Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes.

Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.

Incremental value of diastolic wall strain in predicting heart failure events in patients with atrial fibrillation.

Diastolic wall strain (DWS), an echocardiographic index based on linear elasticity theory, has been identified as a predictor of heart failure (HF) in patients with sinus rhythm. However, its effectiveness in atrial fibrillation (AF) patients remains uncertain. This study aims to assess DWS as a predictor of HF in AF patients with preserved ejection fraction. We analysed a prospective database of AF patients undergoing transthoracic echocardiography. AF patients with reduced left ventricular ejection fraction (< 50%), posterior wall motion abnormality, hypertrophic cardiomyopathy, valvular heart disease, pericardial disease, congenital heart disease, or history of pacemaker/implantable cardioverter-defibrillator implantation or cardiac surgery were excluded. The study followed patients until HF development, death, or last visit. Follow-up for patients who underwent catheter ablation was censored on the date of their procedure. HF was ascertained based on the Framingham criteria. DWS was calculated using a validated formula: DWS = (PWs -PWd)/PWs, where PWs is the posterior wall thickness at end-systole and PWd is the posterior wall thickness at end-diastole. Among 411 study patients (mean age 69.6 years, 66% men), 20 (5%) was underwent catheter ablation and 57 (14%) developed HF during a mean follow-up of 82 months. Cox-proportional hazards demonstrated that low DWS (≤ 0.33) significantly predicted HF events (hazard ratio [HR] 3.28, 95% confidence interval [CI]) 1.81-5.94, P < 0.0001), independent of age (per 10 years; HR 1.99, 95% CI 1.35-2.93, P < 0.001), indexed left ventricular mass (per 10 g/m2; HR 1.16, 95% CI 1.05-1.27, P < 0.01), and indexed left atrial volume (per 10 mL/m2; HR 1.14, 95% CI 1.04-1.24, P < 0.01). Additionally, global log-likelihood ratio chi-square statistics indicated that DWS incrementally predicts HF development beyond age, indexed left ventricular mass, and left atrial volume (P < 0.001).

H2ARDD score as a feasible predictor of heart failure events in patients with atrial fibrillation: a validation study.

It was reported that the H2ARDD score (organic heart diseases = 2 points, anemia = 1 point, renal dysfunction = 1 point, diabetes = 1 point, and diuretic use = 1point; range 0 to 6 points) may help identify patients with AF at high risk for HF events. However, this score has not been externally validated. The objective of this study was to evaluate the usefulness of H2ARDD score in predicting HF events in patients with AF. We used a prospective database of patients with AF, and Cox-proportional hazards models were used to assess the risk of HF events. The outcome of interest was defined as HF events including new-onset HF and death from HF. Of 562 AF patients, 518 (mean 69.7 ± 9.7 years-old, 64.9% men) met study criteria, and 84 (16.2%) developed HF events during a mean follow-up of 54 ± 42 months. In multivariable analyses, H2ARDD score was shown as a significant predictor for HF events [hazard ratio (HR): 1.56, 95% confidence interval (CI): 1.36-1.79], independent of age (per 10 years, HR: 1.35, 95% CI: 1.03-1.78). In the Kaplan-Meier analyses stratified by H2ARDD score categories (0-2, 3-4, 5-6), the patients with higher H2ARDD scores had significantly worse HF event-free survival (log-rank P < 0.0001). The area under the ROC curve was 0.71 (95% CI: 0.65-0.77, P < 0.0001). The sensitivity and specificity at a cut-off score of ≥ 3 were 60% and 71%, respectively. In conclusion, the H2ARDD score may be feasible for HF risk stratification in patients with AF.

Diagnostic accuracy and clinical usefulness of erythrocyte creatine content to predict the improvement of anaemia in patients receiving maintenance haemodialysis.

BACKGROUND: The improvement of anaemia over time by erythropoiesis stimulating agent (ESA) is associated with better survival in haemodialysis patients. We previously reported that erythrocyte creatine content, a marker of erythropoietic capacity, was a reliable marker to estimate the effectiveness of ESA. The aim of this study was to examine the accuracy and clinical usefulness of erythrocyte creatine content to predict the improvement of anaemia in haemodialysis patients. METHODS: ESA dose was fixed 3 months prior to the enrollment and was maintained throughout the study period. Erythrocyte creatine content and haematologic indices were measured at baseline in 92 patients receiving maintenance haemodialysis. Haemoglobin was also measured 3 months after. Improvement of anaemia was defined as ≥ 0.8 g/dL change in haemoglobin from baseline to 3 months. RESULTS: Erythrocyte creatine content was significantly higher in 32 patients with improvement of anaemia compared to 60 patients with no improvement of anaemia (2.47 ± 0.74 vs. 1.57 ± 0.49 µmol/gHb, P = 0.0001). When 9 variables (erythrocyte creatine content, ESA dose, reticulocyte, haptoglobin, haemoglobin at baseline, serum calcium, intact parathyroid hormone, transferrin saturation and serum ferritin) were used in the multivariate logistic regression analysis, erythrocyte creatine emerged as the most important variable associated with the improvement of anaemia (P = 0.0001). The optimal cut-off point of erythrocyte creatine content to detect the improvement of anaemia was 1.78 µmol/gHb (Area under the curve: 0.86). Sensitivity and specificity of erythrocyte creatine content to detect the improvement of anaemia were 90.6% and 83.3%. CONCLUSION: Erythrocyte creatine content is a reliable marker to predict the improvement of anaemia 3 months ahead in patients receiving maintenance haemodialysis.

Elevated Aminotransferase Levels and Intracerebral Hemorrhage Deaths in a General Japanese Population.

Although chronic liver disease has been associated with cardiovascular disease, to which metabolic syndrome might be related, intracerebral hemorrhage (ICH) generally has not been focused. Associations of chronic liver disease assessed by aspartate (AST) and alanine (ALT) aminotransferase levels with ICH deaths were examined using 15,952 subjects without a history of cardiovascular disease who underwent annual health checkups in 1997 in Japan. Proportional hazards regression analyses adjusted for age, sex, hypertension, current smoking, diabetes mellitus, drinking habits, excess body weight, and hypercholesterolemia were performed. During a mean follow-up of 18.6 ± 7.2 years, there were 227 stroke deaths (including 124 ischemic and 60 ICH deaths) and 135 coronary deaths. Elevated aminotransferase levels, defined as a serum AST or ALT level of ≥ 30 IU/L were significantly associated with ICH deaths (hazard ratio (HR) = 2.72, 95% confidence interval (CI) = 1.56-4.73, P = 0.0004). Because elevated aminotransferase levels are frequently observed in alcoholic or metabolic liver diseases, additional analyses were performed to examine the effect of drinking habits and/or metabolic syndrome on the association of elevated aminotransferase levels with ICH deaths. After exclusion of subjects with any drinking habit (n = 9,941), elevated aminotransferase levels were significantly associated with ICH deaths (HR = 2.88, 95%CI = 1.44-5.76, P = 0.0028). After exclusion of subjects with at least one metabolic syndrome component (n = 5,672), elevated aminotransferase levels were significantly associated with ICH deaths (HR = 6.47, 95% CI = 1.85-22.6, P = 0.0035). Elevated aminotransferase levels were not associated with ischemic stroke or coronary deaths in any models. Elevated aminotransferase levels were significantly associated with ICH deaths, independent of drinking habits, or metabolic syndrome.

Frequency and Distribution of Sheet and Nodular Calcification in Coronary Arteries in Japanese Patients.

Whether a nodular calcification (NC), which is the precursor to intracoronary thrombosis, is focally or diffusely distributed in the coronary tree has major implications for ongoing efforts to identify. This study aimed to investigate the frequency and spatial distribution patterns of sheet calcification (SC) and NC in a 3-vessel examination of autopsied human hearts.A total of 323 coronary artery specimens from 110 cadavers were obtained from autopsy cases. After fixation and decalcification, the coronary artery trees were cut every 5 mm into 4-µm transverse cross-sections for histological assessment. An SC was defined as a plate-like calcification of > 1 quadrant of the vessel or > 3 mm in diameter, and NC as nodular calcium deposits separated by fibrin, and a deposit size > 1 mm in diameter.Of the 6,306 histological cross-sections, SCs and NCs were identified in 1,627 (26%) and 233 (4%) cross-sections, respectively. SCs and NCs had a similar distribution pattern in all 3 coronary arteries. In the left anterior descending artery (LAD), NCs were predominantly located in the proximal segment: the first 45 mm from the LAD ostium (72%) and the first 60 mm from the LAD ostium (84%), respectively. However, NCs were evenly distributed throughout the length of the coronary artery in the right coronary artery (RCA) and left circumflex artery (LCX).NCs coexisted with SCs, and tended to cluster in predictable parts within the proximal segments of the LAD, but were evenly distributed throughout the RCA and LCX in coronary arteries from cadavers.

Factors Associated with Coronary In-Stent Restenosis after Drug-Eluting Stent Implantation in Patients on Chronic Hemodialysis.

AIMS: Recently, drug-eluting stents (DESs) have been widely adopted for patients on chronic hemodialysis (HD). However, whether DES implantation is associated with a reduced rate of in-stent restenosis (ISR) is unclear. We investigated the incidence of ISR and its predictors in patients on HD after DES implantation. METHODS AND RESULTS: We analyzed 194 consecutive patients (331 lesions) on HD who underwent follow-up angiography after DES implantation. ISR was observed in 74 lesions (22.4%). Angiographically, the relative incidence of AHA/ACC type C lesion was increased (47 vs. 32%; p = 0.043), the minimal lumen diameter (MLD) before DES implantation was smaller (0.82 ± 0.49 vs. 0.97 ± 0.45 mm; p < 0.01), and the lesion length (LL) was increased (30.2 ± 16.1 vs. 24.4 ± 12.1 mm; p = 0.023) in lesions with ISR compared to those without ISR. The rate of rotational atherectomy use was also increased in lesions with ISR compared to those without ISR (50% vs. 25%; p < 0.01). In a multivariate analysis, the MLD before DES implantation (odds ratio [OR] = 0.50, 95% confidence interval [CI] 0.27-0.91, p = 0.024), LL (OR = 1.02, 95% CI 1.00-1.04, p = 0.030) and the use of rotational atherectomy (OR = 2.71, 95% CI 1.55-4.72, p < 0.01) were independent predictors of ISR. The incidence of ISR was similar between lesions treated with the first-generation (25.8%) and the second-generation DESs (20.4%). CONCLUSIONS: ISR was observed in 74 lesions (22.4%). A small MLD, long LL, and the use of rotational atherectomy were independent predictors of ISR after DES implantation in patients on HD. There was no significant difference in the ISR rate between the first- and the second-generation DESs.

Increased Incidence of ECG Abnormalities in the General Population During the COVID-19 Pandemic.

To examine the effect of the COVID-19 pandemic on the cardiovascular system in the general population, we compared ECG changes after the onset of the COVID-19 pandemic with those before the pandemic period. The incidence of newly appeared ECG abnormalities (T wave abnormalities, ST-segment depression including minor changes, and abnormal Q waves) from 2019 to 2020 (COVID-19 period) was compared with that from 2018 to 2019 (control period) in subjects 40 to 74 years of age without a history of cardiovascular disease who had 12-lead ECG recordings during annual health checkups offered to adult citizens of Moriguchi City, Osaka, Japan. Logistic regression analyses were performed after adjusting for cardiovascular risk factors. There were 5,221 eligible subjects in the control period and 4,100 eligible subjects in the COVID-19 period. The incidences of newly appeared ECG abnormalities were 5.2% for T wave abnormalities, 2.8% for ST-segment depression, and 1.1% for abnormal Q waves in the control period, whereas they were 5.8%, 4.3%, and 1.7% respectively, in the COVID-19 period. The incidence of ST-segment depression (odds ratio (OR) = 1.59, 95% confidence interval (CI) = 1.27-1.98, P < 0.0001) and that of abnormal Q waves (OR = 1.56, 95%CI = 1.09-2.22, P = 0.0149) in the COVID-19 period were significantly higher compared to those of the control period. In conclusion, increased incidences of newly appeared ST-segment depression and abnormal Q waves were observed during the COVID-19 pandemic period.

Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.

The incidence, natural history, and predictive factors for tissue protrusion after drug-eluting stent implantation.

OBJECTIVES AND BACKGROUND: Although tissue protrusion (TP) between the stent struts after stent implantation has been implicate as a potential factor of stent failure, the incidence, natural history, and predictive factor of TP after stent implantation remains unclear. This prospective study evaluated the fate of TP after drug-eluting stent (DES) deployment using optical coherence tomography (OCT). METHOD AND RESULT: This study analyzed TP for 42 lesions after DES in which three serial OCTs, including preprocedure, postprocedure, and 1-month after the procedure were performed. TP was classified into the five groups: (a) persistent, (b) progressive, (c) healed, (d) regressive, and (e) late-acquired. Immediately after the procedure, 100 TPs in 37 lesions (88%) were identified. Of those, 53 (53%) were persistent, 3 (3%) were progressive, 20 (20%) were healed, and 24 (24%) were regressed at 1-month follow-up. Seven TPs in five patients (13%) were observed only at 1-month follow-up (late-acquired). CONCLUSION: In lesions with late-acquired TP, calcified nodule was identified as an underlying plaque morphology on preprocedural OCT. A serial OCT analysis found TP occurred not only immediately after DES implantation, but also 1-month after DES implantation.

Additional decrease in fractional flow reserve in the left anterior descending artery after hand-grip exercise during pharmacological coronary hyperemia.

Maximal hyperemia at the time of fractional flow reserve (FFR) measurement is generally induced by vasodilators, even when hyperemia at the onset of angina symptoms is caused by exercise stress. This study was designed to evaluate whether pharmacological hyperemia could be used as a substitute for exercise-induced hyperemia during FFR measurement. Twenty-two patients with angiographically intermediate stenosis in the left anterior descending artery (LAD) were prospectively enrolled. FFR measurements were repeated in the following two conditions while the pressure-wire was positioned in the same segment; (1) during pharmacological hyperemia induced by intracoronary administration of 2 mg nicorandil, (2) immediately after isotonic hand-grip exercise for 90 s (50% of maximum voluntary contraction) followed by intracoronary administration of 2 mg nicorandil. Isotonic hand-grip exercise increased systolic blood pressure (130 ± 19 versus 150 ± 22 mmHg, p < 0.001), heart rate (71 ± 11 versus 79 ± 13 bpm, p < 0.001), and cardiac output (5.1 ± 1.2 versus 5.9 ± 1.5 L/min, p < 0.001), which indicated an increased afterload on the left ventricle. After the hand-grip exercise, FFR significantly decreased from 0.86 ± 0.06 to 0.84 ± 0.06 (p < 0.001). A percent increase in systolic blood pressure and cardiac output after hand-grip exercise strongly correlated with ΔFFR (r = - 0.65, p < 0.001 and r = - 0.55, p < 0.001, respectively). An increase in cardiac output with hand-grip exercise during pharmacological hyperemia could induce an additional decrease in FFR for lesions located in the LAD.

Influence of different physiological hemodynamics on fractional flow reserve values in the left coronary artery and right coronary artery.

BACKGROUND: Although the left coronary artery (LCA) has a flow profile in that most blood flow occurs during diastole rather than systole, the right coronary artery (RCA) has a flow pattern that is less diastolic dominant. This study assessed whether coronary pressure waveforms distal to stenoses with the same fractional flow reserve (FFR) was the same between the LCA and RCA. METHODS: A total of 347 vessels from 318 patients who underwent FFR measurements were included. Conventional FFR was calculated as the ratio of the mean coronary distal pressure (Pd) to the mean aortic pressure (Pa) at maximal hyperemia. The pressure drop ratios in systole (PDRsystole) and diastole (PDRdiastole) were calculated as the sum of (Pa minus Pd) divided by the sum of Pa at the intracoronary diastolic and systolic pressure phases, respectively. RESULTS: Analysis of covariance of the regression line of correlation between conventional FFR and PDRsystole revealed that the slope was significantly greater in the RCA than in the left anterior descending artery (LAD) and left circumflex artery (LCX) (-0.765, -0.578, and -0.589, p < 0.001). On the other hand, the regression line of correlation between conventional FFR and PDRdiastole found that the slope was significantly greater in the LAD and LCX than in the RCA (-1.349, -1.318, and -1.223, p < 0.001). CONCLUSIONS: The pressure waveform distal to the stenosis differs between the LCA and RCA. In the LCA, the decrease in diastolic pressure mainly contributed to the drop in FFR, whereas in the RCA, it was the decrease in systolic pressure.

Evaluation of recombinant human erythropoietin responsiveness by measuring erythrocyte creatine content in haemodialysis patients.

BACKGROUND: One of the main causes of anaemia in patients with end-stage renal disease is relative deficiency in erythropoietin production. Eythropoiesis stimulating agent (ESA), a potent haematopoietic growth factor, is used to treat anaemia in haemodialysis patients. The effect of ESA is usually assessed by haematological indices such as red blood cell count, haemoglobin concentration and haematocrit, but erythrocyte indices do not provide information of the rapid change in erythropoietic activity. As erythrocyte creatine directly assess erythropoiesis, the aim of this study was to evaluate the effect of ESA in haemodialysis patients by measuring the erythrocyte creatine content. METHODS: ESA dose was fixed 3 months prior to the enrollment and was maintained throughout the entire study period. Erythrocyte creatine was measured with haematologic indices in 83 haemodialysis patients. Haemoglobin was also measured 3 months after. RESULTS: ESA dose (152.4 ± 62.9 vs. 82.2 ± 45.5 units/kg/week, P = 0.0001) and erythrocyte creatine (2.07 ± 0.73 vs. 1.60 ± 0.41 µmol/gHb, p = 0.0003) were significantly higher in 27 patients with haemoglobin <10 g/dL compared to 56 patients with haemoglobin ≥10 g/dL. There was a fair correlation between ESA dose and the concentration of creatine in the erythrocytes (r = 0.55, P < 0.0001). Increase in haemoglobin (>0.1 g/dL) was observed in 37 patients, whereas haemoglobin did not increase in 46 patients. Erythrocyte creatine levels were significantly higher in those patients with an increase in haemoglobin compared to those without (2.04 ± 0.64 vs. 1.52 ± 0.39 µmol/gHb, p < 0.0001). When 8 variables (ESA dose, erythropoietin resistance index, C-reactive protein, intact parathyroid hormone, iron supplementation, presence of anaemia, erythrocyte creatine and reticulocyte) were used in the multivariate logistic analysis, erythrocyte creatine levels emerged as the most important variable associated with increase in haemoglobin (Chi-square = 6.19, P = 0.01). CONCLUSION: Erythrocyte creatine, a useful marker of erythropoietic capacity, is a reliable marker to estimate ameliorative effectiveness of ESA in haemodialysis patients.

Serum Angiopoietin-Like Protein 2 and NT-Pro BNP Levels and Their Associated Factors in Patients with Chronic Heart Failure Participating in a Phase III Cardiac Rehabilitation Program.

Angiopoietin-like protein 2 (ANGPTL2) promotes chronic inflammation and plays a key role in the pathogenesis of heart failure. Cardiac rehabilitation (CR) is an integral component of heart failure management and has been shown to have anti-inflammatory effects. However, ANGPTL2 concentration in chronic heart failure patients undergoing CR has not been evaluated. This study aimed to investigate serum ANGPTL2 levels and their associated factors and compare the results with those of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with chronic heart failure undergoing phase III CR.A total of 56 patients were enrolled. Clinical characteristics including body composition, grip strength, exercise tolerance, duration of CR, blood counts and biochemistry, and echocardiographic parameters were evaluated for their association with serum ANGPTL2 and NT-proBNP levels.The median (first and third quartiles) value of ANGPTL2 was 4.05 (2.70-5.57) ng/mL. Clinical parameters that correlated with serum ANGPTL2 levels were body weight, body mass index, body fat mass, body fat percentage, anaerobic threshold (AT), C-reactive protein, and total protein (TP), which were mostly distinct from those that correlated with serum NT-proBNP levels. A multivariate analysis revealed that AT and TP were independent factors related to ANGPTL2 levels, whereas age, left ventricular ejection fraction, and left atrial dimension were independently related to NT-proBNP levels.These observations suggest that CR increases the exercise tolerance and exhibits anti-inflammatory effects simultaneously, and this situation is reflected by decreased serum ANGPLT2 and TP levels. ANGPTL2 may be a useful marker of inflammation and impaired exercise tolerance in patients with chronic heart failure.

Differential influence of lesion length on fractional flow reserve in intermediate coronary lesions between each coronary artery.

OBJECTIVES: This study evaluated whether the influence of lesion length on functional significance is similar between each target artery. BACKGROUND: In the presence of a similar moderate degree of stenosis, the fractional flow reserve (FFR) in the left anterior descending coronary artery (LAD) is more often <0.80 than in the other arteries. METHODS: A total of 221 lesions with intermediate stenosis on coronary angiography that underwent FFR measurement for the evaluation of myocardial ischemia were enrolled. Quantitative coronary angiographic analysis including percent diameter stenosis and lesion length was performed. The area under the receiver operating characteristics (ROC) curve was estimated for the best cutoff value as a predictor of FFR value of ≤0.80 for each coronary artery. RESULTS: Although lesion length was similar among the lesions with an FFR >0.80 at different locations, the mean lesion length was significantly longer for lesions in the right coronary artery (RCA) with an FFR ≤0.80 than for those in the LAD and left circumflex artery (13.4 ± 3.4 vs. 8.6 ± 3.1 vs. 12.0 ± 3.7 mm, p < .001). ROC analysis demonstrated that the optimal cutoff value of lesion length for predicting an FFR ≤0.80 was 10.0 mm in the LAD (0.56 area under the curve [AUC], 48% sensitivity, and 76% specificity), whereas 13.1 mm in the RCA (0.84 AUC, 67% sensitivity, and 93% specificity). CONCLUSIONS: The impact of lesion length on myocardial ischemia is different for each coronary artery. A longer lesion length is required in the RCA than in the LAD to achieve an FFR ≤0.80.

Heart Failure in Atrial Fibrillation　- An Update on Clinical and Echocardiographic Implications.

Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and has unfavorable consequences such as stroke, heart failure (HF), and death. HF is the most common adverse event following AF and the leading cause of death. Therefore, identifying the association between AF and HF is important to establish risk stratification for HF in AF. Recent studies suggested that left atrial and ventricular fibrosis is an important link between AF and HF, and the prognostic impact may differ with respect to HF subtype, stratified with left ventricular ejection fraction (EF). Mortality risk in patients with concurrent AF and HF with reduced EF (HFrEF) appears slightly higher compared with those with concurrent AF and HF with preserved EF (HFpEF). On the other hand, the prognostic impact of HF in AF is similar between HFrEF and HFpEF. Further, left atrial size, as well as left atrial and left ventricular functional assessment, are reported to be useful for the prediction of HF in AF, incremental to the conventional risk factors. In this review, we focus on the epidemiological, pathophysiological, and prognostic associations between AF and HF, and review the clinical and echocardiographic predictors for HF in AF.

Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are reported to prevent cardiovascular events by a mechanism possibly including diuresis and sodium excretion. In this respect, diuresis-induced compensatory upregulation of the renin-angiotensin-aldosterone (RAA) system should be clarified and we performed a randomized controlled trial using dapagliflozin, an SGLT2I. Hypertensive diabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomly assigned to a dapagliflozin group (DAPA) or a control group (CTRL) with the difference in the changes in plasma renin activity (PRA) after 24 weeks of the treatment as the primary outcome. PRA, plasma aldosterone concentration (PAC), age, sex, BMI, blood pressure, pulse rate, eGFRcys, and HbA1c were not different between the groups at baseline. After 24 weeks, the changes in the PRA from the baseline of the DAPA (n = 44) and CTRL (n = 39) groups were 6.30 ± 15.55 and 1.42 ± 11.43 ng/mL/h, respectively (p = 0.11) although the power of detection was too small. However, post hoc nonparametric analyses revealed that there was a definite increase in the PRA and PAC in the DAPA group (p < 0.0001 and p = 0.00025, respectively) but not in the CTRL group. The PRA in the DAPA group after 24 weeks treatment was significantly elevated compared to the CTRL group (p = 0.013) but not for the PAC. Accordingly, it would be suggested that dapagliflozin may not induce a profound increase, if any, in PAC after 24 weeks of treatment in hypertensive type 2 diabetic patients under RAA suppression.

Shortened red blood cell age in patients with end-stage renal disease who were receiving haemodialysis: a cross-sectional study.

BACKGROUND: The causes of anaemia in patients with end-stage renal disease include a relative deficiency in erythropoietin production and complex clinical conditions. We aimed to investigate the underlying mechanisms of anaemia in patients with end-stage renal disease who were undergoing maintenance dialysis by measuring erythrocyte creatine levels. METHODS: In a cross-sectional study, we evaluated 69 patients with end-stage renal disease who were receiving haemodialysis (n = 55) or peritoneal dialysis (n = 14). Erythrocyte creatine level, a quantitative marker of mean red blood cell (RBC) age, was measured. RESULTS: The mean RBC age was significantly shorter in the haemodialysis group than in the peritoneal dialysis group (47.7 days vs. 59.8 days, p < 0.0001), although the haemoglobin levels were comparable between the groups. A Spearman correlation coefficient analysis revealed that shortened RBC age positively correlated with transferrin saturation (r = 0.54), ferritin level (r = 0.47), and haptoglobin level (r = 0.39) but inversely related with reticulocyte (r = - 0.36), weekly doses of erythropoiesis-stimulating agents (ESAs; r = - 0.62), erythropoietin resistance index (r = - 0.64), and intradialytic ultrafiltration rate (r = - 0.32). CONCLUSIONS: Shortened RBC age was observed in patients who were receiving maintenance haemodialysis and was associated with iron deficiency, greater haptoglobin consumption, higher ESA requirements, and poor erythropoietin responsiveness, as well as with greater intradialytic fluid extraction.

Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients.

PURPOSE: Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with a favorable outcome has not been clearly identified. The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). METHODS: We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiography before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 42 patients (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler-derived early diastolic velocity (E/e'). RESULTS: There were no significant differences in patient characteristics and echocardiographic parameters at baseline. The change in LVEF from baseline to follow-up was 5.0 ± 6.9% in the tofogliflozin group and - 0.6 ± 5.5% in the control group; difference significant, p = 0.006. The change in E/e' was - 1.7 ± 3.4 in the tofogliflozin group and 0.7 ± 4.1 in the control group; difference significant, p = 0.024. CONCLUSIONS: In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

Diastolic wall strain as a predictor of age-related cardiovascular events in patients with preserved left ventricular ejection fraction.

Diastolic wall strain (DWS) was reported as a simple and feasible echocardiographic index in assessing left ventricular (LV) diastolic stiffness. We sought to evaluate whether DWS predicts age-related cardiovascular events. Patients referred for transthoracic echocardiogram, those with preserved LV ejection fraction and no clinical heart failure were studied. Cardiovascular events were ascertained using Framingham criteria (myocardial infarction, coronary insufficiency, stroke, transient ischemic attack, congestive heart failure, or cardiovascular death). DWS was calculated with a validated formula. Cox proportional hazards modeling was used to assess the risk of cardiovascular events. Of a total number of 962 patients (mean age 60.9 ± 14.9 years, 48.0% men), 69 (7.2%) developed at least 1 cardiovascular event during a mean follow-up of 43 ± 32 months. After adjusting for cardiovascular comorbidities in a multivariable model, low DWS (≦ 0.33) was a significant independent predictor of cardiovascular events [hazard ratio (HR): 1.87, 95% confidential interval (CI) 1.04-3.36, P = 0.04]. Echocardiographic assessment of DWS may help in identifying the patients at increased risk for future age-related cardiovascular events.