Publications by authors named "Wataru Shimizu"

620 Publications

Clinical features and long-term prognosis of patients with congestive heart failure taking tolvaptan: a comparison of patients with preserved and reduced left ventricular ejection fraction.

Heart Vessels 2021 Oct 14. Epub 2021 Oct 14.

Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5 Bunkyo-ku, Sendagi, Tokyo, 113-0022, Japan.

Few studies have investigated the clinical benefit of the long-term use of tolvaptan (TLV) for heart failure (HF). This study evaluated the long-term prognosis of patients administered TLV for > 1 year among patients who had HF with preserved ejection fraction (HFpEF) and those who had HF with reduced ejection fraction (HFrEF). Overall, 591 consecutive patients were admitted to our hospital and administered TLV for HF between 2011 and 2018. We retrospectively enrolled 147 patients who were administered TLV for > 1 year. We divided them into the HFpEF group (n = 77, 52.4%) and the HFrEF group (n = 70; 47.6%). Their clinical backgrounds and long-term prognosis were examined. Compared with the patients in the HFrEF group, the patients in the HFpEF group were significantly older and included more women. Moreover, the HFpEF group showed significantly lower all-cause mortality (38.6% vs. 24.7%; log-rank, P = 0.014) and cardiovascular mortality during the average 2.7-year follow-up. Univariate analysis revealed that all-cause mortality was correlated with male sex, HFpEF, and changes in serum creatinine levels from baseline. Multivariate analysis revealed that HFpEF was an independent influencing factor for all-cause mortality (hazard ratio, 0.44; 95% confidence interval, 0.23-0.86; P = 0.017). Long-term administration of TLV may be more beneficial for HFpEF than for HFrEF.
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http://dx.doi.org/10.1007/s00380-021-01957-1DOI Listing
October 2021

Impact of the COVID-19 Pandemic on ST-elevation Myocardial Infarction from a Single-center Experience in Tokyo.

Intern Med 2021 Sep 25. Epub 2021 Sep 25.

Division of Cardiovascular Intensive Care, Nippon Medical School Hospital, Japan.

Objective The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on global healthcare systems. Some studies have reported the negative impact of COVID-19 on ST-elevation myocardial infarction (STEMI) patients; however, the impact in Japan remains unclear. This study investigated the impact of the COVID-19 pandemic on STEMI patients admitted to an academic tertiary-care center in Tokyo, Japan. Methods In this retrospective, observational, cohort study, we included 398 consecutive patients who were admitted to our institute from January 1, 2018, to March 10, 2021, and compared the incidence of hospitalization, clinical characteristics, time course, management, and outcomes before and after March 11, 2020, the date when the World Health Organization declared COVID-19 a pandemic. Results There was a 10.7% reduction in hospitalization of STEMI patients during the COVID-19 pandemic compared with that in the previous year (117 vs. 131 cases). During the COVID-19 pandemic, the incidence of late presentation was significantly higher (26.5% vs. 12.1%, p<0.001), and the onset-to-door (241 [IQR: 70-926] vs. 128 [IQR: 66-493] min, p=0.028) and door-to-balloon (72 [IQR: 61-128] vs. 60 [IQR: 43-90] min, p<0.001) times were significantly longer than in the previous year. Furthermore, the in-hospital mortality was higher, but the difference was not significant (9.4% vs. 5.0%, p=0.098). Conclusions The COVID-19 pandemic significantly impacted STEMI patients in Tokyo and resulted in a slight decrease in hospitalization, a significant increase in late presentation and treatment delays, and a slight but nonsignificant increase in mortality. In the COVID-19 era, the acute management system for STEMI in Japan must be reviewed.
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http://dx.doi.org/10.2169/internalmedicine.8220-21DOI Listing
September 2021

A case of effective Delorme's procedure for colonic mucosal prolapse after intersphincteric resection.

J Surg Case Rep 2021 Sep 14;2021(9):rjab359. Epub 2021 Sep 14.

Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University Hospital, Hiroshima, Japan.

Recent surgical technical improvements, such as endoscopic surgery with intersphincteric resection (ISR), could help avoid a permanent colostomy for patients with low-lying rectal tumors. However, the problems associated with anal dysfunction following ISR remain unresolved. We performed ISR and temporary ileostomy in a patient with low-lying rectal cancer. After evaluating the stability of the anastomosis, we planned to close the ileostomy, but the patient developed post-operative colonic mucosal prolapse (CMP). Although there are treatment methods available for CMP, there is no consensus on the treatment for post-operative CMP. In this case, we performed Delorme's procedure because the method has been reported to have advantages in terms of improving post-operative anal function. Post-operative anorectal manometry showed improvement in maximum squeeze pressure, and the patient's anal function improved; subsequently, ileostomy closure was performed. Delorme's procedure may be useful for patients with CMP after ISR to achieve good post-operative anal function.
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http://dx.doi.org/10.1093/jscr/rjab359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440137PMC
September 2021

Impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after catheter ablation of atrial fibrillation: insights from AF frontier ablation registry.

Heart Vessels 2021 Sep 15. Epub 2021 Sep 15.

National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

The impact of catheter ablation for atrial fibrillation (AF) on cardiovascular events and mortality is controversial. We investigated the impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after AF ablation from a Japanese multicenter cohort of AF ablation. We investigated 3326 consecutive patients (25.8% female, mean age 63.3 ± 10.3 years) who underwent catheter ablation for AF from the atrial fibrillation registry to follow the long-term outcomes and use of anti coagulants after ablation (AF frontier ablation registry). The primary endpoint was a composite of stroke, transient ischemic attack, cardiovascular events, and all-cause death. During a mean follow-up of 24.0 months, 2339 (70.3%) patients were free from AF after catheter ablation, and the primary composite endpoint occurred in 144 (4.3%) patients. The AF nonrecurrence group had a significantly lower incidence of the primary endpoint (1.8 per 100 person-years) compared with the AF recurrence group (3.0 per 100 person-years, p = 0.003). The multivariate analysis revealed that freedom from AF (hazard ratio 0.61, 95% confidence interval 0.44-0.86, p = 0.005) was independently associated with the incidence of the composite event. In the multicenter cohort of AF ablation, sinus rhythm maintenance after catheter ablation was independently associated with lower rates of major adverse cardiac and cerebrovascular events.
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http://dx.doi.org/10.1007/s00380-021-01929-5DOI Listing
September 2021

Design and rationale of the EVOCATION trial: A prospective, randomized, exploratory study comparing the effect of evolocumab on coronary microvascular function after percutaneous coronary intervention in patients with stable coronary artery disease.

J Cardiol 2021 Sep 10. Epub 2021 Sep 10.

Department of Cardiovascular and Renal Medicine, Hyogo College of Medicine, Hyogo, Japan. Electronic address:

Percutaneous coronary intervention (PCI) is a standard treatment in patients with stable coronary artery disease (CAD); however, periprocedural myocardial infarction (PMI) remains a common complication of PCI. Aggressive lipid-lowering therapy with statin has shown to reduce the incidence of PMI by preventing coronary microvascular dysfunction. It is unclear whether evolocumab, a potent lipid-lowering agent, could diminish microvascular damage after PCI. The EVOCATION trial (jRCTs051180022) is a multicenter, randomized, open-label, active-controlled, parallel-group, exploratory, investigator-initiated clinical study to evaluate whether pretreatment with evolocumab could decrease the index of microvascular resistance (IMR) after PCI in patients with stable CAD. This study population consists of 100 patients with stable CAD who will undergo PCI and have high low-density lipoprotein cholesterol levels despite administration of maximum tolerated dose of statins for at least 2 weeks. Eligible patients are randomized in a 1:1 ratio to receive either evolocumab 140 mg every 2 weeks in addition to standard of care treatment or standard of care treatment only for 2-6 weeks before PCI. The primary endpoint is IMR after PCI. The EVOCATION trial will evaluate whether pretreatment with evolocumab reduces periprocedural microvascular damage in patients with stable CAD undergoing PCI.
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http://dx.doi.org/10.1016/j.jjcc.2021.08.024DOI Listing
September 2021

Myocardial ultrastructure can augment genetic testing for sporadic dilated cardiomyopathy with initial heart failure.

ESC Heart Fail 2021 Sep 6. Epub 2021 Sep 6.

Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.

Aims: The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing.

Methods And Results: Endomyocardial biopsy and whole-exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0-64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non-synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy-susceptibility and 41 arrhythmia-susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A-band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I-band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033).

Conclusions: Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large-scale studies are required to confirm whether these ultrastructural findings are related to the causative genes.
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http://dx.doi.org/10.1002/ehf2.13596DOI Listing
September 2021

Clinical significance of the N-terminal pro-brain natriuretic peptide and B-type natriuretic peptide ratio in the acute phase of acute heart failure.

Eur Heart J Acute Cardiovasc Care 2021 Aug 25. Epub 2021 Aug 25.

Division of Intensive Care Unit, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba 270-1694, Japan.

Aims: Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) levels are rarely evaluated simultaneously in the acute phase of acute heart failure (AHF).

Method And Results: A total of 1207 AHF patients were enrolled, and 1002 patients were analysed. Blood samples were collected within 15 min of admission. Patients were divided into two groups according to the median value of the NT-proBNP/BNP ratio [low-NT-proBNP/BNP group (Group L) vs. high-NT-proBNP/BNP group (Group H)]. A multivariate logistic regression model showed that the C-reactive protein level (per 1-mg/dL increase), Controlling Nutrition Status score (per 1-point increase), and estimated glomerular filtration rate (eGFR, per 10-mL/min/1.73 m2 increase) were independently associated with Group H [odds ratio (OR) 1.049, 95% confidence interval (CI) 1.009-1.090, OR 1.219, 95% CI 1.140-1.304, and OR 1.543, 95% CI 1.401-1.698, respectively]. A Kaplan-Meier curve analysis showed that the prognosis was significantly poorer in Group H than in Group L, and a multivariate Cox regression model revealed Group H to be an independent predictor of 180-day mortality [hazard ratio (HR) 3.084, 95% CI 1.838-5.175] and HF events (HR 1.963, 95% CI 1.340-2.876). The same trend in the prognostic impact was significantly observed in the low-BNP (<810 pg/mL, n = 501), high-BNP (≥810 pg/mL, n = 501), and low-eGFR (<60 mL/min/1.73 m2, n = 765) cohorts, and tended to be observed in normal-eGFR (≥60 mL/min/1.73 m2, n = 237) cohort.

Conclusion: A high NT-proBNP/BNP ratio was associated with a non-cardiac condition (e.g. inflammatory reaction, nutritional status, and renal dysfunction) and is independently associated with adverse outcomes in AHF.
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http://dx.doi.org/10.1093/ehjacc/zuab068DOI Listing
August 2021

Effect of Empagliflozin Versus Placebo on Body Fluid Balance in Patients With Acute Myocardial Infarction and Type 2 Diabetes Mellitus: Subgroup Analysis of the EMBODY Trial.

J Card Fail 2021 Aug 21. Epub 2021 Aug 21.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: The development of heart failure is associated with fluid balance, including that of extracellular water (ECW) and intracellular water (ICW). This study determined whether sodium-glucose cotransporter 2 inhibitors affect fluid balance and improve heart failure in patients after acute myocardial infarction.

Methods And Results: EMBODY was a prospective, randomized, double-blinded, placebo-controlled trial of Japanese patients with acute myocardial infarction and type 2 diabetes. Overall, 55 patients who underwent bioelectrical impedance analysis were randomized to receive once daily 10 mg empagliflozin or placebo 2 weeks after acute myocardial infarction onset. We investigated the time course of body fluid balance measured using the bioelectrical impedance analysis device, InBody. The primary end points were changes in body fluid balance from weeks 0 to 24. Changes between baseline and week 24 in the empagliflozin and placebo groups were -0.21 L (P = .127) and +0.40 L (P = .001) in ECW (P = .001) and -0.23 L (P = .264) and +0.74 L (P < .001) in ICW (P < .001), respectively. In a stratified analysis, the rise in ECW and ICW was significantly attenuated in the empagliflozin group in contrast to the placebo group in participants with a body mass index of 25 or higher but not in those with a body mass index of less than 25.

Conclusions: Early sodium-glucose cotransporter 2 inhibitor administration may attenuate changes in ECW and ICW.
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http://dx.doi.org/10.1016/j.cardfail.2021.07.022DOI Listing
August 2021

Vulnerable atherosclerotic plaque features: findings from coronary imaging.

J Geriatr Cardiol 2021 Jul;18(7):577-584

Division of Cardiology, Nippon Medical School, Tokyo, Japan.

Pathological studies have suggested that features of vulnerable atherosclerotic plaques likely to progress and lead to acute cardiovascular events have specific characteristics. Given the progress of intravascular coronary imaging technology, some large prospective studies have detected features of vulnerable atherosclerotic plaques using these imaging modalities. However, the rate of cardiovascular events, such as acute coronary syndrome, has been found to be considerably reduced in the limited follow-up period available in the statin era. Additionally, not all disrupted plaques lead to thrombus formation with clinical presentation. If sub-occlusive or occlusive thrombus formation does not occur, a thrombus on a disrupted plaque will organize without any symptoms, forming a "healed plaque". Although vulnerable plaque detection using intracoronary imaging is focused on "thin-cap fibroatheroma" leading to plaque rupture, superficial plaque erosion is increasingly recognized; however, the underlying mechanism of thrombus formation on eroded plaques is not well understood. One of intravascular imaging, optical coherence tomography (OCT) has the highest image resolution and has enabled detailed characterization of the plaque . Here, we reviewed the status and limitations of intravascular imaging in terms of detecting vulnerable plaque through mainly OCT studies. We suggested that vulnerable plaque should be reconsidered in terms of eroded plaque and healed plaque and that both plaque and circulating blood should be assessed in greater detail accordingly.
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http://dx.doi.org/10.11909/j.issn.1671-5411.2021.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352771PMC
July 2021

Hemodynamic Collapse Caused by Cardiac Dysfunction and Abdominal Compartment Syndrome in a Patient with Mitochondrial Disease.

Intern Med 2021 Aug 13. Epub 2021 Aug 13.

Department of Cardiovascular Medicine, Nippon Medical School, Japan.

We herein report a case of mitochondrial disease with heart and intestinal tract involvement resulting in hemodynamic collapse. A 66-year-old woman was transferred to our hospital because of cardiogenic shock. Vasopressors were administered, and a circulatory support device was deployed. However, her hemodynamics did not improve sufficiently, and we detected abdominal compartment syndrome caused by the aggravation of chronic intestinal pseudo-obstruction as a complication. Insertion of a colorectal tube immediately decreased the intra-abdominal pressure, improving the hemodynamics. Finally, we diagnosed her with mitochondrial disease, concluding that the resulting combination of acute heart failure and abdominal compartment syndrome had aggravated the hemodynamics.
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http://dx.doi.org/10.2169/internalmedicine.7729-21DOI Listing
August 2021

Rationale and design of the HINODE study: Heart failure indication and sudden cardiac death prevention trial Japan.

J Arrhythm 2021 Aug 20;37(4):1031-1037. Epub 2021 Jul 20.

Department of Cardiology Faculty of Medicine University of Tsukuba Ibaraki Japan.

Background: Randomized trials in Western countries have provided evidence that prophylactic implantable cardioverter-defibrillator (ICD) therapy reduces mortality in heart failure (HF) patients with reduced left ventricular ejection fraction. However, the risk of life-threatening ventricular arrhythmias in Japanese HF patients sharing similar risk factors is still unknown.

Methods: The Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan trial (NCT03185832) is a prospective, multicenter registry designed to collect data on ventricular arrhythmia, HF events, and mortality in Japanese HF patients. Japanese patients with HF and 2-5 predefined risk factors who were indicated for cardiac device implantation based on European Society of Cardiology guidelines were enrolled in four treatment arms: implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy defibrillator (CRT-D), HF pacing (PA; Pacemaker and cardiac resynchronization pacemaker), and nondevice (ND) cohorts and followed for a minimum of 12 months. Since it is anticipated that some baseline patient characteristics and risk factors will differ significantly from those reported in predominantly Western populations, event rates will be compared to a propensity-matched population from the MADIT RIT trial. Primary endpoints are composite rates of first appropriately treated ventricular arrhythmias (VA) or/and life-threatening VA symptoms for the ICD and CRT-D cohorts. For nondevice and PA cohorts, the primary outcome is all-cause mortality.

Conclusions: The Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan is a large prospective multicenter registry with defined device treatment cohorts and will provide data for risk stratification for cardiovascular events in Japanese HF patients.
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http://dx.doi.org/10.1002/joa3.12577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339090PMC
August 2021

The association between late-phase early recurrence within the blanking period after atrial fibrillation catheter ablation and long-term recurrence: Insights from a large-scale multicenter study.

Int J Cardiol 2021 Oct 31;341:39-45. Epub 2021 Jul 31.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo 113-8603, Japan.

Background: The relationship between the timing of the first early recurrence and late recurrence after a single catheter ablation procedure for atrial fibrillation is controversial.

Methods: The Efficacy of Short-Term Use of Antiarrhythmic Drugs After Catheter Ablation for Atrial Fibrillation trial followed 2038 patients who underwent radiofrequency catheter ablation for atrial fibrillation.

Results: Of the patients, 907 (45%) had early recurrences within 90 days after the initial ablation. We divided these patients into two groups according to the timing of the first early recurrence episode, namely the ER group (early recurrence during the early phase; 0-30 days, n = 814) and ER group (early recurrence during the late phase; 31-90 days, n = 93). Three years after ablation, patients with early recurrences had a significantly lower event-free rate from late recurrences after a 90-day blanking period than patients without early recurrences (36.2% and 74.2%, respectively; log-rank, P < 0.0001). Three years after ablation, the event-free rate was significantly higher in the ER than the ER group (38.3% and 17.1%, respectively; log-rank, P < 0.0001). Moreover, the event-free rate at 3 years in the ER group was extremely low (5.6%) in patient with non-paroxysmal atrial fibrillation.

Conclusion: Early recurrences were strongly associated with late recurrences, especially in patients with the first recurrence episode at >1 month within the blanking period after a single ablation procedure. Therefore, these patients should undergo close observation during follow-up, when they had especially with non-paroxysmal atrial fibrillation.
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http://dx.doi.org/10.1016/j.ijcard.2021.07.053DOI Listing
October 2021

Estimating the Posttest Probability of Long QT Syndrome Diagnosis for Rare Variants.

Circ Genom Precis Med 2021 Aug 26;14(4):e003289. Epub 2021 Jul 26.

Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Departments of Medicine & Pharmacology (K.K., Y.W., C.E., M.J.O., A.M.G., J.D.M., D.M.R., B.C.K., B.M.K.), Vanderbilt University Medical Center, Nashville, TN.

Background: The proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. This raises the question of whether these variants can be useful predictors of disease. To answer this question, we assessed the degree to which the presence of a variant in the cardiac potassium channel gene was diagnostically predictive for the autosomal dominant long QT syndrome.

Methods: We estimated the probability of a long QT diagnosis given the presence of each variant using Bayesian methods that incorporated variant features such as changes in variant function, protein structure, and in silico predictions. We call this estimate the posttest probability of disease. Our method was applied to over 4000 individuals heterozygous for 871 missense or in-frame insertion/deletion variants in and validated against a separate international cohort of 933 individuals heterozygous for 266 missense or in-frame insertion/deletion variants.

Results: Our method was well-calibrated for the observed fraction of heterozygotes diagnosed with long QT syndrome. Heuristically, we found that the innate diagnostic information one learns about a variant from 3-dimensional variant location, in vitro functional data, and in silico predictors is equivalent to the diagnostic information one learns about that same variant by clinically phenotyping 10 heterozygotes. Most importantly, these data can be obtained in the absence of any clinical observations.

Conclusions: We show how variant-specific features can inform a prior probability of disease for rare variants even in the absence of clinically phenotyped heterozygotes.
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http://dx.doi.org/10.1161/CIRCGEN.120.003289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373797PMC
August 2021

Clinical Significance of the Fibrosis-4 Index in Patients with Acute Heart Failure Requiring Intensive Care.

Int Heart J 2021 Jul 17;62(4):858-865. Epub 2021 Jul 17.

Department of Cardiovascular Medicine, Nippon Medical School.

The Fibrosis-4 (FIB4) index could indicate the liver fibrosis in patients with chronic hepatic diseases. It was calculated using the following formula: (age × aspartate aminotransferase [U/L]) / (platelet count [10/μL] × √alanine aminotransferase [U/L]). However, the clinical impact of the FIB4 index in the acute phase of acute heart failure (AHF) has not been sufficiently investigated.A total 1,468 AHF patients were analyzed. The median FIB4 index was 2.71 [1.85-4.22]. The patients were divided into three groups according to the quartiles of their FIB4 index (low-FIB4 [Q1, ≤ 1.847], middle-FIB4 [Q2/Q3, 1.848-4.216], and high-FIB4 [Q4, ≥ 4.216] groups). A Kaplan-Meier curve analysis showed that the prognosis, such as all-cause mortality and HF events within 365 days, was significantly poorer in the high-FIB4 group than in the middle-FIB4 and low-FIB4 groups. A multivariate Cox regression model identified high FIB4 index as an independent predictor of 365-day all-cause death (hazard ratio (HR): 1.660, 95% CI: 1.136-2.427) and HF events (HR: 1.505, 95% CI: 1.145-1.978). The multivariate logistic regression analysis showed that the high plasma volume status (PVS) (Q4, odds ratio [OR]: 2.099, 95% CI: 1.429-3.082), low systolic blood pressure (SBP) (< 100 mmHg, OR: 3.825, 95% CI: 2.504-5.840), and low left ventricular ejection fraction (< 40%, OR: 1.321, 95% CI: 1.002-1.741) were associated with a high FIB4 index.A high FIB4 index can predict adverse outcomes in AHF patients, which indicate that congestive liver and liver hypoperfusion occur due to low cardiac output in the acute phase of AHF.
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http://dx.doi.org/10.1536/ihj.20-793DOI Listing
July 2021

Differential diagnosis between LQT1 and LQT2 by QT/RR relationships using 24-hour Holter monitoring: A multicenter cross-sectional study.

Ann Noninvasive Electrocardiol 2021 Sep 10;26(5):e12878. Epub 2021 Jul 10.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: The clinical course and therapeutic strategies in the congenital long QT syndrome (LQTS) are genotype-specific. However, accurate estimation of LQTS genotype is often difficult from the standard 12-lead ECG.

Objectives: This study aims to evaluate the utility of QT/RR slope analysis by the 24-hour Holter monitoring for differential diagnosis of LQTS genotype between LQT1 and LQT2.

Methods: This cross-sectional study enrolled 54 genetically identified LQTS patients (29 LQT1 and 25 LQT2) recruited from three medical institutions. The QT-apex (QTa) interval and the QT-end (QTe) interval at each 15-second were plotted against the RR intervals, and the linear regression (QTa/RR and QTe/RR slopes, respectively) was calculated from the entire 24-hour and separately during the day or night-time periods of the Holter recordings.

Results: The QTe/RR and QTa/RR slopes at the entire 24-hour were significantly steeper in LQT2 compared to those in LQT1 patients (0.262 ± 0.063 vs. 0.204 ± 0.055, p = .0007; 0.233 ± 0.052 vs. 0.181 ± 0.040, p = .0002, respectively). The QTe interval was significantly longer, and QTe/RR and QTa/RR slopes at daytime were significantly steeper in LQT2 than in LQT1 patients. The receiver operating curve analysis revealed that the QTa/RR slope of 0.211 at the entire 24-hour Holter was the best cutoff value for differential diagnosis between LQT1 and LQT2 (sensitivity: 80.0%, specificity: 75.0%, and area under curve: 0.804 [95%CI = 0.68-0.93]).

Conclusion: The continuous 24-hour QT/RR analysis using the Holter monitoring may be useful to predict the genotype of congenital LQTS, particularly for LQT1 and LQT2.
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http://dx.doi.org/10.1111/anec.12878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411756PMC
September 2021

Successful Prophylactic Endovascular Therapy for a Rapidly Expanding Hepatic Arterial Aneurysm in a Patient with Vascular Ehlers-Danlos Syndrome.

Ann Vasc Dis 2021 Jun;14(2):163-167

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Vascular Ehlers-Danlos syndrome (vEDS) causes fatal vascular complications due to vascular fragility. However, invasive therapeutic procedures are generally avoided except in emergencies. We report a case of vEDS presenting with rapid expansion of a hepatic arterial aneurysm successfully treated using prophylactic endovascular therapy. A 43-year-old woman with vEDS confirmed by genetic testing was hospitalized for a symptomatic hepatic arterial aneurysm that expanded rapidly within a week. Prophylactic coil embolization was then successfully performed. Although the general applicability of this approach cannot be determined, prophylactic endovascular therapy can clearly be an option for arterial aneurysms at high risk of rupture.
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http://dx.doi.org/10.3400/avd.cr.20-00144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241546PMC
June 2021

Management of Congenital Long-QT Syndrome: Commentary From the Experts.

Circ Arrhythm Electrophysiol 2021 Jul 9;14(7):e009726. Epub 2021 Jul 9.

Clinical Cardiovascular Research Center, University of Rochester Medical Center, NY (W.Z.).

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.
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http://dx.doi.org/10.1161/CIRCEP.120.009726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301722PMC
July 2021

Effect of Empagliflozin Versus Placebo on Plasma Volume Status in Patients with Acute Myocardial Infarction and Type 2 Diabetes Mellitus.

Diabetes Ther 2021 Aug 8;12(8):2241-2248. Epub 2021 Jul 8.

Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-0022, Japan.

Introduction: Plasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been recently evaluated as a prognostic marker in patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether a sodium-glucose cotransporter 2 (SGLT2) inhibitor affects the alleviation of heart failure and improvement of PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF).

Methods: The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of an SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. In total, 105 patients were randomized (1:1) to receive 10 mg empagliflozin or a placebo (once daily), 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS at baseline and weeks 4, 12, and 24.

Results: Overall, 96 patients were included in the subgroup analysis set (age 64.3 ± 10.9 years, 80.2% men; 46 in the empagliflozin group and 50 in the placebo group). Body weight and PVS decreased in the empagliflozin group compared with the placebo group at 24 weeks (- 2.2 vs. + 0.1 kg, P < 0.001, and - 5.1 vs. - 0.3%, P < 0.001, respectively). Decreased PVS, defined as a change in PVS of < - 4.5%, was associated with the administration of empagliflozin (odds ratio 2.61, 95% confidence interval 1.11-6.15, P = 0.028). N-terminal pro b-type natriuretic peptide levels decreased in both the empagliflozin and placebo groups (1028.7-370.3 pg/mL, P < 0.001, and 1270.6-673.7 pg/mL, P < 0.01, respectively).

Conclusion: Empagliflozin reduced the body weight and PVS. Early SGLT2 inhibitor administration in patients with AMI, CHF, and T2DM can therefore be effective in reducing the body weight and PVS.

Trial Registration: UMIN 000030158.
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http://dx.doi.org/10.1007/s13300-021-01103-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342682PMC
August 2021

Empagliflozin confers reno-protection in acute myocardial infarction and type 2 diabetes mellitus.

ESC Heart Fail 2021 Oct 7;8(5):4161-4173. Epub 2021 Jul 7.

Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-0022, Japan.

Aims: Although the reno-protective effects of sodium-glucose cotransporter 2 inhibitors are known in patients with heart failure or type 2 diabetes mellitus (T2DM), this effect has not been confirmed in patients with acute myocardial infarction (AMI).

Methods And Results: The prospective, multicentre, randomized, double-blind, placebo-controlled EMBODY trial investigated patients with AMI and T2DM in Japan. The eligible patients included adults aged 20 years or older, diagnosed with AMI and T2DM, and who could be discharged within 2-12 weeks after the onset of AMI. One hundred and five patients were randomized (1:1) to receive once daily 10 mg empagliflozin or placebo within 2 weeks of AMI onset. In this sub-analysis, we investigated the time course of renal functional parameters such as serum creatinine levels and estimated glomerular filtration rate (eGFR) from baseline to Weeks 4, 12, and 24. Ninety-six patients (64 ± 11 years, 78 male) were included in the full analysis (n = 46 and 50 in the empagliflozin and placebo groups, respectively). We used serum creatinine and eGFR as indicators of renal function. In the placebo group, eGFR decreased from 66.14 mL/min/1.73 m at baseline to 62.77 mL/min/1.73 m by Week 24 (P = 0.023) but remained unchanged in the empagliflozin group (from 64.60 to 64.36 mL/min/1.73 m , P = 0.843). In the latter group, uric acid improved from 5.8 mg/dL at baseline to 4.9 mg/dL at Week 24 (P < 0.001). In the earlier analysis of 56 patients with eGFR ≥ 60 mL/min/1.73 m , the eGFR decreased and the serum creatinine increased from baseline to 24 weeks in the placebo group, significantly different to the empagliflozin group (-6.61 vs. +0.22 mL/min/1.73 m , P = 0.008 and +0.063 vs. -0.001 mg/dL, P = 0.030, respectively). The changes in serum creatinine and eGFR from baseline to Week 24 were significantly correlated with those in uric acid in the placebo group (r = 0.664, P < 0.001 and r = -0.675, P < 0.001, respectively) but not in the empagliflozin group.

Conclusions: Empagliflozin prevented the kidney functional decline in patients with AMI and T2DM, especially those with baseline eGFR ≥ 60 mL/min/1.73 m . Early administration of sodium-glucose cotransporter 2 inhibitors in these patients is considered desirable for renal protection.
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http://dx.doi.org/10.1002/ehf2.13509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497324PMC
October 2021

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

Eur Heart J 2021 07;42(29):2854-2863

Omics Research Center, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan.

Aims: The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability.

Methods And Results: Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves.

Conclusion: In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.
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http://dx.doi.org/10.1093/eurheartj/ehab254DOI Listing
July 2021

Different Determinants of the Recurrence of Atrial Fibrillation and Adverse Clinical Events in the Mid-Term Period After Atrial Fibrillation Ablation.

Circ J 2021 Jul 3. Epub 2021 Jul 3.

Tokyo Women's Medical University Hospital.

Background: It is unclear whether there are differences in the clinical factors between atrial fibrillation (AF) recurrence and adverse clinical events (AEs), including stroke/transient ischemic attack (TIA), major bleeding, and death, after AF ablation.Methods and Results:We examined the data from a retrospective multicenter Japanese registry conducted at 24 cardiovascular centers between 2011 and 2017. Of the 3,451 patients (74.1% men; 63.3±10.3 years) who underwent AF ablation, 1,046 (30.3%) had AF recurrence and 224 (6.5%) suffered AEs (51 strokes/TIAs, 71 major bleeding events, and 36 deaths) over a median follow-up of 20.7 months. After multivariate adjustment, female sex, persistent and long-lasting persistent AF (vs. paroxysmal AF), and stepwise increased left atrial diameter (LAd) quartiles were significantly associated with post-ablation recurrences. A multivariate analysis revealed that an age ≥75 years (vs. <65 years), body weight <50 kg, diabetes, vascular disease, left ventricular (LV) ejection fraction <40% (vs. ≥50%), Lad ≥44 mm (vs. <36 mm), and creatinine clearance <50 mL/min were independently associated with AE incidences, but not with recurrences.

Conclusions: This study disclosed different determinants of post-ablation recurrence and AEs. Female sex, persistent AF, and enlarged LAd were determinants of post-ablation recurrence, whereas an old age, comorbidities, and LV and renal dysfunction rather than post-ablation recurrence were AEs determinants. These findings will help determine ablation indications and post-ablation management.
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http://dx.doi.org/10.1253/circj.CJ-21-0326DOI Listing
July 2021

Extrinsic sex hormones rather than gender itself contribute directly to the electrocardiographic phenotype.

Authors:
Wataru Shimizu

Heart Rhythm 2021 Jul;18(7):1210-1211

Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2021.03.027DOI Listing
July 2021

Impact of beta-blocker use on the long-term outcomes of heart failure patients with chronic obstructive pulmonary disease.

ESC Heart Fail 2021 Oct 29;8(5):3791-3799. Epub 2021 Jun 29.

Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-0022, Japan.

Aims: The number of patients with both chronic obstructive pulmonary disease (COPD) and heart failure (HF) is increasing in Asia, and these conditions often coexist. We previously revealed a tendency of beta-blocker underuse among patients with HF with reduced ejection fraction (HFrEF) and COPD in Asian countries other than Japan. Here, we evaluated the impact of cardio-selective beta-blocker use on the long-term outcomes of patients with HF and COPD.

Methods And Results: Among the 5232 patients with HFrEF (left ventricular ejection fraction of <40%) prospectively enrolled from 11 Asian regions in the ASIAN-HF registry, 412 (7.9%) had a history of COPD. We compared the clinical characteristics and long-term outcomes of the patients with HF and COPD according to the use and type of beta-blockers used: cardio-selective beta-blockers (n = 149) vs. non-cardio-selective beta-blockers (n = 124) vs. no beta-blockers (n = 139). The heart rate was higher, and the outcome was poorer in the no beta-blocker group than in the beta-blocker groups. The 2 year all-cause mortality was significantly lower in the non-cardio-selective beta-blocker group than in the no beta-blocker group. Further, the cardiovascular mortality significantly decreased in the non-cardio-selective beta-blocker group before (hazard ratio: 0.36; 95% confidence interval: 0.18-0.73; P = 0.004) and after adjustments (hazard ratio: 0.37; 95% confidence interval: 0.19-0.73; P = 0.005), but not in the cardio-selective beta-blocker group.

Conclusions: Beta-blockers reduced the all-cause mortality of patients with HFrEF and COPD after adjusting for age and heart rate, although the possibility of selection bias could not be completely excluded due to multinational prospective registry.
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http://dx.doi.org/10.1002/ehf2.13489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497364PMC
October 2021

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

J Arrhythm 2021 Jun 8;37(3):481-534. Epub 2021 Apr 8.

The First Affiliated Hospital of Nanjing Medical University Nanjing China.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.
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http://dx.doi.org/10.1002/joa3.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207384PMC
June 2021
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