Left atrial reservoir strain is a marker of atrial fibrotic remodeling in patients undergoing cardiovascular surgery: Analysis of gene expression.

Left atrial strain (LAS) measured by two-dimensional speckle tracking echocardiography (2DSTE) is considered to be a marker of LA structural remodeling, but it remains unsettled. We investigated the potential usefulness and clinical relevance of LAS to detect atrial remodeling including fibrosis by analyzing gene expression in cardiovascular surgery patients. Preoperative 2DSTE was performed in 131 patients (92 patients with sinus rhythm [SR] patients including paroxysmal AF [PAF], 39 atrial fibrillation [AF]) undergoing cardiovascular surgery. Atrial samples were obtained from the left atrial appendages, and mRNA expression level was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR) in 59 cases (24 PAF, 35 AF). Mean value of left atrial reservoir strain (mLASr) correlated with left atrial volume index (LAVI), and left atrial conduit strain (mLAScd). mLASr also correlated with left atrial contractile strain (mLASct) in SR patients including PAF. mLASr was significantly lower, and LAVI was higher, in the AF group, compared with SR patients including PAF. The expression of COL1A1 mRNA encoding collagen type I α1 significantly increased in AF patients (p = 0.031). mLASr negatively correlated with COL1A1 expression level, and multivariate regression analysis showed that mLASr was an independent predictor of atrial COL1A1 expression level, even after adjusting for age, sex, and BMI. But, neither mLAScd / mLASct nor LAVI (bp) correlated with COL1A1 gene expression. The expression level of COL1A1 mRNA strongly correlated with ECM-related genes (COL3A1, FN1). It also correlated ECM degradation-related genes (MMP2, TIMP1, and TIMP2), pro-fibrogenic cytokines (TGFB1 encoding TGFß1, END1, PDGFD, CTGF), oxidant stress-related genes (NOX2, NOX4), ACE, inflammation-related genes (NLRP, IL1B, MCP-1), and apoptosis (BAX). Among the fibrosis-related genes examined, univariable regression analysis showed that log (COL1A1) was associated with log (TGFB1) (adjusted R2 = 0.685, p<0.001), log (NOX4) (adjusted R2 = 0.622, p<0.001), log (NOX2) (adjusted R2 = 0.611, p<0.001), suggesting that TGFB1 and NOX4 was the potent independent determinants of COL1A1 expression level. mLASr negatively correlated with the ECM-related genes, and fibrosis-related gene expression level including TGFB1, NOX2, and NLRP3 in PAF patients. PAF patients with low mLASr had higher expression of the fibrosis-related gene expression, compared with those with high mLASr. These results suggest that LASr correlates with atrial COL1A1 gene expression associated with fibrosis-related gene expression. Patients with low LASr exhibit increased atrial fibrosis-related gene expression, even those with PAF, highlighting the utility of LAS as a marker for LA fibrosis in cardiovascular surgery patients.

Pathophysiological roles of the serum acylcarnitine level and acylcarnitine/free carnitine ratio in patients with cardiovascular diseases.

Introduction: L-carnitine exerts protective effects, such as maintaining mitochondrial functions and decreasing reactive oxygen species, while acylcarnitine (AC) is linked to the development of heart failure and atherosclerosis. Hypothesis: Serum carnitines play important pathophysiological roles in cardiovascular diseases. Methods: Pre-operative biochemical data were obtained from 117 patients (71 men, average age 69.9 years) who underwent surgery for cardiovascular diseases. Measurements included pre-operative biochemical data including estimated glomerular filtration rate (eGFR), physical functions, skeletal muscle mass index (SMI) measured by bioelectrical impedance analysis, anterior thigh muscle thickness (MTh) measured by ultrasound, and routine echocardiography. Carnitine components were measured with the enzyme cycling method. Muscle wasting was diagnosed based on the Asian Working Group for Sarcopenia criteria. Results: Plasma brain natriuretic peptide (BNP) level was correlated with serum free carnitine (FC) and AC level, and the acylcarnitine/free carnitine ratio (AC/FC). AC/FC was elevated with stage of chronic kidney disease. In multivariate analysis, log (eGFR) and log (BNP) were extracted as independent factors to define log (serum AC) (eGFR: ß = 0.258, p = 0.008; BNP: ß = 0.273, p = 0.011), even if corrected for age, sex and body mass index. AC/FC was negatively correlated with hand-grip strength (r = -0.387, p = 0.006), SMI (r = -0.314, p = 0.012), and anterior thigh MTh (r = -0.340, p = 0.014) in men. Conclusions: A significant association between serum AC level and AC/FC, and chronic kidney disease and heart failure exists in patients with cardiovascular diseases who have undergone cardiovascular surgery. Skeletal muscle loss and muscle wasting are also linked to the elevation of serum AC level and AC/FC.

Sodium Restriction Counseling Reduces Cardiac Events in Patients With Heart Failure.

BACKGROUND: Many heart failure (HF) guidelines recommend sodium restriction for patients with HF, but the outcome of sodium restriction counseling (SRC) for HF patients is still unknown. We wanted to clarify whether SRC reduces cardiac events in patients with HF.Methods and Results:Overall, 800 patients (77±12 years) who were hospitalized for HF were enrolled. During HF hospitalization, patients received SRC; patients were required to have a salt intake of <6 g/day. After discharge, death or HF rehospitalization events were investigated. During a mean follow-up of 319±252 days, 83 patients died, and 153 patients were rehospitalized for HF. SRC significantly decreased all-cause death (odds ratio, 0.42; 95% confidence interval [CI], 0.23-0.76; P<0.01), especially cardiac death of hospitalized HF patients after discharge. In the multivariate analysis adjusted for age, sex, SRC, body mass index, hypertension, dyslipidemia, ß-blockers, and mineralocorticoid receptor antagonist intake, cardiac rehabilitation, and the type of HF, SRC remained a significant predictor of death. Kaplan-Meier analysis showed that SRC significantly reduced deaths and the combined outcome of HF rehospitalization and death. In patients with reduced left ventricular ejection fraction, SRC significantly decreased the mortality rate (odds ratio, 0.27; 95% CI, 0.10-0.71; P<0.01). CONCLUSIONS: SRC reduced the mortality rate after discharge of hospitalized HF patients.

Association of serum leptin and adiponectin concentrations with echocardiographic parameters and pathophysiological states in patients with cardiovascular disease receiving cardiovascular surgery.

Leptin and adiponectin are important regulators of energy metabolism and body composition. Leptin exerts cardiodepressive effects, whereas adiponectin has cardioprotective effects, but several conflicting findings have been reported. The aim of the present study was to assess the relationship between serum leptin and adiponectin levels and echocardiographic parameters and pathophysiological states in patients with cardiovascular disease (CVD) receiving cardiovascular surgery. A total of 128 patients (79 males, average age 69.6 years) that had surgery for CVD including coronary artery bypass graft (CABG) and valve replacement were recruited in this study. Preoperative serum adiponectin and leptin concentrations were measured by enzyme-linked immunosorbent assay and compared with preoperative echocardiographic findings. Body fat volume and skeletal muscle volume index (SMI) were estimated using bioelectrical impedance analysis. We also measured grip strength and gait speed. Sarcopenia was diagnosed based on the recommendations of the Asian Working Group on Sarcopenia. Positive correlations were found between adiponectin and brain natriuretic peptide (BNP), age, left atrial diameter (LAD), E/e' (early-diastolic left ventricular inflow velocity / early-diastolic mitral annular velocity), and left atrial volume index (LAVI). Negative correlations were observed between adiponectin and body mass index (BMI), estimated glomerular filtration rate (eGFR), triglyceride, hemoglobin, and albumin. Serum leptin was positively correlated with BMI, total cholesterol, triglyceride, albumin, body fat volume, and LV ejection fraction (LVEF), whereas it was negatively correlated with BNP and echocardiographic parameters (LAD, LV mass index (LVMI), and LAVI). Multiple regression analysis showed associations between log (leptin) and log (adiponectin) and echocardiographic parameters after adjusting for age, sex, and BMI. Serum adiponectin was negatively correlated with leptin, but positively correlated with tumor necrosis factor α (TNFα), an inflammatory cytokine. In males, serum leptin level had a positive correlation with skeletal muscle volume and SMI. However, adiponectin had a negative correlation with anterior mid-thigh muscle thickness, skeletal muscle volume and SMI. And, it was an independent predictive factor in males for sarcopenia even after adjusted by age. These results suggest that leptin and adiponectin may play a role in cardiac remodeling in CVD patients receiving cardiovascular surgery. And, adiponectin appears to be a marker of impaired metabolic signaling that is linked to heart failure progression including inflammation, poor nutrition, and muscle wasting in CVD patients receiving cardiovascular surgery.

Growth Differentiation Factor-15 (GDF-15) is a Biomarker of Muscle Wasting and Renal Dysfunction in Preoperative Cardiovascular Surgery Patients.

Frailty and sarcopenia increase the risk of complications and mortality when invasive treatment such as cardiac surgery is performed. Growth differentiation factor-15 (GDF-15) involves various pathophysiological conditions including renal dysfunction, heart failure and cachexia. We investigated the pathophysiological roles of preoperative GDF-15 levels in cardiovascular surgery patients. Preoperative skeletal muscle index (SMI) determined by bioelectrical impedance analysis, hand-grip strength, 4 m gait speed, and anterior thigh muscle thickness (TMth) measured by echocardiography were assessed in 72 patients (average age 69.9 years) who underwent cardiovascular surgery. The preoperative serum GDF-15 concentration was determined by enzyme-linked immunosorbent assay. Circulating GDF-15 level was correlated with age, brain natriuretic peptide, and estimated glomerular filtration rate (eGFR). It was also negatively correlated with SMI, hand-grip strength, and anterior TMth. In multivariate analysis, eGFR and anterior TMth were the independent determinants of GDF-15 concentration even after adjusting for age, sex, and body mass index. Alternatively, the GDF-15 level was an independent determinant of eGFR and anterior TMth. We concluded that preoperative GDF-15 levels reflect muscle wasting as well as renal dysfunction in preoperative cardiovascular surgery patients. GDF-15 may be a novel biomarker for identify high-risk patients with muscle wasting and renal dysfunction before cardiovascular surgery.