Impact of renal function on mid-term outcomes in heart failure patients treated with tolvaptan.

BACKGROUND:: Although tolvaptan, an electrolyte-free water diuretic for congestive heart failure (HF), is reported to have no effect on long-term mortality or HF-related morbidity, there may exist some subgroups of patients who may receive beneficial effect of tolvaptan. The purpose of this study was to identify clinical factors associated with mid-term effect of tolvaptan on clinical outcomes of patients who discharged after acute HF. METHODS:: We retrospectively analyzed 140 patients (88 male; mean age, 77.1 ± 11.0 years) with acute HF who received tolvaptan (initial dose 8.6 ± 3.6 mg/day) during their hospitalization. They were divided into two groups according to how the tolvaptan was used at discharge; 77 in the tolvaptan-continued group and 63 in the discontinued group. RESULTS:: The Cox proportional hazards model revealed that eGFR was the only independent predictor for the occurrence of mid-term cardiac events (composite of re-hospitalization due to HF and all-cause death; aHR = 0.9870, p = 0.02597). The Kaplan-Meier survival curves of the two groups demonstrated no difference in cumulative event-free rates. In the subgroup with preserved renal function at admission (eGFR ⩾ 30 ml/min/1.73 m2), the continuous use of tolvaptan increased composite events (aHR = 2.130, p = 0.02549). CONCLUSIONS:: The continuous use of tolvaptan after discharge did not affect mid-term cardiac events of HF overall but may be associated with increased cardiac events in the subgroup with preserved renal function. These findings suggest that the tolvaptan administration might need to be limited to treatment of in-hospital acute HF.

CVIT expert consensus document on primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) in 2018.

While primary percutaneous coronary intervention (PCI) has significantly contributed to improve the mortality in patients with ST segment elevation myocardial infarction even in cardiogenic shock, primary PCI is a standard of care in most of Japanese institutions. Whereas there are high numbers of available facilities providing primary PCI in Japan, there are no clear guidelines focusing on procedural aspect of the standardized care. Whilst updated guidelines for the management of acute myocardial infarction were recently published by European Society of Cardiology, the following major changes are indicated; (1) radial access and drug-eluting stent over bare metal stent were recommended as Class I indication, and (2) complete revascularization before hospital discharge (either immediate or staged) is now considered as Class IIa recommendation. Although the primary PCI is consistently recommended in recent and previous guidelines, the device lag from Europe, the frequent usage of coronary imaging modalities in Japan, and the difference in available medical therapy or mechanical support may prevent direct application of European guidelines to Japanese population. The Task Force on Primary Percutaneous Coronary Intervention of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) has now proposed the expert consensus document for the management of acute myocardial infarction focusing on procedural aspect of primary PCI.

Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone: Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether Pioglitazone Protects DM Patients Against Re-Infarction (PPAR Study).

BACKGROUND: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM. METHODS: In this multicentre, prospective, randomised, open, blinded-endpoint trial, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke. FINDINGS: HbA1C levels were 5·9 and 5·8% (p = 0·71) at baseline and 6·0 and 5·8% (p < 0·01) at 2 years for the control and pioglitazone groups, respectively.The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662-1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786-32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051-3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618-1·237, p = 0·45). INTERPRETATION: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.

Does Treatment of Impaired Glucose Tolerance Improve Cardiovascular Outcomes in Patients with Previous Myocardial Infarction?

PURPOSE: We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT). METHODS: This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day, n = 424) or no drugs (n = 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure. RESULTS: The age, ratio of males, and HbA1C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan-Meier analysis showed no significant between-group difference with respect to cardiovascular events [12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82-1.86)]; there were no significant differences in secondary endpoints. CONCLUSION: Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00212017.

Overview of the 81st Annual Scientific Meeting of the Japanese Circulation Society　- Cardiovascular Medicine for the Next Generation.

The 81stAnnual Scientific Meeting of the Japanese Circulation Society was held in Kanazawa, Japan, on March 17-19, 2017 under a miraculously clear sky. The frontlines of healthcare and medicine are dramatically changing. Thus, "Cardiovascular Medicine for Next Generation" was chosen as the main theme of this meeting. The program was constructed around major identified issues, including renewal of our understanding of basic cardiovascular medicine, translational research, and preventive molecular medicine, all of which are anticipated to transcend the medical field over the next generation. Despite the provincial location, 15,672 participants, including more than 400 from overseas countries, attended the 3-day meeting, and there were in-depth discussions in the various sessions. In particular, to our great pleasure, Her Imperial Highness Princess Takamado kindly attended the opening ceremony and extended congratulations to us. The meeting successfully completed and we sincerely appreciate the great cooperation and support from all affiliates.

Impact of combined lipid lowering and blood pressure control on coronary plaque: myocardial ischemia treated by percutaneous coronary intervention and plaque regression by lipid lowering and blood pressure controlling assessed by intravascular ultrasonography (MILLION) study.

The aim of the study was to elucidate the aggressive reduction of both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) reduced coronary atherosclerotic plaque volume compared with a standard treatment of LDL-C and BP in Japanese patients with coronary artery disease (CAD). This study is a prospective, randomized, and open-labelled with a blind-endpoint evaluation study. A total of 97 patients (81 men, mean age 62.0 ± 9.6) with CAD undergoing intravascular ultrasonography (IVUS)-guided percutaneous coronary intervention (PCI) were randomized, and 68 patients had IVUS examinations at baseline and at 18-24 months follow-up. Patients were randomly assigned to standard or aggressive strategies targeting LDL-C and a BP of 100 mg/dL and 140/90 mmHg vs. 70 mg/dL and 120/70 mmHg, respectively. The primary endpoint was the percent change in coronary plaque volume. Both standard and aggressive strategies succeeded to achieve target levels of LDL-C and BP; 74.9 ± 14.7 vs. 63.7 ± 11.9 mg/dL (NS) and 124.1 ± 9.4/75.8 ± 7.7 vs. 113.6 ± 9.6/65.8 ± 9.4 mmHg (systolic BP; NS, diastolic BP; p < 0.05), respectively. Both groups showed a significant reduction in the coronary plaque volume of -9.4 ± 10.7% and -8.7 ± 8.6% (NS) in standard and aggressive therapies, respectively. Both standard and aggressive intervention significantly regressed coronary plaque volume by the same degree, suggesting the importance of simultaneous reductions of LDL-C and BP for prevention of CAD.

Impact of combined lipid lowering with blood pressure control on coronary plaque regression: rationale and design of MILLION study.

A line of epidemiological studies suggests that the accumulation of coronary risk factors promotes the progression of coronary atherosclerosis. Recent clinical studies showed that aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy using statins could regress coronary atheroma and reduce major cardiovascular events. Additionally, therapy that controlled amlodipine-based blood pressure reduced major cardiovascular events in patients with hypertension compared with an atenolol-based regimen. An open-label randomized multicenter study is primarily planned to evaluate the changes in coronary atheroma volume using intravascular ultrasonography 18-24 months after intensive lowering of LDL-cholesterol and blood pressure compared with a standard therapy indicated by current guidelines in Japanese patients with coronary artery disease (CAD). The secondary endpoints include changes in serum lipid levels, inflammatory markers, glucose markers and blood pressure. In total, 100 subjects with CAD who are undergoing percutaneous coronary intervention will be tested. The MILLION study will provide new evidence and therapeutic standards for the prevention of CAD in Japanese patients by controlling both LDL-C levels and blood pressure.

Impact of lesion morphology and associated procedures for left main coronary stenting on angiographic outcome after intervention: sub-analysis of Heart Research Group of Kanazawa, HERZ, Study.

Whether the lesion morphology and associated interventional procedures for the left main coronary artery disease (LMCA) could affect clinical outcome is still controversial. Therefore, we examined the impact of lesion morphology and associated procedures on clinical and angiographic outcomes of stenting for the LMCA. Among 7,660 patients with coronary intervention registered, we analyzed early angiographic results of 228 patients (179 men, mean age 69.4 years) concerned with LMCA lesions. In 121 out of 228 patients having long-term angiographic results, we examined the occurrence of major adverse coronary events (MACE) particularly in terms of the presence of acute coronary syndrome (ACS), the kind of stents, bear metal or drug eluting, the lesion morphology and associated procedures. Early angiographic success rate of LMCA stenting was 100 %, and clinical success rate was 94.3 %. During follow-up period for 3 years, MACE was observed in 17 patients. Under these conditions, multiple stenting (p < 0.01) and complicated procedures such as such as Y-stent, T-stent and crush stent (p < 0.01) were listed as risks for MACE, although there was no statistical difference in kinds of stent. Multivariate analysis demonstrated the significant disadvantage of complicated procedures using the bear metal stent on the occurrence of MACE (p < 0.01). These results demonstrate that the complicated procedures have great impact on clinical and angiographic outcomes after stenting for LMCA lesions, and suggest the simple procedure with a single stent for LMCA lesions in the present cohort. Whether the presence of ACS can affect the prognosis should further be sought.

Three cases of iatrogenic coronary ostial stenosis after aortic valve replacement.

BACKGROUND: Iatrogenic coronary ostial stenosis (ICOS) is a rare but potentially life-threatening complication of aortic valve replacement (AVR). This complication is usually diagnosed by angiography and treated with aortocoronary bypass surgery. CASE REPORTS: In the present 3 cases pre-operative coronary angiography confirmed normal coronary arteries and they underwent uncomplicated AVR. Coronary lesions were clinically manifest within 4 months after surgery, and repeat coronary angiography demonstrated bilateral ostial stenosis in 1 patient and left main trunk stenosis in the other 2. Two cases were detected by multidetector computed tomography (MDCT) before angiography. MDCT and Virtual Histology suggested fibrous tissue formation in the lesions. All 3 patients were successfully underwent percutaneous coronary intervention (PCI) and stenting. The post-procedure clinical course has been uneventful, except for elective stenting of a recurrent lesion in 1 asymptomatic patient. CONCLUSIONS: The incidence of ICOS after AVR is low. Noninvasive MDCT is useful for early diagnosis and PCI is a possible alternative treatment. ICOS may be caused by fibrous tissue formation, and therefore be distinct from conventional atherosclerosis.

gamma-Irradiation-induced DNA damage enhances NO production via NF-kappaB activation in RAW264.7 cells.

We investigated the mechanism of augmentation of nitric oxide (NO) production in the murine macrophage cell line RAW264.7 after gamma-irradiation. The cells treated with interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) showed enhanced NO production by gamma-irradiation in a dose-dependent manner, accompanying the induction of inducible nitric oxide synthase (iNOS) expression. Nuclear factor kappa B (NF-kappaB) activation was induced 1 h after gamma-irradiation dose-dependently, which was detected by the degradation of I-kappaB. Inhibitors of I-kappaB degradation, MG132 and N(alpha)-p-tosyl-L-lysine chloromethyl ketone (TLCK), suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production, showing that gamma-irradiation induced NO production via NF-kappaB activation. Although NF-kappaB is known to be a redox-sensitive transcription factor, the antioxidant agents N-acetyl-cysteine (NAC) and 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (trolox) showed no suppression and treatment with H(2)O(2) showed only slight enhancement of IFN-gamma-induced NO production. The DNA damaging agents camptothecin and etoposide enhanced IFN-gamma-induced NO production and showed I-kappaB degradation, indicating that the increase in NO production was due to direct DNA damage. Furthermore, 3-aminobenzamide (3AB) and benzamide, inhibitors of poly (ADP-ribose) polymerase (PARP) that are activated upon recognition of DNA strand breaks, suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production and the I-kappaB degradation by gamma-irradiation. We concluded that (1) the increase in NO production was due to direct DNA damage by gamma-irradiation, and that (2) PARP activation through DNA damage induced NF-kappaB activation, leading to iNOS expression and NO production.