Somatic Mosaicism in Biology and Disease.

Contrary to earlier beliefs, every cell in the individual is genetically different due to somatic mutations. Consequently, tissues become a mixture of cells with distinct genomes, a phenomenon termed somatic mosaicism. Recent advances in genome sequencing technology have unveiled possible causes of mutations and how they shape the unique mutational landscape of the tissues. Moreover, the analysis of sequencing data in combination with clinical information has revealed the impacts of somatic mosaicism on disease processes. In this review, we discuss somatic mosaicism in various tissues and its clinical implications for human disease.

Exosomal miR206 Secreted From Growing Muscle Promotes Angiogenic Response in Endothelial Cells.

BACKGROUND: Resistance exercise is beneficial in patients with lower extremity arterial disease. Muscle-derived exosomes contain many types of signaling molecules, including microRNAs (miRNAs). Here, we tested the hypothesis that exosomal miRNAs secreted by growing muscles promote an angiogenic response in endothelial cells (ECs).Methods and Results: Skeletal muscle-specific conditional Akt1 transgenic (Akt1-TG) mice, in which skeletal muscle growth can be induced were used as a model of resistance training. Remarkable skeletal muscle growth was observed in mice 2 weeks after gene activation. The protein amount in exosomes secreted by growing muscles did not differ between Akt1-TG and control mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway frequency analysis of 4,665 target genes, identified using an miRNA array miRNAs, revealed a significant increase in Akt and its downstream signaling pathway genes. Among the upregulated miRNAs, miR1, miR133, and miR206 were significantly upregulated in the serum of Akt1-TG mice. miR206 was also increased in insulin-like growth factor (IGF)-1-stimulated hypertrophied myotubes. Exogenous supplementation of exosomal miR206 to human umbilical vein ECs promoted angiogenesis, as assessed using the spheroid assay, and increased the expression of angiogenesis-related transcripts. CONCLUSIONS: Exosomal miR206 is upregulated in the blood of Akt1-TG mice and in IGF-stimulated cultured myotubes. Exogenous supplementation of miR206 promoted an angiogenic response in ECs. Our data suggest that miR206 secreted from growing muscles acts on ECs and promotes angiogenesis.

Rationale and Design of Prospective, Multicenter, Double-Arm Clinical Trial to Investigate the Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus (TOP-HFPEF Trial).

BACKGROUND: Recent large clinical trials have revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes not only in patients with heart failure with reduced ejection fraction, but also in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). However, the effect of SGLT2 inhibitors on left ventricular (LV) diastolic function is still controversial. METHODS AND RESULTS: The TOP-HFPEF trial (Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus) is a multicenter, double-arm, open-label, confirmatory, investigator-initiated clinical study to investigate the effect of SGLT2 inhibitor on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus. The participants are randomly assigned (1:1) to the tofogliflozin group (20 mg once daily) or the control group (administration or continuation of antidiabetic drugs other than SGLT2 inhibitors). The estimated number of patients to be enrolled in this trial is 90 in total (45 in each group). The participants are followed up for 52 weeks with tofogliflozin or control drugs. The primary endpoint is the change in E/e' assessed by echocardiography from the baseline to the end of this study (52 weeks). This trial will also evaluate the effects of tofogliflozin on cardiovascular events, biomarkers, other echocardiographic parameters, the occurrence of atrial fibrillation, and renal function. CONCLUSIONS: The TOP-HFPEF trial will clarify the efficacy of an SGLT2 inhibitor, tofogliflozin, on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus.

Elevation of end-tidal CO2 during exercise is attenuated in patients with cardiac amyloidosis.

Reduced exercise tolerance is one of the hallmarks of patients with cardiac amyloidosis (CA), but detailed biological responses during exercise were not investigated. The purpose of this study was to compare the cardiopulmonary exercise test (CPX) parameters between CA patients and propensity-matched heart failure patients. This was a single-center, retrospective, observational study of patients diagnosed with CA. The control group was extracted by propensity score matching from patients who underwent CPX for chronic heart failure during the same period. Clinical data including assessment of biological responses during CPX were compared between the patients with CA (CA group, n = 16) and the control group (non-CA group, n = 16). Echocardiography suggested more impaired diastolic function in the CA group than in the non-CA group. There was no significant difference between groups in the fraction of end-tidal carbon dioxide (FETCO2) at rest. However, the difference between the FETCO2 at rest and the FETCO2 at the respiratory compensation point (ΔFETCO2) was significantly smaller in the CA group than in the non-CA group (0.40% ± 0.37% vs. 0.82% ± 0.33%; p = 0.002). Only in the CA group, there was a significant negative correlation between the ΔFETCO2 and the E/e' ratio on echocardiography (r = - 0.521; p = 0.039) and the serum high-sensitivity troponin T concentration (r = - 0.501; p = 0.048). In conclusion, patients with CA may find it difficult to increase cardiac output during exercise due to severe diastolic dysfunction.

Hemoglobin is an independent predictor of improvement exercise tolerance in male patients with non-ischemic cardiomyopathy.

Exercise intolerance is a symptom of chronic heart failure (CHF). The magnitude of exercise tolerance, as measured by peak oxygen uptake (peak VO2), is strongly associated with prognosis in patients with CHF. We aimed to evaluate the factors associated with improved exercise tolerance in patients with HF. In this prospective study, we recruited patients who were diagnosed with non-ischemic cardiomyopathy between September 2017 and September 2021. All patients underwent cardiopulmonary exercise testing at discharge and 6 months after enrollment. The patients were stratified according to whether peak VO2 was increased or not at 6 months. One hundred patients with a reduced left-ventricular ejection fraction (LVEF < 50%) were enrolled. Improvement of peak VO2 was observed in 74 patients. In male patients, hemoglobin level was higher in the increased peak VO2 group than in the non-increased group (15.0 ± 1.9 g/dL vs. 13.1 ± 2.1 g/dL; p < 0.01). Baseline hemoglobin level was positively correlated with the percentage change in peak VO2 (Spearman's r = 0.248, p = 0.040). Kaplan-Meier analysis demonstrated that adverse cardiac events were significantly less frequent in the increased peak VO2 group than in the non-increased group (log-rank test, p = 0.032). Multivariate logistic regression analysis identified hemoglobin level as an independent predictor of improved peak VO2 [odds ratio (OR) 1.60; 95% confidence interval (CI) 1.05-2.44; p = 0.027]. Baseline hemoglobin level is an independent predictor of improved peak VO2 in male patients with non-ischemic cardiomyopathy.

Evaluation of novel indices of walking performance taking oxygen desaturation into account during six-minute walk test in cardiovascular disease patients.

In pulmonary disease patients since oxygen desaturation during 6-min walk test (6MWT) affects walk distance (6MWD), some novel indices such as desaturation/distance ratio [DDR, oxygen desaturation area (DAO2)/6MWD] and distance-saturation product [DSP, 6MWD × minimum peripheral oxygen saturation (SpO2)] are evaluated. However, there has been no study examining these indices that consider exercise-induced desaturation (EID) in patients with cardiovascular disease. In 94 cardiovascular disease patients without pulmonary complications, 6MWT and echocardiography were performed at the entry of cardiac rehabilitation. SpO2 was measured during 6MWT using a continuously monitorable pulse oximeter, and DSP and DDR were calculated using minimum SpO2 and DAO2 [sum of (100-SpO2) per second during 6MWT], respectively. EID was defined as SpO2 decrease of ≥ 4% or minimum SpO2 of < 90% during 6MWT. DSP was slightly lower and DDR was markedly higher in patients with EID than in those without. When examining correlations of DSP and DDR with their components, DSP was correlated with 6MWD much closely than minimum SpO2, while DDR was correlated as closely with DAO2 as 6MWD. Furthermore, DAO2, but not minimum SpO2, had a direct correlation with 6MWD. As for associations with cardiac function, DSP was correlated with several cardiac parameters, but DDR was not correlated with any of these parameters. Our findings suggest that oxygen desaturation during 6MWT affects walking distance in cardiovascular disease patients even without pulmonary complications and that DDR is more appropriate than DSP as an index of walking performance that takes EID into consideration, independently of cardiac function.

The E/e' ratio on echocardiography as an independent predictor of the improvement of left ventricular contraction in patients with heart failure with reduced ejection fraction.

OBJECTIVE: Clinical feature of heart failure with improved ejection fraction (HFimpEF) remains to be fully elucidated. The present study investigated the association of clinical and echocardiographic parameters with the subsequent improvement of left ventricular ejection fraction (LVEF) in heart failure with reduced ejection fraction (HFrEF). METHODS: From outpatients with a history of hospitalized for heart failure, 128 subjects diagnosed as HFrEF (LVEF <40%) on heart failure hospitalization were enrolled and longitudinally surveyed. During follow-up periods more than 1 year, 58 and 42 patients were identified as HFimpEF (improved LVEF to ≥40% and its increase of ≥10 points) and persistent HFrEF, respectively. RESULTS: There was no difference in age or sex between the two groups with HFimpEF and persistent HFrEF. The rate of ischemic heart disease was lower and that of tachyarrhythmia was higher in the HFimpEF group than in the persistent HFrEF group. At baseline (i.e., on heart failure hospitalization), LVEF did not differ between the two groups, but left ventricular systolic and diastolic diameters were already smaller and the ratio of early diastolic transmitral velocity to early diastolic tissue velocity (E/e') was lower in the HFimpEF group. A multiple logistic regression analysis revealed that lower baseline E/e' was a significant determinant of HFimpEF, independently of confounding factors such as ischemic heart disease, tachyarrhythmia, and baseline left ventricular dimension. CONCLUSION: Our findings indicate that the lower ratio of E/e' in the acute phase of heart failure onset is an independent predictor of the subsequent improvement of LVEF in HFrEF patients.

Angioscopic Ulcerated Plaques in the Femoropopliteal Artery Associated with Impaired Infrapopliteal Runoff.

PURPOSE: To determine the correlation between upstream atherosclerosis in the femoropopliteal arteries, assessed using angioscopy, and impaired infrapopliteal runoff. MATERIALS AND METHODS: Thirty-one patients with peripheral arterial disease who underwent endovascular therapy and angioscopy were prospectively included. Yellow plaque color scores were semiquantitatively determined as 0, 1, 2, or 3. Irregular plaques with rough surfaces, similar to gastric ulcers, were defined as ulcerated plaques (UPs). Angioscopic data were correlated with angiographic runoff scores (ARS). RESULTS: UPs were detected in 74.2% of enrolled diseased legs using angioscopy. Mural thrombi were more commonly observed in the femoropopliteal artery in patients with UPs than in those without UPs (91.3% vs 37.5%, respectively; P = .006) and were frequently found on the UPs (21/23 patients with UPs). Univariate and multivariate linear regression analyses revealed that the presence of UPs was positively and independently associated with a poor ARS and that oral anticoagulant use was independently associated with a preferable ARS (standardized ß = 0.462, P = .004 and standardized ß = -0.411, P = .009, respectively, in the multivariate analysis). CONCLUSIONS: UPs, associated with mural thrombi and diagnosed by angioscopic examination, were demonstrated to be one of the factors associated with poor infrapopliteal runoff.

Dynapenia is an independent predictor of cardio-cerebrovascular events in patients undergoing hemodialysis.

The number of patients on maintenance hemodialysis (HD) diagnosed with sarcopenia has been increasing through as individuals age. Recent focus is on the condition termed, "dynapenia," which reduces only muscle function, as opposed to sarcopenia, which reduces both muscle mass and function. However, the association between dynapenia and cardio-cerebrovascular (CV) events in patients undergoing HD is largely unknown. The purpose of this study was to evaluate whether sarcopenia and dynapenia are associated with the onset of CV events in patients undergoing HD. We retrospectively analyzed 342 patients undergoing HD between January and December 2018. Patients who underwent HD thrice per week for > 3 months were included in the analysis. We adopted the Asian Working Group on Sarcopenia criteria for the diagnosis of sarcopenia and dynapenia. In this study, 244 patients undergoing HD were enrolled. The prevalence of sarcopenia was 38.5%. Sarcopenia was determined to be an independent contributor to CV events in patients undergoing HD. To investigate the clinical relevance of dynapenia in patients with HD, patients without sarcopenia were further divided into dynapenia and non-dynapenia groups. Among 150 patients without sarcopenia, 46 were diagnosed with dynapenia. In the Kaplan-Meier analysis, the rate of CV events was significantly different among the three groups in a stratified manner, with the highest rate in the sarcopenia group and the lowest rate in the non-sarco-dynapenia group. Both patients with sarcopenia and dynapenia had significantly increased CV events compared to those with non-sarco-dynapenia (HR 8.00; 95% CI 2.73-34.1; p < 0.0001 vs. HR 4.85; 95% CI 1.28-23.0; p < 0.02). Both sarcopenia and dynapenia resulted in significantly higher CV events than non-sarco-dynapenia in patients undergoing HD. Therefore, clinicians should evaluate muscle function in addition to muscle quantity to estimate CV events in patients undergoing HD.

Kinetics of atrial and brain natriuretic peptides during hemodialysis are regulated in association with different cardiac functional changes.

The blood levels of atrial and brain natriuretic peptides (ANP and BNP) are both increased markedly in hemodialysis patients, but the kinetics of the two are not always parallel. The present study investigated the association of changes in ANP and BNP levels before and after dialysis with changes in cardiac function in hemodialysis patients. A total of 57 patients (mean age 64 years, 47 males and 10 females) on maintenance hemodialysis with sinus rhythm were enrolled. Blood samples were taken at the beginning and end of dialysis, and plasma levels of ANP and BNP were measured. Changes in cardiac function during dialysis were examined by echocardiography performed just before and after dialysis. Both plasma ANP and BNP concentrations decreased significantly after hemodialysis, but the rate of decrease in BNP [mean ± SD, 555 ± 503 to 519 ± 477 pg/mL (- 6.4%), P = 0.011] was much smaller than that in ANP [233 ± 123 to 132 ± 83 pg/mL (- 43.4%), P < 0.001]. As for the relation to the changes in echocardiographic parameters before and after dialysis, the decrease in inferior vena cava diameter had a close correlation with the decrease in ANP (r = 0.528, P < 0.001), but not BNP. In contrast, the decrease in left ventricular end-diastolic volume index was correlated only with the decrease in BNP (r = 0.297, P = 0.035). The peak velocity ratio of early diastolic to atrial filling decreased with preload reduction by dialysis, and its decrease was more strongly correlated with the decrease in BNP (r = 0.407, P = 0.002) than that in ANP (r = 0.273, P = 0.040). These results demonstrated that in hemodialysis patients, the decrease in plasma ANP by a single dialysis was essentially caused by blood volume reduction, while BNP decrease was mainly induced by the reduction of left ventricular overload. Our findings indicate that the kinetics of both peptides during dialysis are regulated by different cardiac and hemodynamic factors.

Delayed stenosis regression after drug-coated balloon angioplasty for femoropopliteal artery lesions.

Paclitaxel has the potential for inducing lumen enlargement by vessel enlargement, healing of dissection, and plaque regression. This study was carried out to determine the possibility of and the relevant factors of delayed stenosis regression after drug-coated balloon (DCB) angioplasty for femoropopliteal (FP) artery lesions. A total 105 de novo FP lesions were finalized with DCB angioplasty in our institute between May 2018 and June 2020. Among them, cases in which residual stenosis was detected by duplex ultrasonography (DUS) after the procedure were included in this study. Significant stenosis was defined as peak systolic velocity ratio ≥ 2.4 by DUS. Follow-up DUS was routinely performed 6 months after the procedure, and we defined cases without stenosis as cases of delayed stenosis regression according to the follow-up DUS. DUS showed that 26 (25.5%) of 102 lesions had residual stenosis after DCB angioplasty, and delayed stenosis regression was observed in 12 (57.1%) of 21 lesions 6 months after the procedure. The percentage of lesions containing calcified plaque as detected by intravascular ultrasound analysis was significantly higher in the non-regression group than in the regression group (18.2% vs. 77.8%, p = 0.02). Vessel remodeling and dissection patterns were not associated with delayed stenosis regression. The results of our analyses indicate that delayed stenosis regression may occur after DCB angioplasty for FP lesions in more than half of cases with residual stenosis. Delayed stenosis regression may be difficult in cases of calcified lesions.

A simple method of sarcopenia detection can predict adverse cardiovascular events in patients with abdominal obesity.

BACKGROUND: Although sarcopenic obesity is associated with a higher risk of cardiovascular events compared with obesity without sarcopenia, it is difficult to diagnose sarcopenia in daily clinical settings. Recently, a simple scoring system has been developed to identify sarcopenia patients based on three variables (age, hand grip strength, and calf circumference). However, the utility of this score for cardiovascular risk stratification in patients with abdominal obesity is unknown. METHODS: We calculated the sarcopenia score in 262 patients with abdominal obesity, defined as a waist circumference ≥90 cm in women or ≥85 cm in men. The composite endpoint of this study was cardiovascular mortality, nonfatal myocardial infarction, stroke, unstable angina, and heart failure hospitalization. RESULTS: Of the 262 patients, 108 had a high sarcopenia score based on previously established criteria (≥105 in men and ≥120 in women). The patients with a high sarcopenia score had a significantly higher plasma level of B-type natriuretic peptide compared with those with a low sarcopenia score (median 56.7, interquartile range [28.2-142.9] vs. 37.9 [13.8-76.1] pg/mL; p < 0.0001). Kaplan-Meier curves revealed a significantly lower event-free survival rate in those with a high compared with a low sarcopenia score (log-rank test p = 0.001), even after adjustment for confounding factors using propensity score matching (log-rank test p = 0.009). Multivariate Cox proportional hazard analysis identified a high sarcopenia score (hazard ratio: 2.46; 95% confidence interval: 1.31-4.64, p = 0.005) as an independent predictor of the primary endpoints. The combination of a high sarcopenia score and low body mass index (<25 kg/m2) predicted a significantly higher risk of future adverse events (p = 0.005). Furthermore, patients with a high sarcopenia score and high B-type natriuretic peptide level (≥200 pg/mL) had the poorest prognosis (p < 0.0001). CONCLUSIONS: This simple screening test for sarcopenia can predict future adverse cardiovascular events in patients with abdominal obesity.

Sirt7 Deficiency Attenuates Neointimal Formation Following Vascular Injury by Modulating Vascular Smooth Muscle Cell Proliferation.

BACKGROUND: Sirt7 is a recently identified sirtuin and has important roles in various pathological conditions, including cancer progression and metabolic disorders. It has previously been reported that Sirt7 is a key molecule in acute myocardial wound healing and pressure overload-induced cardiac hypertrophy. In this study, the role of Sirt7 in neointimal formation after vascular injury is investigated.Methods and Results:Systemic (Sirt7-/-) and smooth muscle cell-specific Sirt7-deficient mice were subjected to femoral artery wire injury. Primary vascular smooth muscle cells (VSMCs) were isolated from the aorta of wild type (WT) and Sirt7-/-mice and their capacity for cell proliferation and migration was compared. Sirt7 expression was increased in vascular tissue at the sites of injury. Sirt7-/-mice demonstrated significant reduction in neointimal formation compared to WT mice. In vitro, Sirt7 deficiency attenuated the proliferation of serum-induced VSMCs. Serum stimulation-induced upregulation of cyclins and cyclin-dependent-kinase 2 (CDK2) was significantly attenuated in VSMCs of Sirt7-/-compared with WT mice. These changes were accompanied by enhanced expression of the microRNA 290-295 cluster, the translational negative regulator of CDK2, in VSMCs of Sirt7-/-mice. It was confirmed that smooth muscle cell-specific Sirt7-deficient mice showed significant reduction in neointima compared with control mice. CONCLUSIONS: Sirt7 deficiency attenuates neointimal formation after vascular injury. Given the predominant role in vascular neointimal formation, Sirt7 is a potentially suitable target for treatment of vascular diseases.

Enhancement patterns detected by multidetector computed tomography are associated with the long-term prognosis of patients with acute myocardial infarction.

The present study investigated the clinical value of myocardial contrast-delayed enhancement (DE) with multidetector computed tomography (MDCT) without iodine re-injection immediately after primary percutaneous coronary intervention (PCI) for predicting future cardiovascular events after acute myocardial infarction (AMI). We performed a prospective study in which 263 consecutive patients with first AMI successfully treated with primary PCI were enrolled. Sixty-four-slice MDCT without the re-injection of contrast medium was performed immediately after PCI. Myocardial DE was considered to be transmural when involving myocardial thickness ≥ 75% (Group A; n = 104), subendocardial (< 75%, Group B; n = 108), or normal (Group C; n = 51). A semiquantitative scale score was defined for 17 left ventricular segments to investigate the extent of the DE area assessed. We examined the relationship between the presence or absence of transmural DE and long-term cardiovascular event rates. The median follow-up period was 3.5 years. Kaplan-Meier survival curves showed that patient prognosis was poorer in the group with Group A than that in the group with Group B, which was equivalent to that with Group C. A multivariate analysis identified the presence of transmural DE as the strongest predictor for future cardiovascular events (hazard ratio: 3.7; P = 0.023). Transmural myocardial DE immediately following primary PCI without an iodine re-injection for AMI is a major risk factor for future cardiovascular events.

Long-term administration of tolvaptan ameliorates annual decline in estimated glomerular filtration rate in outpatients with chronic heart failure.

Protective effects of tolvaptan against worsening renal function in acute heart failure have been shown. However, long-term effects of its agent on renal function remain to be elucidated. The present study investigated retrospectively whether long-term treatment with tolvaptan exerts renoprotective effects in patients with chronic heart failure, by comparing serial changes in estimated glomerular filtration rate (eGFR) for years before and after tolvaptan administration. From 63 outpatients with chronic heart failure taking diuretics including tolvaptan, 34 patients whose eGFR levels were continuously measured for more than 6 months both before and after administration of tolvaptan (average dose, 7.8 mg/day at the end of the follow-up period) were selected as eligible for the present analyses. All eGFR values were separately plotted before and after the initiation of treatment with tolvaptan (except hospitalization periods) along the time course axis and the slope of the linear regression curve was calculated as an annual change in eGFR. The mean follow-up periods before and after tolvaptan administration were 1197 and 784 days (3.3 and 2.1 years), respectively. Changing rates of eGFR per year were significantly ameliorated after treatment with tolvaptan (mean ± SD, - 8.02 ± 9.35 to - 1.62 ± 5.09 mL/min/1.73m2 /year, P = 0.001). In echocardiographic parameters, inferior vena cava (IVC) diameter significantly decreased after tolvaptan administration, and the decrease in IVC diameter was correlated with the improvement of eGFR decline slope after administration of tolvaptan (P = 0.0075). This longitudinal observational study indicated that long-term treatment with tolvaptan ameliorated annual decline in eGFR in outpatients with chronic heart failure. Our findings suggest that tolvaptan has a protective effect against chronically worsening renal function in heart failure patients.

Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2-Mediated Paracrine Signaling.

BACKGROUND: Heart failure, which is a major global health problem, is often preceded by pathological cardiac hypertrophy. The expansion of the cardiac vasculature, to maintain adequate supply of oxygen and nutrients, is a key determinant of whether the heart grows in a physiological compensated manner or a pathological decompensated manner. Bidirectional endothelial cell (EC)-cardiomyocyte (CMC) cross talk via cardiokine and angiocrine signaling plays an essential role in the regulation of cardiac growth and homeostasis. Currently, the mechanisms involved in the EC-CMC interaction are not fully understood, and very little is known about the EC-derived signals involved. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how ECs regulate CMC homeostasis could provide novel therapeutic targets for heart failure. METHODS: Genetic mouse models were used to delete vascular endothelial growth factor (VEGF) receptors, adeno-associated viral vectors to transduce the myocardium, and pharmacological inhibitors to block VEGF and ErbB signaling in vivo. Cell culture experiments were used for mechanistic studies, and quantitative polymerase chain reaction, microarrays, ELISA, and immunohistochemistry were used to analyze the cardiac phenotypes. RESULTS: Both EC deletion of VEGF receptor (VEGFR)-1 and adeno-associated viral vector-mediated delivery of the VEGFR1-specific ligands VEGF-B or placental growth factor into the myocardium increased the coronary vasculature and induced CMC hypertrophy in adult mice. The resulting cardiac hypertrophy was physiological, as indicated by preserved cardiac function and exercise capacity and lack of pathological gene activation. These changes were mediated by increased VEGF signaling via endothelial VEGFR2, because the effects of VEGF-B and placental growth factor on both angiogenesis and CMC growth were fully inhibited by treatment with antibodies blocking VEGFR2 or by endothelial deletion of VEGFR2. To identify activated pathways downstream of VEGFR2, whole-genome transcriptomics and secretome analyses were performed, and the Notch and ErbB pathways were shown to be involved in transducing signals for EC-CMC cross talk in response to angiogenesis. Pharmacological or genetic blocking of ErbB signaling also inhibited part of the VEGF-B-induced effects in the heart. CONCLUSIONS: This study reveals that cross talk between the EC VEGFR2 and CMC ErbB signaling pathways coordinates CMC hypertrophy with angiogenesis, contributing to physiological cardiac growth.

Association between debulking area of rotational atherectomy and platform revolution speed-Frequency domain optical coherence tomography analysis.

OBJECTIVES: In this study, we sought to investigate the association between revolution speed of rotational atherectomy (RA) and debulking area assessed by frequency domain-optical coherence tomography (FD-OCT). BACKGROUND: The number of patients with severe calcified coronary artery disease requiring treatment with calcium ablation, such as RA, is increasing. However, there is little evidence available regarding the association between debulking area and revolution speed during RA. METHODS: We retrospectively investigated 30 consecutive severely calcified coronary lesions in 29 patients who underwent RA under FD-OCT guidance. The association between preset revolution speed of RA and burr size-corrected debulking area of the calcified lesion was evaluated using a multivariable regression model with nonlinear restricted-cubic-spline, which can help assess nonlinear associations between variables. RESULTS: The median age of study participants was 73 years (quartile 65-78); 82.8% were male. The median burr size was 1.5 mm (1.5-1.75); median total duration of ablation was 120 s (100-180). FD-OCT revealed that the post-procedural minimum lumen area increased significantly from 1.64 mm2 (1.40-2.09) to 2.45 mm2 (2.11-2.98) (p < .001). In addition, the burr size-corrected debulking area increased significantly as the preset revolution speed decreased (p = .018), especially when the revolution speed was less than 150,000 rpm. This result implies that additional lumen gain will be obtained by decreasing rpm when the burr speed is set at <150,000 rpm. CONCLUSIONS: FD-OCT demonstrated that RA with lower revolution speed, below 150,000 rpm, has the potential to achieve greater calcium debulking effect in patients with severe calcified coronary lesions.

Soluble urokinase-type plasminogen activator receptor represents exercise tolerance and predicts adverse cardiac events in patients with heart failure.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a membrane-binding protein that is released into the blood stream by immune activation. Recent reports suggest that circulating suPAR levels are associated with adverse cardiovascular outcomes. Exercise tolerance is an independent predictor of prognosis in patients with heart failure (HF); however, the relationship between serum suPAR level and exercise tolerance is unclear. We prospectively enrolled 94 patients who were hospitalized for worsening of HF. All patients underwent a symptom-limited cardiopulmonary exercise test to evaluate exercise tolerance. The median value of serum suPAR was 4848 pg/ml. During follow up, 44 patients (47%) were admitted for all-cause mortality and re-hospitalization for HF. Median serum suPAR was significantly higher in the patients with cardiac events than in the patients with non-event group. Patients were divided into two groups according to circulating suPAR levels. Kaplan-Meier analysis demonstrated that adverse cardiac events were significantly higher in the high suPAR group (log-rank p = 0.023). Multivariate analysis revealed that suPAR was independently correlated with the parameters of exercise tolerance such as anaerobic threshold (p = 0.007) and peak oxygen uptake (p = 0.005). suPAR levels predicted adverse cardiac events and independently correlated with the parameters of exercise tolerance. suPAR could be a useful surrogate biomarker of exercise tolerance in patients with HF.

Prognostic value of high-sensitive troponin T for predicting cardiovascular events after atrial fibrillation ablation.

BACKGROUND AND OBJECTIVES: This study aimed to evaluate the utility of high-sensitive troponin T (hs-TnT) for predicting AF recurrence and major adverse cardiovascular events (MACE) after AF ablation. METHODS AND RESULTS: A total of 227 consecutive patients with AF (mean age, 66 ± 10 years; persistent AF, n = 98) who underwent an initial ablation were enrolled. We measured hs-TnT before AF ablation and divided the patients into three groups according to the hs-TnT level: low, lesser than or equal to 0.005 µg/L (n = 54); medium, 0.006-0.013 µg/L (n = 127); and high, greater than or equal to0.014 µg/L (n = 46). We evaluated the composite endpoint of AF recurrence or MACE (including death, stroke, acute coronary syndrome, and heart failure hospitalization) after the ablation. The median hs-TnT level was 0.008 µg/L. The values of chronic kidney disease prevalence, CHA2 DS2 -VASc score, B-type natriuretic peptide level, and left atrial diameter were the highest in the high hs-TnT group among the three groups. During a mean follow-up of 15 ± 8 months, AF recurrence and MACE occurred in 56 (25%) and 9 (4%) patients, respectively. The high hs-TnT group had the highest incidence of AF recurrence and MACE among the three groups (high: 39% and 15%, medium: 22% and 2%, and low: 19% and 0%, respectively; log-rank P < .05). In multivariate analysis, hs-TnT greater than or equal to 0.014 µg/L and persistent AF were independent predictors of the composite endpoint. CONCLUSION: Hs-TnT may be a useful marker for predicting AF recurrence or MACE after AF ablation.