Hypoxia-inducible factor-prolyl hydroxylase inhibitor Roxadustat (FG-4592) reduces renal fibrosis in Dahl salt-sensitive rats.

OBJECTIVE: Although hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anemia, their effects on cardiac and renal dysfunction remain unknown. We previously reported on Dahl salt-sensitive rats, in a rat model of salt-sensitive hypertension, that exhibited anemia and impaired expression of duodenal iron transporters after the development of hypertensive cardiac and renal dysfunction. Therefore, we investigated the effects of Roxadustat (FG-4592), an HIF-PH inhibitor, on anemia, iron regulation, and cardiac and renal dysfunction in Dahl salt-sensitive rats. METHODS: Six-week-old male Dahl salt-sensitive rats were fed a normal or high-salt diet for 8 weeks. A further subset of Dahl salt-sensitive rats, that were fed a high-salt diet, was administered Roxadustat for 8 weeks. RESULTS: Dahl salt-sensitive rats fed a high-salt diet developed hypertension, cardiac and renal dysfunction, and anemia after 8 weeks of feeding. Roxadustat increased hemoglobin and serum erythropoietin levels in Dahl salt-sensitive rats fed a high-salt diet. With regard to the iron-regulating system, Roxadustat lowered hepatic hepcidin gene expression and increased the gene expression of duodenal iron transporters, such as cytochrome b and divalent metal transporter 1 , in Dahl salt-sensitive rats fed a high-salt diet. Roxadustat did not affect the development of hypertension and cardiac hypertrophy in Dahl salt-sensitive rats with a high-salt diet; however, Roxadustat treatment attenuated renal fibrosis in these rats. CONCLUSIONS: Roxadustat ameliorated anemia with affecting the gene expression of the iron-regulating system, and did not affect cardiac hypertrophy but attenuated renal fibrosis in Dahl salt-sensitive rats fed a high-salt diet.

A randomized, double-blind, placebo-controlled pilot trial of low-intensity pulsed ultrasound therapy for refractory angina pectoris.

BACKGROUND: Despite the advances in the treatment of cardiovascular diseases, effective treatment remains to be established to improve the quality of life and prognosis of patients with chronic coronary syndromes. This study was aimed to evaluate the effectiveness and safety of the low-intensity pulsed ultrasound (LIPUS) therapy, which we have developed as a novel non-invasive angiogenic therapy through upregulation of endothelial nitric oxide synthase (eNOS). METHODS AND FINDINGS: We conducted a randomized, double-blind, placebo-controlled (RCT) pilot trial of the LIPUS therapy for patients with refractory angina pectoris. The patients who received optimal medical therapy without indication of PCI or CABG due to the lack of graftability or complexity of coronary lesions were enrolled. They were randomly divided into the LIPUS treatment group (N = 31) and the placebo group (N = 25) in a 1:1 fashion. The LIPUS therapy was performed in a transthoracic manner for 20 min for 3 sections each (mitral, papillary muscle, and apex levels) under the conditions that we identified; frequency 1.875 MHz, intensity 0.25 MPa, and 32 cycles. The primary endpoint was weekly use of nitroglycerin. Secondary endpoints included stress myocardial perfusion imaging and others. The average weekly nitroglycerin use (times/week) was decreased from 5.50 to 2.44 in the LIPUS group and from 5.94 to 2.83 in the placebo group. The changes in the average weekly nitroglycerin use were comparable; -3.06 (95% CI: -4.481 to -1.648) in the LIPUS group (P<0.01) and -3.10 (95% CI: -4.848 to -1.356) in the placebo group (P<0.01). No adverse effects were noted. CONCLUSIONS: In the present study, the LIPUS therapy did not further ameliorate chest pain as compared with optimal medications alone in patients with refractory angina pectoris. The present findings need to be confirmed in another trial with a large number of patients. (Registration ID: UMIN000012369).

Communicating Coronary and Ventricular Pseudoaneurysms Complicating Coronary Artery Perforation.

We present the case of a 75-year-old man who experienced rebleeding after surgical treatment of grade III coronary perforation, resulting in intertwined complications including communicating coronary and ventricular pseudoaneurysms. The percutaneous intervention of sealing the rebleeding site with a covered stent implantation managed this rare pseudoaneurysm successfully. (Level of Difficulty: Advanced.).

Crosstalk between Iron and Arteriosclerosis.

Iron is an important element for life; however, intracellular labile iron overload can lead to the generation of reactive oxygen species and cellular damage. Although iron is mainly utilized for heme synthesis and is incorporated into hemoglobin, body iron status is often implicated in the pathogenesis of cardiovascular diseases. In a cell, iron is used for basic processes such as cell growth, maintenance, and repair. Thus, iron is considered to be involved in the pathogenesis of arteriosclerosis. In fact, clinical and experimental studies have shown an association between iron and arteriosclerosis. These data suggest the crosstalk between iron and arteriosclerosis. However, iron metabolism in arteriosclerosis is often complicated, and the systemic and cellular mechanisms of iron homeostasis in arteriosclerosis remain completely unsolved. Thus, in this review, we aimed to examine the role of iron in arteriosclerosis.

Anemia has an impact on prognosis in heart failure with preserved ejection fraction with mild chronic kidney disease.

BACKGROUND: Anemia and chronic kidney disease (CKD) are common in patients with heart failure with preserved left ventricular fraction (HFpEF). However, it is entirely unknown about the impact of anemia on prognosis in HFpEF patients with CKD. In this study, we investigated the impact of anemia on prognosis and the optimal hemoglobin (Hb) levels to predict prognosis in HFpEF patients with CKD. METHODS AND RESULTS: We prospectively examined 523 consecutive HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL /min/1.73 m2. The prevalence rate of anemia was 78% in HFpEF patients with CKD by using the World Health Organization criteria. Kaplan-Meier analysis for all-cause mortality and heart failure rehospitalization demonstrated that anemic patients had poor prognosis compared with non-anemic patients in HFpEF patients with CKD, but not those without CKD. According to the degree of CKD, anemia affected prognosis in HFpEF patients with mild CKD (45 ≤ eGFR < 60), but not those with moderate to severe CKD (15 ≤ eGFR < 45). Additionally, multivariate analysis revealed that anemia and Hb levels were independent predictors of composite outcomes in HFpEF patients with mild CKD, but not those with moderate to severe CKD. Finally, survival classification and regression tree analysis showed that the optimal Hb levels to predict composite outcomes were 10.7 g/dL in those with mild CKD. CONCLUSIONS: Anemia has an impact on prognosis in HFpEF patients, especially among those with mild CKD.

Mechanisms of gradual pressure drop in angiographically normal left anterior descending and right coronary artery: Insights from wave intensity analysis.

BACKGROUND: This study evaluated the mechanism of decline in coronary pressure from the proximal to the distal part of the coronary arteries in the left anterior descending (LAD) versus the right coronary artery (RCA) from the insight of coronary hemodynamics using wave intensity analysis (WIA). METHODS: Twelve patients with angiographically normal LAD and RCA were prospectively enrolled. Distal coronary pressure, mean aortic pressure, and average peak velocity were measured at 4 different positions: 9, 6, 3, and 0 cm distal from each coronary ostium. RESULTS: The distal-to-proximal coronary pressure ratio during maximum hyperemia gradually decreased in proportion to the distance from the ostium (0.92±0.03 and 0.98±0.03 at 9 cm distal to the LAD and RCA ostium). WIA showed the dominant forward-traveling compression wave gradually decreased and the backward-traveling suction wave gradually decreased in proportion to the decrease in coronary pressure through the length of the non-diseased LAD but not the RCA. CONCLUSIONS: The pushing wave and suction wave intensities on WIA were diminished in proportion to the distance from the ostium of the LAD despite the wave intensity not changing across the length of the RCA, which may lead to gradual intracoronary pressure drop in the angiographically normal LAD.

Iron and cardiovascular diseases.

Iron is a necessary element for life; however, excess iron leads to oxidative stress by the Fenton reaction. Iron deficiency is prevalent in patients with heart failure, while iron overload is associated in the pathogenesis of atherosclerosis. These findings suggest the "iron paradox" in cardiovascular diseases. Iron metabolism in cardiovascular diseases is complex, and the mechanisms regulating systemic and cellular iron metabolism in cardiovascular diseases remain completely unknown. In this review, we focus on the role of iron in cardiovascular diseases.

Reduced lifespan of erythrocytes in Dahl/Salt sensitive rats is the cause of the renal proximal tubule damage.

We studied the mechanisms of anemia and the influence of anemia on renal pathology in Dahl/Salt Sensitive (Dahl/SS) rat, a model of cardio-renal-anemia syndrome. Erythrocyte lifespan was shortened and associated with decreased hemoglobin level in the Dahl/SS rats given high-salt diet. Serum haptoglobin decreased, reticulocytes increased, and erythropoiesis in the bone marrow and extramedullary hematopoiesis in the spleen was markedly stimulated by increased serum erythropoietin in them. As a mechanism of hemolysis, we investigated the incidence of eryptosis, suicidal death of erythrocytes. Eryptosis was increased, and red blood cell-derived microparticles, small particle which are generated in hemolytic disease, were also increased in Dahl/SS rats fed with high-salt diet. Deposition of hemosiderin and mitochondrial morphologic abnormality, a sign of ferroptosis, in proximal renal tubules was associated with intravascular hemolysis. Treatment with deferasirox, an oral iron chelator, reduced the renal proximal tubular injury and the glomerular sclerosis in Dahl/SS rats fed with high-salt diet. In conclusion, reduced half-life of erythrocytes induced by hemolysis is the major cause of anemia in Dahl/SS rat. Iron accumulation induced by hemolysis causes renal proximal tubule injury and accelerates renal damage in this model.

Effect of Oral Qing-Dai Medication on Pulmonary Arterial Pressure Levels in Patients With Ulcerative Colitis.

BACKGROUND: Qing-Dai (QD) treatment of patients with ulcerative colitis (UC) sometimes causes pulmonary arterial hypertension (PAH). However, the relationship of QD treatment to pulmonary arterial systolic pressure (PASP) in patients with UC has not been clarified.Methods and Results:The 27 patients with UC who were screened for PAH by transthoracic echocardiography (TTE) and underwent repeat TTE at 1 year were analyzed in this prospective observational study. Mean age was 44.0 years old, and median follow-up duration was 392. During the follow-up, 21 patients continued QD treatment (continuous group) and 6 patients discontinued the treatment (discontinuous group). In all patients, no significant difference in PASP levels between baseline and at follow-up was observed (21.4 vs. 21.3 mmHg, P=0.802). Furthermore, the mean PASP of patients in the continuous group did not differ from baseline to follow-up (21.4 mmHg to 22.6 mmHg, P=0.212); however, in the discontinuous group mean PASP was significantly decreased (21.5 mmHg to 16.8 mmHg, P=0.005). Moreover, changes in PASP from baseline to follow-up differed between the continuous and discontinuous groups (+1.1 mmHg vs. -4.7 mmHg, P=0.004). In addition, multivariable analyses revealed that only the duration of oral QD at baseline affected the increase of PASP. CONCLUSIONS: In patients with UC, QD treatment may have an undesirable association with an increase in PASP.

Impact of peripheral artery disease on prognosis after myocardial infarction: The J-MINUET study.

BACKGROUND: Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events, including myocardial infarction (MI), stroke, and cardiovascular death. However, the impact of PAD on prognosis in Japanese patients with acute MI remains unclear. METHODS: The Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET) is a prospective multicenter registry that registered 3283 patients with acute MI. Among them, 2970 patients with available data of PAD were divided into the following 4 groups: 2513 patients without prior MI or PAD (None group), 320 patients with only prior MI (Prior MI group), 100 patients with only PAD (PAD group), and 37 patients with both previous MI and PAD (Both group). The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina. RESULTS: The 3-year cumulative incidence of the primary endpoint was 26.9% in None group, 41.4% in Prior MI group, 48.0% in PAD group, and 60.3% in Both group (p < 0.001). In multivariate analysis, hazard ratio using None group as reference was 1.55 (95% confidence intervals 1.25-1.91; p < 0.001) for MI group, 2.26 (1.61-3.07; p < 0.001) for PAD group, and 2.52 (1.52-3.90; p < 0.001) for Both group. CONCLUSIONS: Concomitant PAD was associated with poor prognosis in Japanese patients with acute MI.

Questionnaire in patients with aborted sudden cardiac death due to coronary spasm in Japan.

OBJECTIVES: We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. METHODS: A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter-defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. RESULTS: The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p < 0.001). Although 16 institutions thought that the spasm provocation tests under the medications had some clinical usefulness of suppressing the next fatal arrhythmias, spasm provocation tests under the medication were performed in just 4 institutions. CONCLUSIONS: In the real world, there was no fundamental strategy for patients with ASCD due to coronary spasm. Each institution has each strategy for these patients. Cardiologists should have the same strategy and the same knowledge about ASCD patients due to coronary spasm in the future.

Manipulation of beta-adrenergic receptor in pressure-overloaded murine hearts mimics adverse and reverse cardiac remodeling.

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure. In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically.

Echocardiography Tips in the Emergency Room.

The emergency room is a principal entrance for the initial management of patients with acute heart failure. Echocardiography may be performed by cardiologists and noncardiologists in the emergency room. Echocardiographic studies require effective technical skills and precise diagnostic knowledge. This article contributes to physicians in the emergency room, general practitioners in training, and medical staff who engage in emergency medicine. This article emphasized the role of echocardiography in light of pathophysiology of acute heart failure in the emergency room and refining the clinical workflow by integrating conventional and innovative knowledge for the initial management of acute heart failure.

Impact of IVUS-Derived Vessel Size on Midterm Outcomes After Stent Implantation in Femoropopliteal Lesions.

Purpose: To identify intravascular ultrasound (IVUS) findings that predict midterm stent patency in femoropopliteal (FP) lesions. Materials and Methods: A retrospective analysis was undertaken of 335 de novo FP lesions in 274 consecutive patients (mean age 72.4±8.2 years; 210 men) who had IVUS assessment before and after successful stent implantation. The mean lesion length was 13.2±9.8 cm. The primary outcome was primary patency at 24 months, defined as freedom from major adverse limb event (MALE) and in-stent restenosis (ISR). MALE was defined as major amputation or any target lesion revascularization (TLR). ISR was defined by a peak systolic velocity ratio >2.4 by duplex ultrasonography. Logistic regression analyses were performed to identify independent predictors of stent patency at 24 months; the results are presented as the odds ratio (OR) and 95% confidence interval (CI). Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal threshold for prediction of stent patency at 24 months. Results: Over the 24-month follow-up, 18 (7%) patients died and 43 (15%) of 286 lesions were responsible for MALE (42 TLRs and 1 major amputation). Primary patency was estimated at 82.5% (95% CI 78.1% to 86.9%) at 12 months and 73.2% (95% CI 67.9% to 78.5%) at 24 months. Multivariable analysis revealed that longer lesion length (OR 0.89, 95% CI 0.82 to 0.97, p<0.01) was an independent predictor of declining patency, while cilostazol use (OR 3.45, 95% CI 1.10 to 10.78, p=0.03) and increasing distal reference external elastic membrane (EEM) area (OR 1.18, 95% CI 1.02 to 1.37, p=0.03) were associated with midterm stent patency. ROC curve analysis identified a distal reference EEM area of 29.0 mm2 as the optimal cut-point for prediction of 24-month stent patency (area under the ROC curve 0.764). Kaplan-Meier estimates of 24-month primary patency were 83.7% (95% CI 78.3% to 89.2%) in lesions with a distal EEM area >29.0 mm2 vs 53.1% (95% CI 42.9% to 63.3%) in those with a distal EEM area ≤29.0 mm2 (p<0.001). Conclusion: In FP lesions with a larger distal vessel area estimated with IVUS, stent implantation can be considered as a reasonable treatment option, with the likelihood of acceptable midterm results.

Clinical Significance and Prognostic Value of Novel Echocardiographic Index for the Severity of Mitral Regurgitation.

Background: Recently, the left ventricular early inflow-outflow index (LVEIO), calculated by dividing mitral E-wave velocity by the left ventricular outflow velocity time integral, has been proposed as a simple method for evaluating mitral regurgitation (MR). This study determined the optimal LVEIO threshold to assess severe MR with different etiologies and assessed its prognostic value. Methods and Results: The records of 18,692 consecutive patients who underwent echocardiography were reviewed. MR was classified into 4 groups: Grade 0/1, no, trivial, or mild MR; Grade 2, moderate MR; Grade 3, moderate to severe MR; and Grade 4, severe MR. The mean (±SD) LVEIO of Grades 0/1, 2, 3, and 4 was 3.6±1.4, 6.0±2.5, 7.4±3.1, and 9.5±2.8, respectively. An optimal LVEIO threshold of 5.4 was determined to distinguish moderate to severe or severe MR from non-severe MR (sensitivity 84%, specificity 91%). Kaplan-Meier survival analysis revealed high mortality in the group with LVEIO ≥5.4 (P=0.009, hazard ratio 1.833). This was found only in primary MR when separate analyses were performed according to etiology. Multivariate analysis revealed that LVEIO was an independent predictor for all-cause death only in primary MR. Conclusions: Using appropriate thresholds, LVEIO is a simple and useful method to diagnose severe MR regardless of etiology. LVEIO can also be useful for predicting prognosis in primary MR.

Anomalous origin of the coronary artery coursing between the great vessels presenting with a cardiovascular event (J-CONOMALY Registry).

AIMS: Anomalous origin of the coronary artery (AOCA) with an inter-arterial course (IAC) between the great vessels poses a risk for a life-threatening cardiovascular event. We assessed, in a registry-based study, the clinical features, treatment strategies, and prognoses of life-threatening cardiovascular events ensuant to AOCA. METHODS AND RESULTS: Included were 65 AOCA patients (48 men/17 women, aged 41 ± 23 years) from 40 clinical centres who had experienced sudden cardiac arrest (SCA) (n = 30), acute myocardial infarction (AMI) (n = 5), angina (n = 23), or syncope (n = 7). The anomalous vessel was the right coronary artery in 72% of patients and left coronary artery in 28%; the ostium was slit-like in 42%. Coronary luminal narrowing ≥75% was absent in patients with SCA or syncope (86% and 57%, respectively), but occlusion or narrowing was seen in those with AMI (100%) or angina (52%). Age ≤40 years, male sex, sporting activity, absence of prodromal symptoms, acutely angled (≤30°) take-off from the aorta, and absence of luminal narrowing of the IAC segment were associated with SCA in this patient group. Coronary vasospasm was inducible in 12 of 17 patients without coronary narrowing. Management included surgical revascularization (n = 26) percutaneous coronary intervention (n = 9), and medical treatment (n = 26). Four SCA patients died while hospitalized; no others died during the median 5.0 (range, 1.8-7.0)-year follow-up period. CONCLUSIONS: In patients with AOCA, age ≤40 years, male sex, sporting activity, and an acute take-off angle appear to be risk factors for SCA. Appropriate management can be beneficial. Confirmation in a large-scale study is warranted.

Effects of Heterozygous TfR1 (Transferrin Receptor 1) Deletion in Pathogenesis of Renal Fibrosis in Mice.

Renal fibrosis is the final pathological process common for several types of end-stage renal diseases, including obstructive nephropathy and diabetic kidney disease. Substantial renal iron loads and oxidative stress have been reported to contribute to the development of renal diseases. TfR1 (transferrin receptor 1) plays a crucial role in cellular iron transport. However, there are no studies investigating TfR1 in the pathophysiology of renal fibrosis. Here, we investigate the role of TfR1 in the development of renal fibrosis. Primarily, to ascertain an association of TfR1 in the pathophysiology of renal fibrosis, we induced unilateral ureteral obstruction in wild-type (WT) and heterozygous TfR1 deleted (TfR1+/-) mice. TfR1+/- mice exhibited attenuated renal fibrosis, along with reduced renal expression of ferritin and 4-hydroxynonenal as compared with WT mice after unilateral ureteral obstruction. In addition, renal expression of TGFß-RI (transforming growth factor-ß receptor I) and Smad2, downstream signaling of TGFß-RI was attenuated in TfR1+/- mice compared with WT mice after unilateral ureteral obstruction. Next, we investigated the role of TfR1 in the development of diabetic kidney disease. No difference was observed in blood glucose levels and urinary albumin:creatinine ratios between WT and TfR1+/- diabetic mice after streptozotocin administration. In contrast, TfR1+/- mice showed suppressed renal fibrosis, along with reduced renal expression of ferritin, 4-hydroxynonenal, TGFß-RI, and Smad2 compared with WT mice after streptozotocin administration. These results suggest that TfR1 plays an important role in the development of renal fibrosis.