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Pulmonary hypertension (PH) is a fatal disease—even with state-of-the-art medical treatment. Non-invasive clinical tools for risk stratification are still lacking. The aim of this study was to investigate the clinical utility of heart rhythm complexity in risk stratification for PH patients. We prospectively enrolled 54 PH patients, including 20 high-risk patients (group A, defined as WHO functional class IV or class III with severely compromised hemodynamics), and 34 low-risk patients (group B). Both linear and non-linear heart rate variability (HRV) variables, including detrended fluctuation analysis (DFA) and multiscale entropy (MSE), were analyzed. In linear and non-linear HRV analysis, low frequency and high frequency ratio, DFAα1, MSE slope 5, scale 5, and area 6–20 were significantly lower in group A. Among all HRV variables, MSE scale 5 (AUC: 0.758) had the best predictive power to discriminate the two groups. In multivariable analysis, MSE scale 5 (p = 0.010) was the only significantly predictor of severe PH in all HRV variables. In conclusion, the patients with severe PH had worse heart rhythm complexity. MSE parameters, especially scale 5, can help to identify high-risk PH patients.

BackgroundPrimary aldosteronism (PA) is a common cause of secondary hypertension and associated with higher incidence of new-onset atrial fibrillation (NOAF). However, the effects of surgical or medical therapies on preventing NOAF in PA patents remain unclear. The aim of this meta-analysis study was to assess the risk of NOAF among PA patients receiving mineralocorticoid receptor antagonist (MRA) treatment, PA patients receiving adrenalectomy, and patients with essential hypertension.MethodsWe performed the meta-analysis of the randomized or observational studies that investigated the incidence rate of NOAF in PA patients receiving MRA treatment versus PA patients receiving adrenalectomy from database inception until December 01, 2020 which were identified from PubMed, Embase, and Cochrane Library.ResultsA total of 172 related studies were reviewed, of which three fulfilled the inclusion criteria, including a total of 2,705 PA patients. The results of meta-analysis demonstrated a higher incidence of NOAF among the PA patients receiving MRA treatment compared to the PA patients receiving adrenalectomy (pooled odds ratio [OR]: 2.83, 95% confidence interval [CI]: 1.76–4.57 in the random effects model, I2 = 0%). The pooled OR for the PA patients receiving MRA treatment compared to the patients with essential hypertension was 1.91 (95% CI: 1.11–3.28). The pooled OR for the PA patients receiving adrenalectomy compared to the patients with essential hypertension was 0.70 (95% CI: 0.28–1.79).ConclusionCompared to the essential hypertension patients and the PA patients receiving adrenalectomy, the patients with PA receiving MRA treatment had a higher risk of NOAF.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42021222022.

Heart failure (HF) is a major cardiovascular disease worldwide, and the early detection and diagnosis remain challenges. Recently, heart rhythm complexity analysis, derived from non-linear heart rate variability (HRV) analysis, has been proposed as a non-invasive method to detect diseases and predict outcomes. In this study, we aimed to investigate the diagnostic value of heart rhythm complexity in HF patients. We prospectively analyzed 55 patients with symptomatic HF with impaired left ventricular ejection fraction and 97 participants without HF symptoms and normal LVEF as controls. Traditional linear HRV parameters and heart rhythm complexity including detrended fluctuation analysis (DFA) and multiscale entropy (MSE) were analyzed. The traditional linear HRV, MSE parameters and DFAα1 were significantly lower in HF patients compared with controls. In regression analysis, DFAα1 and MSE scale 5 remained significant predictors after adjusting for multiple clinical variables. Among all HRV parameters, MSE scale 5 had the greatest power to differentiate the HF patients from the controls in receiver operating characteristic curve analysis (area under the curve: 0.844). In conclusion, heart rhythm complexity appears to be a promising tool for the detection and diagnosis of HF.

Pulmonary hypertension is a fatal disease, however reliable prognostic tools are lacking. Heart rhythm complexity analysis is derived from non-linear heart rate variability (HRV) analysis and has shown excellent performance in predicting clinical outcomes in several cardiovascular diseases. However, heart rhythm complexity has not previously been studied in pulmonary hypertension patients. We prospectively analyzed 57 patients with pulmonary hypertension (31 with pulmonary arterial hypertension and 26 with chronic thromboembolic pulmonary hypertension) and compared them to 57 age- and sex-matched control subjects. Heart rhythm complexity including detrended fluctuation analysis (DFA) and multiscale entropy (MSE) and linear HRV parameters were analyzed. The patients with pulmonary hypertension had significantly lower mean RR, SDRR, pNN20, VLF, LF, LF/HF ratio, DFAα1, MSE slope 5, scale 5, area 1–5 and area 6–20 compared to the controls. Receiver operating characteristic curve analysis showed that heart rhythm complexity parameters were better than traditional HRV parameters to predict pulmonary hypertension. Among all parameters, scale 5 had the greatest power to differentiate the pulmonary hypertension patients from controls (AUC: 0.845, P

Primary aldosteronism has been associated with myocardial fibrosis, and is the most common cause of secondary hypertension. We previously showed that aldosterone can induce the secretion of galectin-3. The aim of this study was to investigate the association between myocardial fibrosis and plasma galectin-3 level in patients with primary aldosteronism. We prospectively analyzed 11 patients with aldosterone-producing adenoma (APA) who received adrenalectomy from December 2006 to October 2008, and 17 patients with essential hypertension as controls. Levels of plasma galectin-3 were determined in both groups, and both groups underwent echocardiography with cyclic variations of integrated backscatter (CVIBS) to characterize tissue initially and 1 year after surgery in the APA group. Diastolic blood pressure, concentration of plasma aldosterone and aldosterone-renin ratio were significantly higher, and serum potassium level and plasma renin activity significantly lower in the APA group compared to the controls. In addition, left ventricular mass index was significantly higher and CVIBS significantly lower in the APA group (7.3±2.0 vs 9.2±1.7 dB, p=0.015). Furthermore, the concentration of plasma galectin-3 was significantly higher in the APA group (2.1±0.9 vs 1.1±0.6 ng/mL, p=0.005) compared to the controls. CVIBS was correlated to plasma galectin-3 level. In the APA group, CVIBS increased significantly (7.3±2.0 to 9.2±2.4 dB, p=0.032) and plasma galectin-3 decreased (2.1±0.9 to 1.2±0.6, p=0.049) 1 year postadrenalectomy. The patients with APA had increased myocardial fibrosis, and this was associated with a higher plasma galectin-3 level. Both increased myocardial fibrosis and plasma galectin-3 level recovered at least partially after adrenalectomy. Trial registration number 200611031R; Results.

Background Primary aldosteronism (PA) is one of the major etiologies for secondary hypertension featuring more prominent left ventricular hypertrophy. The purpose of the study was to investigate the predictive factors of left ventricular mass index (LVMI) regression in patients with PA after adrenalectomy. Methods We prospectively analyzed 30 patients with aldosterone-producing adenoma (APA) who received adrenalectomy from October 2006 to September 2008. Echocardiography was performed preoperation and 1 year after operation. Results Thirty patients with aldosterone-producing adenoma undergoing adrenalectomy were enrolled. In a 1-year follow-up, LVMI decreased significantly by an average of 18.6%. Net LVMI decrease (ΔLVMI) was associated with preoperative LVMI, preoperative serum potassium level, baseline systolic blood pressure (SBP), baseline diastolic blood pressure, net SBP decrease (ΔSBP), net diastolic blood pressure decrease, preoperative/postoperative change of log-transformed plasma aldosterone concentration, preoperative/postoperative change of log-transformed plasma renin activity, and preoperative/postoperative change of serum potassium level (Δserum potassium level). In a multiple regression analysis, preoperative LVMI (β = −0.287, P = 0.049), ΔSBP (β = 0.518, P = 0.01), and Δserum potassium level (β = −20.471, P = 0.014) were significantly correlated with ΔLVMI. Conclusions The LVMI in patients with PA regressed significantly after adrenalectomy. Preoperative LVMI, ΔSBP, and Δserum potassium levels are independent factors associated with the degree of LVMI regression.

// Yen-Tin Lin 1,* , Yen-Hung Lin 2,5,* , Xue-Ming Wu 1 , Chi-Lun Ko 3 , Ruoh-Fang Yen 3 , Ying-Hsein Chen 2 , Ron-Bin Hsu 4 , Chi-Ming Lee 2 , Shoei-Shen Wang 4 , Ming-Fong Chen 2,6 and Yen-Wen Wu 2,3,7,8 1 Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan 2 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 3 Department of Nuclear Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 4 Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 5 Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, USA 6 Cardiovascular Research Laboratory, Cardiovascular Center, Clinical Outcome Research and Training Center, Big Data Center, China Medical University Hospital, China Medical University, Taichung, Taiwan 7 Cardiology Division of Cardiovascular Medical Center, Department of Nuclear Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan 8 National Yang-Ming University School of Medicine, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Yen-Wen Wu, email: // Keywords : fibrosis; restrictive filling; ventriculography Received : October 04, 2016 Accepted : November 24, 2016 Published : December 04, 2016 Abstract Myocardial fibrosis leads to a restrictive diastolic filling pattern of the left ventricle which is associated with a poor prognosis in patients with heart failure. We investigated the relationship between cardiac fibrosis and restrictive filling pattern of the left ventricle measured by Tc99m left ventriculography in patients with chronic symptomatic heart failure. Serum cardiac extracellular matrix markers including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2,9 (MMP-2,9), and tissue inhibitor of MMP-1 (TIMP-1) were analyzed. Fifty-one (39 males) patients were enrolled. Their median age was 51.8 years, and median left ventricular ejection fraction was 31.9%. Time to peak filling rate of the left ventricle was significantly correlated with serum levels of the three cardiac extracellular matrix markers (TIMP-1, PIIINP, and MMP-2). The patients with a restrictive diastolic filling pattern of the left ventricle (time to peak filling rate ≤ 154 ms) had significantly higher levels of these extracellular matrix markers. In receiver operating characteristic curve analysis, areas under the curve of PIIINP, TIMP-1, and MMP-2 were 0.758, 0.695, and 0.751 to predict the presence of a restrictive pattern. In C -statistics, all three cardiac extracellular matrix markers significantly increased the area under the curve after adding creatinine. In net reclassification improvement and integrated discrimination improvement models, PIIINP and MMP-2 significantly improved the predictive power of age, creatinine and brain natriuretic peptide. In conclusion, serum extracellular matrix markers are significantly correlated with restrictive diastolic filling pattern of the left ventricle in patients with heart failure.

Primary aldosteronism not only results in hypertension but also stiffer arteries. The time course and factors predicting the reversal of arterial stiffness after treatment are unclear. We prospectively enrolled 102 patients with aldosterone-producing adenoma (APA) from March 2006 to January 2012. We measured the pulse wave velocity (PWV) between brachial-ankle (baPWV) and heart-ankle (haPWV) before, 6 and 12 months after their adrenalectomy. After treatment, the PWV decreased significantly during the first 6 months (both p 0-6mo) and baseline baPWV were significantly associated with the decrease in baPWV at 6 months (ΔbaPWV0-6mo). The associated factors of the change in haPWV at 6 months (ΔhaPWV0-6mo) were baseline haPWV, ΔDBP0-6mo and change in log-transformed plasma renin activity. Our result suggested that reversal of arterial stiffness in APA patients occurred early after adrenalectomy and determined by baseline vascular condition, hemodynamic factors, and humoral factors.

Aldosterone induces myocardial fibrosis. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis. This study tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process. We prospectively enrolled 54 patients with primary aldosteronism, and measured plasma TIMP-1 and echocardiographic parameters. In the cell study, we investigated the possible molecular mechanism by which aldosterone induces TIMP-1 secretion and the effects on collagen accumulation. In the animal study, we measured serum TIMP-1 levels, cardiac TIMP-1 levels, and cardiac structure in an aldosterone infusion mouse model using implantation of aldosterone pellets. In patients with primary aldosteronism, plasma TIMP-1 was correlated with 24-hour urinary aldosterone, left ventricular mass, and impairment of left ventricular diastolic function. In human cardiac fibroblasts, TIMP-1 protein and mRNA expressions were significantly increased by aldosterone through the glucocorticoid receptor/PI3K/Akt/nuclear factor-κB pathway. TIMP-1 small-interfering RNA significantly reduced aldosterone-induced collagen accumulation, and aldosterone did not alter the levels of collagen1a1 or matrix metalloproteinase-1 mRNA. The aldosterone-induced TIMP-1 expression was inversely related to matrix metalloproteinase-1 activity. Furthermore, in the animal model, the serum and cardiac levels of TIMP-1 were significantly elevated in the mice that received aldosterone infusion. This elevation was blocked by RU-486 but not by eplerenone, suggesting that the effect was through glucocorticoid receptors. In a long-term aldosterone infusion model, serum TIMP-1 was associated with serum aldosterone level, cardiac structure, and fibrosis. In conclusion, aldosterone induced TIMP-1 expression in vivo and in vitro. This increased TIMP-1 expression resulted in enhanced collagen accumulation via the suppression of matrix metalloproteinase-1 activity.