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.

Physiological Role of Serum Growth Differentiation Factor-15 (GDF-15) Level and Iron Metabolism in Community-Dwelling Older Adults.

Background Anemia is common in older adults and, together with heart failure and chronic kidney disease, forms a vicious cycle, whereas diseases such as chronic inflammation and cancer are associated with the anemia of chronic disease (ACD). Researchers have linked growth differentiation factor-15 (GDF-15) to a variety of conditions such as cardiovascular disease, inflammation, cancer, and kidney disease, and have reported hepcidin as a biomarker for iron regulation in ACD. Therefore, anemia, GDF-15, and hepcidin have significance in aging physiology. Hypothesis GDF-15 and hepcidin play important physiological roles in community-dwelling older adults. This study sought to explore the relationship between these biomarkers and anemia, inflammation, or other health outcomes. Methods This was a prospective study of 73 community-dwelling older adults (six men and 67 women, mean age of 76.3 years). Their serum iron level, percentage transferrin saturation (TSAT), high-sensitivity C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) were measured. Enzyme-linked immunosorbent assays were used to assess their serum GDF-15, ferritin, and hepcidin levels. The participants' grip strength and walking speed were measured. The skeletal muscle mass index (SMI) of each participant was determined by bioelectrical impedance analysis. Results The GDF-15 level was significantly inversely correlated with serum iron, ferritin, and hepcidin levels; percentage TSAT; the eGFR; and gait speed. Serum hepcidin was positively correlated with levels of ferritin, albumin, and hemoglobin. Handgrip strength, SMI, and hs-CRP were not correlated with either GDF-15 or hepcidin levels. After adjusting for age, sex, and body mass index (BMI), multivariate analysis identified the log GDF-15 and serum iron level (log GDF-15: ß=-0.248, iron: ß=0.296) as significant factors determining hemoglobin levels, whose findings have significance due to novel results. Multivariate analysis identified eGFR and levels of hemoglobin and hepcidin as significant factors associated with log GDF-15 (eGFR: ß=-0.406, hemoglobin: ß=-0.269, hepcidin: ß=-0.235). Similarly, ferritin and albumin levels were identified as significant factors associated with hepcidin levels (ferritin: ß=0.590, Alb: ß=0.277). Conclusions Anemia in community-dwelling older adults was determined not only by increasing serum iron levels but also by decreasing GDF-15 levels. Also, the increasing GDF-15 level was determined by a decreasing hepcidin level as well as the presence of anemia and renal dysfunction, and the decreasing hepcidin level was determined by decreasing stored iron and decreasing albumin levels. Serum GDF-15 and hepcidin could potentially inform diagnostic or treatment strategies for anemia or age-related health conditions.

Transcatheter aortic valve-in-surgical aortic valve for a patient with repeated healed endocarditis: a case report.

BACKGROUND: Transcatheter valve replacement is contraindicated in patients with active infective endocarditis. However, few reports suggest that it could be beneficial for high-risk surgical patients with healed infective endocarditis. Here, we report a case of a surgical transcatheter aortic valve in a patient with healed repeated prosthetic valve endocarditis using a stentless valve. CASE PRESENTATION: A 79-year-old female who underwent the Bentall procedure using a stentless valve and coronary artery bypass grafting for annuloaortic ectasia 22 years ago was hospitalized for stage II bioprosthetic valve failure. The patient had a history of prosthetic valve endocarditis three times: the first and second prosthetic valve endocarditis occurred 15 years ago, and the third prosthetic valve endocarditis occurred 3 years ago. The causative organisms were Campylobacter fetus and Enterococcus faecalis. With appropriate antibiotic therapy, the lesion was localized and healed completely without valve destruction; however, the patient developed rapid aortic regurgitation. Based on a review of the patient's history of prosthetic valve endocarditis, the absence of signs of infection, and clinical findings of transesophageal echocardiography and computed tomography, a diagnosis of structural valve deterioration with healed infective endocarditis was made. Subsequently, a transcatheter aortic valve in a surgical aortic valve using a balloon-expandable type was performed, because the patient had a high surgical risk of 12.7%. The patient's postoperative course was uneventful. At the 1-year follow-up, there were no signs of infection or valve abnormalities. CONCLUSIONS: Transcatheter valve replacement can be a treatment option for high-risk surgical patients with healed limited lesions in infective endocarditis.

Relationship between the serum GDF-15 concentration and muscle function in female patients receiving aortic valve replacement (TAVR, SAVR): Comparison with healthy elderly female subjects.

Purpose: Sarcopenia is closely associated with postoperative prognosis in patients undergoing cardiovascular surgery. Growth differentiation factor (GDF)-15 is involved in the pathogenesis of cardiovascular disease. We examined the relationship between the serum GDF-15 concentration and muscle function in patients receiving aortic valve replacement and healthy elderly subjects. Methods: Forty-three female patients undergoing aortic valve surgery (79.9 ± 6.4 years; transcatheter aortic valve replacement [TAVR] n = 19, conventional surgical aortic valve replacement [SAVR] n = 24) and 64 healthy elderly female subjects (75.9 ± 6.1 years) were included. Walking speed, grip strength, and skeletal muscle mass index (SMI) by a multifrequency bioelectrical impedance analyzer were measured to determine the presence of sarcopenia. Preoperative serum GDF-15 concentration was measured by enzyme-linked immunosorbent assay. Results: The GDF-15 level was higher in patients receiving aortic valve replacement than in healthy elderly subjects (aortic valve replacement: 1624 ± 1186 pg/mL vs. healthy: 955 ± 368 pg/mL, p < 0.001). Multivariate linear regression analysis showed that the serum GDF-15 level determined grip strength independently of the high-sensitivity C-reactive protein level and eGFR, even after adjusting for age (ß = -0.318, p = 0.025). Sarcopenia was found in 12.5% of healthy elderly subjects, 83.3% of patients with TAVR, and 64.3% of patients with SAVR. The GDF-15 concentration that defined sarcopenia was 1109 pg/mL in subjects including patients receiving aortic valve replacement. Conclusions: The preoperative serum GDF-15 concentration, which was higher in female patients receiving aortic valve replacement than in healthy elderly subjects, may be a serum marker of sarcopenia.

Effects of switching from clopidogrel to prasugrel at the chronic phase after coronary stenting on antiplatelet action and vascular endothelial function: Switch-Pras study.

Compared to clopidogrel, prasugrel has a lower incidence of ischemic events following percutaneous coronary intervention (PCI) because of an early reduction during the acute phase in P2Y12 reaction units (PRU). The objective of this study was to compare the antiplatelet effect and vascular endothelial function of both drugs during the chronic phase after PCI. Patients who had undergone PCI and were confirmed to have no restenosis by follow-up coronary angiography under dual anti-platelet therapy with clopidogrel (75 mg/day) and aspirin (100 mg/day) were randomized to either continue clopidogrel or switch to prasugrel (3.75 mg/day). At baseline, prior to randomization we determined the CYP2C19 genotype. At the baseline and 24 weeks after randomization, the P2Y12 reactivity unit (PRU) was measured using the VerifyNow™ P2Y12 assay. Endothelial function was evaluated by flow-mediated vasodilation (FMD) and reactive hyperemia peripheral arterial tonometry (RH-PAT), while and circulating CD34+/CD133+/CD45low progenitor cells were measured by flow cytometric analysis. Serum high-sensitivity C-reactive protein (hsCRP) level was also measured. The PRU was reduced significantly in the prasugrel group (P = 0.0008), especially in patients who were intermediate or poor metabolizers based on the CYP2C19 genotype (P < 0.0001). This reduction was not observed in the clopidogrel group. The number of CD34+/CD133+/CD45low cells increased in the clopidogrel group (P = 0.008), but not in the prasugrel group. The hsCRP, FMD and reactive hyperemia index measured by RH-PAT did not change in either group. Prasugrel is potentially better than clopidogrel for preventing thrombotic events, although clopidogrel may have an advantage over prasugrel in terms of preventing atherosclerotic events. Proper use of thienopyridine drugs based on the CYP2C19 genotype has promising clinical potential.

Association of serum growth differentiation factor-15 with eGFR and hemoglobin in healthy older females.

PURPOSE: Anemia and sarcopenia associated with renal dysfunction caused by cytokine imbalance can contribute to decreased quality of life for older individuals. Growth differentiation factor-15 (GDF-15) is associated with renal dysfunction, although whether it is related to anemia or sarcopenia is unclear. In this study we examined the association of GDF-15 with renal function, hemoglobin and sarcopenia in healthy community-dwelling older females in Japan. METHODS: A total of 66 healthy older community-dwelling females (age: 75.8 ± 6.2 years) were enrolled for this study. Skeletal muscle mass index was determined by bioelectrical impedance analysis. Hand-grip strength and walking speed were also assessed. Serum GDF-15 concentration was determined by enzyme-linked immunosorbent assay and both hemoglobin (Hb) level and estimated glomerular filtration rate (eGFR) were measured. RESULTS: Serum GDF-15 levels positively correlated with age but negatively correlated with eGFR and walking speed. In multiple regression analysis, eGFR and hemoglobin (Hb) were independent variables to predict serum GDF-15 levels, even after adjusting for age and body mass index (eGFR: ß = -0.423, p < 0.001; Hb: ß = -0.363, p = 0.004). Serum GDF-15 level was an independent variable to predict eGFR and Hb. CONCLUSIONS: Both Hb and eGFR are predictors for serum GDF-15 concentration in healthy older females. In these community-dwelling older females, renal dysfunction via GDF-15 may be accompanied by anemia, but not sarcopenia.

Clinical Usefulness of New R-R Interval Analysis Using the Wearable Heart Rate Sensor WHS-1 to Identify Obstructive Sleep Apnea: OSA and RRI Analysis Using a Wearable Heartbeat Sensor.

Obstructive sleep apnea (OSA) is highly associated with cardiovascular diseases, but most patients remain undiagnosed. Cyclic variation of heart rate (CVHR) occurs during the night, and R-R interval (RRI) analysis using a Holter electrocardiogram has been reported to be useful in screening for OSA. We investigated the usefulness of RRI analysis to identify OSA using the wearable heart rate sensor WHS-1 and newly developed algorithm. WHS-1 and polysomnography simultaneously applied to 30 cases of OSA. By using the RRI averages calculated for each time series, tachycardia with CVHR was identified. The ratio of integrated RRIs determined by integrated RRIs during CVHR and over all sleep time were calculated by our newly developed method. The patient was diagnosed as OSA according to the predetermined criteria. It correlated with the apnea hypopnea index and 3% oxygen desaturation index. In the multivariate analysis, it was extracted as a factor defining the apnea hypopnea index (r = 0.663, p = 0.003) and 3% oxygen saturation index (r = 0.637, p = 0.008). Twenty-five patients could be identified as OSA. We developed the RRI analysis using the wearable heart rate sensor WHS-1 and a new algorithm, which may become an expeditious and cost-effective screening tool for identifying OSA.

Flow-Mediated Vasodilation and Reactive Hyperemia Index in Heart Failure with Reduced or Preserved Ejection Fraction.

Vascular endothelial dysfunction is part of the underlying pathophysiology of heart failure. However, there are no reports in which vascular endothelial function of both conduit arteries and microvasculature was assessed in patients with heart failure. This study was aimed to assess vascular endothelial function separately in heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF). We performed simultaneous measurement of both flow-mediated vasodilation for endothelial function of conduit arteries and reactive hyperemia-peripheral arterial tonometry for that of microvasculature in 88 consecutive patients with chronic heart failure. In 55 patients with ischemic heart disease as an underlying cause of heart failure, flow-mediated vasodilation value was comparable between the two groups of HFrEF (left ventricular ejection fraction < 50%, n = 31) and HFpEF (left ventricular ejection fraction ≥ 50%, n = 24). Reactive hyperemia index measured by reactive hyperemia peripheral arterial tonometry, however, was lower in HFrEF patients compared to HFpEF patients (P = 0.014). In contrast, among 33 patients with non-ischemic heart disease, the degree of flow-mediated vasodilation was lower in HFpEF patients (n = 18) compared with HFrEF patients (n = 15) (P = 0.009), while reactive hyperemia index was comparable between the two groups. The clinical and pathophysiological significance of endothelial function in heart failure differs between conduit artery and microvasculature, and these differences may contribute to the underlying pathophysiology of HFpEF and HFrEF, as well as in ischemic heart disease and non-ischemic heart disease.

Phase Angle as an Indicator of Sarcopenia, Malnutrition, and Cachexia in Inpatients with Cardiovascular Diseases.

Malnutrition is associated with sarcopenia, cachexia, and prognosis. We investigated the usefulness of phase angle (PhA) as a marker of sarcopenia, cachexia, and malnutrition in 412 hospitalized patients with cardiovascular disease. We analyzed body composition with bioelectrical impedance analysis, and nutritional status such as controlling nutritional status (CONUT) score. Both skeletal muscle mass index (SMI) and PhA correlated with age, grip strength and knee extension strength (p < 0.0001) in both sexes. The SMI value correlated with CONUT score, Hb, and Alb in males. Phase angle also correlated with CONUT score, Hb, and Alb in males, and more strongly associated with these nutritional aspects. In females, PhA was correlated with Hb and Alb (p < 0.001). In both sexes, sarcopenia incidence was 31.6% and 32.4%; PhA cut-off in patients with sarcopenia was 4.55° and 4.25°; and cachexia incidence was 11.5% and 14.1%, respectively. The PhA cut-off in males with cachexia was 4.15°. Multivariate regression analysis showed that grip strength and brain natriuretic peptide (BNP) were independent determinants of SMI, whereas grip strength, BNP, and Hb were independent determinants of PhA. Thus, PhA appears to be a useful marker for sarcopenia, malnutrition, and cachexia in hospitalized patients with cardiovascular disease.

Add-on ezetimibe treatment to low-dose statins vs medium-intensity statin monotherapy in coronary artery disease patients with poorly controlled dyslipidemia.

Although ezetimibe has potential value as an add-on therapy to statins, it is not established whether the addition of ezetimibe to statin therapy is more effective than double-dose statin monotherapy. We conducted a crossover design study. Twenty-one coronary artery disease (CAD) patients whose lipid profiles had not achieved Japanese guideline recommendations (JAS 2017), despite receiving low-dose statin therapy, were divided into two groups. Group A received ezetimibe 10 mg in addition to the baseline dose of statin for the first 3 months and was then switched to monotherapy with a double dose of statin for the next 3 months. Group B first received a double dose of statin for 3 months and was then switched to ezetimibe 10 mg in addition to a baseline dose of statin for the next 3 months. Compared with the baseline, double-dose statin therapy reduced low-density lipoprotein (LDL)-cholesterol (from 118 ± 22 to 104 ± 15 mg/dL, P < 0.05) and malondialdehyde-modified LDL (MDA-LDL) (from 142 ± 35 to 126 ± 24 U/L, P < 0.05) but did not lower high-sensitivity C-reactive protein (hsCRP) (3.02 ± 0.47 and 2.98 ± 0.41 log [ng/ml]). The addition of ezetimibe to a baseline dose of statin further reduced LDL-cholesterol (to 89 ± 15, P < 0.0001) and MDA-LDL (to 114 ± 22 U/L, P < 0.001) and reduced hsCRP (to 2.78 ± 0.38 log (ng/ml), P < 0.05). The changes in the levels of MDA-LDL (R = 0.548, P = 0.010) and hsCRP (R = 0.473, P < 0.05) were significantly correlated with the change in the LDL-cholesterol level after the addition of ezetimibe. Add-on ezetimibe treatment appears superior to double-dose statin therapy in CAD patients with poorly controlled dyslipidemia in terms of reductions in LDL-cholesterol level, lipid peroxidation, and inflammation.