objective of this study was to determine the inter- and intra-observer reliability of the data generated by standard commercially available software., Methods: Data from 20 adenosine stress CMRI (1.5 T) studies were analyzed using commercially available CAAS MRV 3.3 software (Pie Medical Imaging B.V., Netherlands) for calculation of the MPRI. The stress CMRI was performed using a standardized protocol in 20 women including 10 women with angina and the absence of obstructive CAD and 10 healthy volunteers. MPRI calculation was made in a standardized manner on separate occasions by two independent observers. A single observer repeated the calculation of MPRI three months later, without reference to the prior data. Basal, mid, and apical segments, for the whole myocardium, sub-endocardium, and sub-epicardium were analyzed. Intra-class correlation coefficients (ICC), repeatability coefficients (RC), and coefficients of variation (CoV) were determined., Results: The MPRI results by repeated software measurements were highly correlated, with potentially important variations in measurement observed. The myocardial inter-observer ICC was 0.80 (95% CI, 0.57, 0.92) with a CoV of 7.5%, and intra-observer ICC was 0.89 (95% CI, 0.77, 0.95) with a CoV of 3.6%. The mid-ventricular level MPRI was most reproducible, with intra-observer ICC at 0.91 (95% CI, 0.77, 0.97); intra-observer measurement was more reproducible than inter-observer measurement., Conclusions: There is variation in measurement of MPRI observed in post processing of perfusion data when using a standardized approach and commercially available software. This has implications in the interpretation of data obtained for clinical and research purposes.

Mortality rates for cardiovascular disease are higher in women than in men, but studies of women have been conducted less frequently. Current pharmacological and nonpharmacological treatment options for women with stable angina are reviewed.

Angiotensin II (ANG II) has been implicated in the pathogenesis of diabetic micro- and macrovascular disease. In vascular smooth muscle cells (VSMCs), ANG II phosphorylates and degrades insulin receptor substrate-1 (IRS-1). While the pathway responsible for IRS-1 degradation in this system is unknown, c-Jun NH(2)-terminal kinase (JNK) has been linked with serine phosphorylation of IRS-1 and insulin resistance. We investigated the role of JNK in ANG II-induced IRS-1 phosphorylation, degradation, Akt activation, glucose uptake, and hypertrophic signaling, focusing on three IRS-1 phosphorylation sites: Ser302, Ser307, and Ser632. Maximal IRS-1 phosphorylation on Ser632 occurred at 5 min, on Ser307 at 30 min, and on Ser302 at 60 min. The JNK inhibitor SP600125 reduced ANG II-induced IRS-1 Ser307 phosphorylation (by 80%), IRS-1 Ser302 phosphorylation (by 70%), and IRS-1 Ser632 phosphorylation (by 50%). However, JNK inhibition had no effect on ANG II-mediated IRS-1 degradation, nor did it reverse the ANG II-induced decrease in Akt phosphorylation or glucose uptake. Transfection of VSMCs with mutants S307A, S302A, or S632A of IRS-1 did not block ANG II-mediated IRS-1 degradation. In contrast, JNK inhibition attenuated insulin-induced upregulation of collagen and smooth muscle α-actin in ANG II-pretreated cells. We conclude that phosphorylation of Ser307, Ser302, and Ser632 of IRS-1 is not involved in ANG II-mediated IRS-1 degradation, and that JNK alone does not mediate ANG II-stimulated IRS-1 degradation, but rather is responsible for the hypertrophic effects of insulin on smooth muscle.

Data support the relevance of blood cholesterol levels, particularly high levels of low-density lipoprotein (LDL), in the pathogenesis and progression of atherosclerosis. A strong and continuous relationship between dyslipidemia and vascular morbidity and mortality has been established. The initial approach to treating dyslipidemia consists of lifestyle modifications followed by pharmacologic therapy, usually beginning with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Some patients with familial hypercholesterolemia (FH) fail to achieve their LDL goal despite aggressive pharmacologic therapy. In certain cases, LDL apheresis may be an effective therapeutic option. In the United States, LDL apheresis is approved for homozygous FH patients with an LDL cholesterol level >/= 500 mg/dL. For patients with heterozygous FH, LDL apheresis may be offered if their LDL is >/= 300 mg/dL, or >/= 200 mg/dL with known coronary artery disease, despite maximum medical treatment. This review focuses on the principles and methods of LDL apheresis, its potential benefit in clinical care, and its current indications.

Objective: Vascular NADPH oxidases (Noxes) have been implicated in cardiovascular diseases; however, the importance of individual Nox homologues remains unclear. Here, the role of the vascular smooth muscle cell (VSMC) Nox1 in neointima formation was studied using genetically modified animal models., Methods and Results: Wire injury-induced neointima formation in the femoral artery, along with proliferation and apoptosis, was reduced in Nox1(y/-) mice, but there was little difference in Tg(SMCnox1) mice compared with wild-type (WT) mice. Proliferation and migration were reduced in cultured Nox1(y/-) VSMCs and increased in Tg(SMCnox1) cells. Tg(SMCnox1) cells exhibited increased fibronectin secretion, but neither collagen I production nor cell adhesion was affected by alteration of Nox1. Using antibody microarray and Western blotting analysis, increased cofilin phosphorylation and mDia1 expression and decreased PAK1 expression were detected in Nox1(y/-) cells. Overexpression of S3A, a constitutively active cofilin mutant, partially recovered reduced migration of Nox1(y/-) cells, suggesting that reduction in cofilin activity contributes to impaired migration of Nox1(y/-) VSMCs., Conclusions: These results indicate that Nox1 plays a critical role in neointima formation by mediating VSMC migration, proliferation, and extracellular matrix production, and that cofilin is a major effector of Nox1-mediated migration. Inhibition of Nox1 may be an efficient strategy to suppress neointimal formation.

Background: Despite recent advances in pharmacologic and device therapy, morbidity and mortality from heart failure (HF) remain high. Yoga combines physical and breathing exercises that may benefit patients with HF. We hypothesized that an 8-week regimen of yoga in addition to standard medical therapy would improve exercise capacity, inflammatory markers, and quality of life (QoL) in patients with HF., Methods and Results: New York Heart Association Class I-III HF patients were randomized to yoga treatment (YT) or standard medical therapy (MT). Measurements included a graded exercise test (GXT) to V O(2Peak) and the following serum biomarkers: interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and extracellular superoxide dismutase (EC-SOD). The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was administered to assess changes in QoL. A total of 19 patients were enrolled after the initial screening. Of the 19 patients, 9 were randomized to YT and 10 to MT. Patients had a mean EF of 25%. GXT time and V O(2Peak) were significantly improved in the YT versus MT groups (+18% in the YT and -7.5% in MT; P = .03 vs. control and +17 in YT and -7.1 in MT; P = .02, respectively). There were statistically significant reductions in serum levels of IL-6 and hsCRP and an increase in EC-SOD in the YT group (all P < .005 vs. MT). MLHFQ scores improved by 25.7% in the YT group and by 2.9% in the MT group., Conclusions: Yoga improved exercise tolerance and positively affected levels of inflammatory markers in patients with HF, and there was also a trend toward improvements in QoL.

Patients with Eisenmenger syndrome experience substantial morbidity and decreased survival rates. In advanced cases, lung transplantation with cardiac repair or heart-lung transplantation is often the only option. The efficacy of endothelin receptor antagonists in Eisenmenger syndrome, which has similar pathophysiology to idiopathic pulmonary hypertension, remains unknown.We retrospectively studied adults with congenital heart disease and Eisenmenger syndrome who were treated with endothelin receptor antagonists. Analysis included chart reviews of clinical evaluations, oxygen saturation levels, functional class, 6-minute walk distances, and pulmonary artery pressures. In the 24 patients studied, Eisenmenger syndrome was caused by ventricular septal defect (6 patients), atrial septal defect (5), atrioventricular canal defect (3), complex congenital heart disease (9), and patent ductus arteriosus (1).Eisenmenger syndrome was treated with bosentan (21 patients) and sitaxsentan (3 patients). On average, therapy lasted 19 +/- 12 months. Subsequently, mean 6-minute walk distances improved from 226 +/- 159 m to 351 +/- 113 m (P = 0.004), and World Health Organization functional class improved > or =1 grade (P < 0.0001). Oxygen saturations increased on therapy from 80.5% to 87% (P < 0.0001). Pulmonary arterial systolic pressures decreased from 97 +/- 21 mmHg to 78 +/- 27 mmHg, and mean pressures from 59 +/- 16 mmHg to 47 +/- 17 mmHg (both P < 0.0001). Neither major complications from therapy nor changes in pulmonary capillary wedge pressure occurred.Endothelin receptor antagonists may play an important role in improving 6-minute walk distance, oxygen saturation, pulmonary artery pressures, and symptoms in adults who have congenital heart defects and Eisenmenger syndrome.

The renin-angiotensin system is a central component of the physiological and pathological responses of cardiovascular system. Its primary effector hormone, angiotensin II (ANG II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension, and congestive heart failure. The myriad effects of ANG II depend on time (acute vs. chronic) and on the cells/tissues upon which it acts. In addition to inducing G protein- and non-G protein-related signaling pathways, ANG II, via AT(1) receptors, carries out its functions via MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases [PDGF, EGFR, insulin receptor], and nonreceptor tyrosine kinases [Src, JAK/STAT, focal adhesion kinase (FAK)]. AT(1)R-mediated NAD(P)H oxidase activation leads to generation of reactive oxygen species, widely implicated in vascular inflammation and fibrosis. ANG II also promotes the association of scaffolding proteins, such as paxillin, talin, and p130Cas, leading to focal adhesion and extracellular matrix formation. These signaling cascades lead to contraction, smooth muscle cell growth, hypertrophy, and cell migration, events that contribute to normal vascular function, and to disease progression. This review focuses on the structure and function of AT(1) receptors and the major signaling mechanisms by which angiotensin influences cardiovascular physiology and pathology.