Left Atrial Strain Provides Incremental Value for Embolism Risk Stratification over CHA2DS2-VASc Score and Indicates Prognostic Impact in Patients with Atrial Fibrillation.

学位記番号:医博甲153

Periostin-expressing cell-specific transforming growth factor-β inhibition in pulmonary artery prevents pulmonary arterial hypertension

Transforming growth factor beta (TGF-β) has been shown to play a critical role in pathogenesis of pulmonary arterial hypertension (PAH) although the precise role of TGF-β signaling remains uncertain. A recent report has shown that periostin (Pn) is one of the most upregulated proteins in human PAH lung compared with healthy lungs. We established type I TGF-β receptor knockout mice specifically with Pn expressing cell (Pn-Cre/Tgfb1fl/fl mice). Increases in PA pressure and pulmonary artery muscularization were induced by hypoxia of 10% oxygen for 4 weeks. Lung Pn expression was markedly induced by 4 week-hypoxia. Pn-Cre/Tgfb1fl/fl mice showed lower right ventricular pressure elevation, inhibition of PA medial thickening. Fluorescent co-immunostaining showed that Smad3 activation in Pn expressing cell is attenuated. These results suggest that TGF-β signaling in Pn expressing cell may have an important role in the pathogenesis of PAH by controlling medial thickening

A Critical Role of Fatty Acid Binding Protein 4 and 5 (FABP4/5) in the Systemic Response to Fasting

During prolonged fasting, fatty acid (FA) released from adipose tissue is a major energy source for peripheral tissues, including the heart, skeletal muscle and liver. We recently showed that FA binding protein 4 (FABP4) and FABP5, which are abundantly expressed in adipocytes and macrophages, are prominently expressed in capillary endothelial cells in the heart and skeletal muscle. In addition, mice deficient for both FABP4 and FABP5 (FABP4/5 DKO mice) exhibited defective uptake of FA with compensatory up-regulation of glucose consumption in these tissues during fasting. Here we showed that deletion of FABP4/5 resulted in a marked perturbation of metabolism in response to prolonged fasting, including hyperketotic hypoglycemia and hepatic steatosis. Blood glucose levels were reduced, whereas the levels of non-esterified FA (NEFA) and ketone bodies were markedly increased during fasting. In addition, the uptake of the 125I-BMIPP FA analogue in the DKO livers was markedly increased after fasting. Consistent with an increased influx of NEFA into the liver, DKO mice showed marked hepatic steatosis after a 48-hr fast. Although gluconeogenesis was observed shortly after fasting, the substrates for gluconeogenesis were reduced during prolonged fasting, resulting in insufficient gluconeogenesis and enhanced hypoglycemia. These metabolic responses to prolonged fasting in DKO mice were readily reversed by re-feeding. Taken together, these data strongly suggested that a maladaptive response to fasting in DKO mice occurred as a result of an increased influx of NEFA into the liver and pronounced hypoglycemia. Together with our previous study, the metabolic consequence found in the present study is likely to be attributed to an impairment of FA uptake in the heart and skeletal muscle. Thus, our data provided evidence that peripheral uptake of FA via capillary endothelial FABP4/5 is crucial for systemic metabolism and may establish FABP4/5 as potentially novel targets for the modulation of energy homeostasis

Exercise Stress Echocardiography in the Diagnostic Evaluation of Heart Failure with Preserved Ejection Fraction

More than half of patients with heart failure have a preserved ejection fraction (HFpEF). The prevalence of HFpEF has been increasing worldwide and is expected to increase further, making it an important health-care problem. The diagnosis of HFpEF is straightforward in the presence of obvious objective signs of congestion; however, it is challenging in patients presenting with a low degree of congestion because abnormal elevation in intracardiac pressures may occur only during physiological stress conditions, such as during exercise. On the basis of this hemodynamic background, current consensus guidelines have emphasized the importance of exercise stress testing to reveal abnormalities during exercise, and exercise stress echocardiography (i.e., diastolic stress echocardiography) may be used as an initial diagnostic approach to HFpEF owing to its noninvasive nature and wide availability. However, evidence supporting the use of this method remains limited and many knowledge gaps exist with respect to diastolic stress echocardiography. This review summarizes the current understanding of the use of diastolic stress echocardiography in the diagnostic evaluation of HFpEF and discusses its strengths and limitations to encourage future studies on this subject

Exercise unmasks distinct pathophysiologic features in heart failure with preserved ejection fraction and pulmonary vascular disease

Aims Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse out- comes in heart failure with preserved ejection fraction (HFpEF). Little is known about the impact of PVD on the pathophysiology of exercise intolerance. Methods and results Heart failure with preserved ejection fraction patients (n= 161) with elevated pulmonary capillary wedge pressure (>= 15 mmHg) at rest were classified into three groups: non-PH-HFpEF (n = 21); PH but no PVD (isolated post-capillary PH, IpcPH; n = 95); and PH with PVD (combined post- and pre-capillary PH, CpcPH; n = 45). At rest, CpcPH-HFpEF patients had more right ventricular (RV) dysfunction and lower pulmonary arterial (PA) compliance compared to all other groups. While right atrial pressure (RAP) and left ventricular transmural pressure (LVTMP) were similar in HFpEF with and without PH or PVD at rest, CpcPH-HFpEF patients demonstrated greater increase in RAP, enhanced ventricular interdependence, and paradoxical reduction in LVTMP during exercise, differing from all other groups (P <0.05). Lower PA compliance was correlated with greater increase in RAP with exercise. During exercise, CpcPH-HFpEF patients displayed an inability to enhance cardiac output, reduction in forward stroke volume, and blunted augmentation in RV systolic performance, changes that were coupled with marked limitation in aerobic capacity. Conclusion Heart failure with preserved ejection fraction patients with PVD demonstrate unique haemodynamic limitations during exercise that constrain aerobic capacity, including impaired recruitment of LV preload due to excessive right heart congestion and blunted RV systolic reserve. Interventions targeted to this distinct pathophysiology require testing in patients with HFpEF and PVD

Sex differences in left ventricular afterload and diastolic function are independent from the aortic size.

BackgroundWomen have a greater risk of heart failure with preserved ejection fraction (HFPEF) than men do, yet the basis for this disparity remains unclear. Greater arterial stiffness and afterload causes left ventricular (LV) diastolic dysfunction, a central mechanism of HFPEF. Because of smaller body habitus, previous reports have used body surface area as a surrogate of the size of the aorta. We performed a comprehensive hemodynamic evaluation of elderly patients with preserved EF and evaluated sex differences in the associations between LV function and afterload, before and after adjusting for the aortic sizes.Methods and resultsFour hundred and forty-three patients (mean age: 73 years, 169 women) who underwent clinically indicated echocardiography and computed tomography (CT) were identified. Linear regression analyses were performed to assess the independent contributions of sex to and its interaction with LV function before and after adjusting for CT-derived aortic length and volume. Although blood pressures were similar between the sexes, women had greater arterial elastance, lower arterial compliance, and greater LV ejection fraction (all pConclusionWomen had worse LV relaxation than men did against the same degree of afterload, before and even after adjusting for the aortic sizes

A Risk Score with Additional Four Independent Factors to Predict the Incidence and Recovery from Metabolic Syndrome: Development and Validation in Large Japanese Cohorts

<div><p>Background</p><p>Although many risk factors for Metabolic syndrome (MetS) have been reported, there is no clinical score that predicts its incidence. The purposes of this study were to create and validate a risk score for predicting both incidence and recovery from MetS in a large cohort.</p><p>Methods</p><p>Subjects without MetS at enrollment (n = 13,634) were randomly divided into 2 groups and followed to record incidence of MetS. We also examined recovery from it in rest 2,743 individuals with prevalent MetS.</p><p>Results</p><p>During median follow-up of 3.0 years, 878 subjects in the derivation and 757 in validation cohorts developed MetS. Multiple logistic regression analysis identified 12 independent variables from the derivation cohort and initial score for subsequent MetS was created, which showed good discrimination both in the derivation (c-statistics 0.82) and validation cohorts (0.83). The predictability of the initial score for recovery from MetS was tested in the 2,743 MetS population (906 subjects recovered from MetS), where nine variables (including age, sex, γ-glutamyl transpeptidase, uric acid and five MetS diagnostic criteria constituents.) remained significant. Then, the final score was created using the nine variables. This score significantly predicted both the recovery from MetS (c-statistics 0.70, p<0.001, 78% sensitivity and 54% specificity) and incident MetS (c-statistics 0.80) with an incremental discriminative ability over the model derived from five factors used in the diagnosis of MetS (continuous net reclassification improvement: 0.35, p < 0.001 and integrated discrimination improvement: 0.01, p<0.001).</p><p>Conclusions</p><p>We identified four additional independent risk factors associated with subsequent MetS, developed and validated a risk score to predict both incident and recovery from MetS.</p></div

Multivariate Logistic Regression Analysis for the Recovery from Metabolic Syndrome and Risk Scoring System in individuals with Prevalent Metabolic Syndrome.

<p>*Odds ratios to predict recovery from MetS (e.g. Odds ratio<1 means less likely to be recovered subsequently).</p><p>Other Abbreviations as in Tables <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133884#pone.0133884.t001" target="_blank">1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133884#pone.0133884.t002" target="_blank">2</a>.</p><p>Multivariate Logistic Regression Analysis for the Recovery from Metabolic Syndrome and Risk Scoring System in individuals with Prevalent Metabolic Syndrome.</p

Final score predicts incidence of MetS in the entire Non-MetS population.

<p>Final risk scores for incident MetS were calculated for each individual participant in the entire population without MetS at enrollment (derivation and validation cohorts combined, n = 13,634) as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133884#pone.0133884.t004" target="_blank">Table 4</a>. Incidence (%) in the bottom table represents the developed MetS cases in the population (n = 1,635). I bars represent 95% confidential interval (CI). Other abbreviations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133884#pone.0133884.g001" target="_blank">Fig 1</a>.</p