Hypodysfibrinogenemia with a Heterozygous Mutation of γCys326Ser by the Novel Transversion of TGT to TCT in a Patient with Pulmonary Thromboembolism and Right Ventricular Thrombus.

We encountered a 45-year-old Japanese man who suffered from pulmonary thromboembolism and huge right ventricular thrombus after inferior vena cava (IVC) filter implantation without apparent thrombus in either the deep veins or inside the IVC filter. The biochemical data showed a discrepancy in the level of fibrinogen between the immunological and thrombin time methods, suggesting hypodysfibrinogenemia. The sequencing of the fibrinogen γ-chain gene (FGG) revealed a novel heterozygous missense mutation in exon 8 - a TGT to TCT transversion in codon 326 - resulting in an amino acid substitution of serine for cysteine (γCys326Ser). The characterization of the protein did not show known mechanisms for thrombosis in dysfibrinogenemia, such as dimer or albumin-binding complex formation. In summary, the current case with a life-threatening thrombotic event was found to have a novel heterozygous missense mutation resulting in γCys326Ser, which was suggested as a predisposing factor of the thrombosis. Known mechanisms responsible for thrombosis in the current case were not demonstrated, suggesting other mechanisms including superimposing inherited and/or acquired risk factors. When a patient presents with unusual thrombosis such as breakthrough pulmonary embolism and huge thrombus in the right ventricle, as in the current case, the laboratory process for heritable thrombophilia should be considered.

Rationale and Design of the Effect of Ivabradine on Exercise Tolerance in Patients With Chronic Heart Failure (EXCILE-HF) Trial　- Protocol for a Multicenter Randomized Controlled Trial.

Background: A high resting heart rate is an independent risk factor for mortality and morbidity in patients with cardiovascular diseases. Ivabradine selectively inhibits the funny current (I f) and decreases heart rate without affecting cardiac conduction, contractility, or blood pressure. The effect of ivabradine on exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) on standard drug therapies remains unclear. Methods and Results: This multicenter interventional trial of patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm treated with standard drug therapies will consist of 2 periods: a 12-week open-label, randomized, parallel-group intervention period (standard drug treatment+ivabradine group and standard drug treatment group) to compare changes in exercise tolerance between the 2 groups; and a 12-week open-label ivabradine treatment period for all patients to evaluate the effect of adding ivabradine on exercise tolerance. The primary endpoint will be the change in peak oxygen uptake (V̇O2) during the cardiopulmonary exercise test from Week 0 (baseline) to Week 12. Secondary endpoints will be time-dependent changes in peak V̇O2 from Week 0 to Weeks 12 and 24. Adverse events will also be evaluated. Conclusions: The EXCILE-HF trial will provide meaningful information regarding the effects of ivabradine on exercise tolerance in patients with HFrEF receiving standard drug therapies and suggestions for the initiation of ivabradine treatment.

Effect of Cardiac Rehabilitation on Glomerular Filtration Rate Using Serum Cystatin C Concentration in Patients With Cardiovascular Disease and Renal Dysfunction.

PURPOSE: Among patients with chronic kidney disease (CKD), little is known about whether the effect of cardiac rehabilitation (CR) on renal function differs across baseline estimated glomerular filtration rate using the serum concentration of cystatin C (eGFRcys). The aim of this study was to evaluate the effect of CR on renal function in patients with CKD. METHODS: We performed a retrospective cohort study of patients with CKD (15 ≤ eGFRcys < 60 mL/min/1.73 m2) who participated in our CR program for cardiovascular disease. First, the patients were divided into three groups according to the baseline severity of the eGFRcys: G3a, G3b, and G4 groups. We compared the eGFRcys before and after the CR in each group. Second, to determine the association of baseline eGFRcys with the effect of CR, we fitted a linear regression model using the percent change in the eGFRcys (%ΔeGFRcys) as an outcome. RESULTS: Of the 203 patients, 122 were in G3a, 60 were in G3b, and 21 were in G4 groups. The mean improvement of eGFRcys in each group was 1.3, 3.1, and 4.8 mL/min/1.73 m2, respectively. The %ΔeGFRcys was larger among patients with lower baseline eGFRcys (0.47% greater improvement of %ΔeGFRcys/one lower baseline eGFRcys; 95% CI, 0.23-0.72%). This association remained significant after adjustment for potential confounders (0.63% greater improvement of %ΔeGFRcys/one lower baseline eGFRcys; 95% CI, 0.35-0.91%). CONCLUSIONS: The effect of CR on renal function was greater in patients with worse renal dysfunction measured by eGFRcys. A CR program could be useful for patients with severe renal dysfunction and it might have a beneficial effect on their renal function.

Antemortem Diagnosis of Pulmonary Tumor Thrombotic Microangiopathy in a Patient with Recurrent Breast Cancer: An Autopsy Case Report.

OBJECTIVE: Herein, we report a case of a patient with recurrent breast cancer who was diagnosed antemortem with pulmonary tumor thrombotic microangiopathy (PTTM) using wedge aspiration cytology of the pulmonary artery after breast cancer surgery. CASE SUMMARY: The patient was a 50-year-old woman who underwent mastectomy and axillary lymph node dissection for stage IIIA (T3N2M0) triple-negative left breast cancer. Postoperative follow-up was performed with radiotherapy and anticancer chemotherapy. Seventeen months after the surgery, the patient was hospitalized for right heart failure and diagnosed with pulmonary arterial hypertension. The patient was diagnosed with PTTM following the detection of malignant cells in the pulmonary artery using wedge aspiration cytology. Anti-pulmonary hypertension therapy was administered; however, the patient did not respond and died 26 days after admission. Autopsy revealed multiple microscopic tumor emboli in the pulmonary artery. In portions of the pulmonary artery without embolization, fibro-cellular intimal hyperplasia and stenosis were observed. Tumor embolism was expressed for CK7+/CK20-, consistent with the primary breast cancer. DISCUSSION: Since the primary pathophysiology of PTTM entails narrowing due to fibro-cellular intimal hyperplasia rather than multiple tumor thrombi, the efficacy of chemotherapy combined with vasodilators is discussed.

Study Design of the Japanese Association of Cardiac Rehabilitation Registry (J-CARRY)　- Protocol for a Prospective, Multicenter, Open Registry.

Background: Guidelines for the prevention and management of cardiovascular disease (CVD) highly recommend cardiac rehabilitation (CR) on the basis of abundant evidence of its effectiveness. However, the current understanding and dissemination of CR in Japan are far from sufficient. Methods and Results: The Japanese Association of Cardiac Rehabilitation Registry (J-CARRY) is an academic society-led prospective multicenter observational registry conducted by the Registration and Facility Accreditation System Committee of the Japanese Association of Cardiac Rehabilitation. Data are collected prospectively using an electronic data capture system. Items related to patients' clinical background and CR, as well as mortality and major adverse cardiac and cerebrovascular events, will be collected in all cases. This Registry started in May 2014, and the number of participating medical institutions is expected to increase to >30; the targeted number of cases exceeded 3,000 per year as of April 30, 2022. Focusing on late Phase II data collection is a novel and significantly different approach compared with previous studies. The results of this study are currently under investigation. Conclusions: J-CARRY will provide real-world data regarding the current status and prognosis of CVD in patients who undergo Phase II CR in Japan.

Impact of bedrest on cardiovascular events and complications associated with temporary pacemakers in patients waiting for permanent pacemaker implantation.

BACKGROUND: Patients with a temporary pacemaker (TPM) for bradycardias are required to maintain bedrest until permanent pacemakers (PPMs) are implanted because of the development of Adams-Stokes syndrome, worsening heart failure, or complications associated with TPMs is anticipated. However, bedrest may be detrimental in patients because it leads to disuse syndrome. This study examined whether bedrest could decrease the incidence of cardiovascular events or complications associated with TPMs in patients waiting for PPM implantation. METHODS: We conducted a retrospective cohort study on 88 patients who had emergency hospitalization for the treatment of bradycardias, and a TPM was inserted during the waiting period before PPM implantation. We divided patients into two groups according to whether they underwent bedrest (Bedrest Group) or not (Ambulation Group) during the period that patients were supported with TPM. We evaluated whether bedrest was a predictor of adverse events using a logistic regression analysis. RESULTS: Adverse events occurred in 31 patients (35%). In the univariate analysis, there was no significant difference in the incidence of adverse events between the Bedrest and Ambulation Groups (39% vs. 29%). In the logistic regression analysis, bedrest was not a predictor of adverse events (odds ratio, 1.40; 95% confidence interval, 0.53-3.68, P = .497). CONCLUSIONS: In patients with TPMs for bradyarrhythmias during the waiting period for PPM implantations, bedrest might not prevent adverse events, such as cardiovascular events and complications associated with TPMs.

Effect of ganglionated plexi ablation by high-density mapping on long-term suppression of paroxysmal atrial fibrillation - The first clinical survey on ablation of the dorsal right plexusus.

BACKGROUND: Long-term outcomes of suppressing paroxysmal atrial fibrillation (PAF) with additive ganglionated plexus (GP) ablation (GPA) remains unknown. OBJECTIVES: The aim of the study is to assess potential role of additional GPA for PAF suppression. METHODS: This study consisted of 225 patients; 68 (group A: 58 male, aged 60 ± 11 years) underwent pulmonary vein isolation (PVI) alone and 157 (group B: 137 male, aged 61 ± 11 years) GPA followed by PVI. GPA was performed based on the high-density mapping with high-frequency stimulation (HFS) delivered to left atrial (LA) major GP. The latter 85 group B patients (54%) underwent ablation to a posteromedial area within superior vena cava as a part of dorsal right atrial GP (SVC-Ao GP). RESULTS: In group B, HFS was applied to 126 ± 32 sites, with a median of 47 GP sites (40.0%) being ablated. In patients undergoing an SVC-Ao GPA, HFS and the SVC-Ao GPA were applied at a median of 15 and 4 sites (29.4%), respectively. The PVI with a GPA provided higher PAF suppression than a PVI alone during more than 4 years of follow-up (56.7% vs 38.2%, odds ratio: 0.42, 95% confidence interval: 0.23-0.76, P < .05), but the SVC-Ao GPA did not provide further suppressive effects. Multivariate analyses revealed that tachycardia-bradycardia syndrome and non-PV foci were independent predictors of PAF recurrence after PVI with a GPA (P < .01). CONCLUSION: GPA to LA major GP by high-density mapping provides long-term benefits for PAF suppression over 4 years of follow-up, but the effect of an empiric SVC-Ao GPA could not be appreciated, suggesting little effect on suppressing non-PV foci.

Effects of cardiac rehabilitation on physical function and exercise capacity in elderly cardiovascular patients with frailty.

BACKGROUND: The effects of cardiac rehabilitation (CR) on long-term prognosis of cardiovascular disease (CVD) are well known. However, the effect of CR on frail CVD patients has not been fully addressed. METHODS: This study consisted of 89 CVD patients with their age ≥65 years old (68 males, 75 ± 6 years), who participated in the outpatient CR program for 3 months. All the patients underwent cardiopulmonary exercise testing and the physical frailty was assessed using the Japanese Version of the Cardiovascular Health Study Standard before and after CR. Based on the assessment of frailty before CR, the patients were divided into the following two groups: frailty group (n = 23) and non-frailty group (n = 66: robust in 10 and pre-frail in 56 patients). RESULTS: In the frailty group, 20 patients (87%) improved from frail status after CR, and usual walking speed, maximal grip strength, and lower extremity strength were significantly improved (1.06±0.20 vs. 1.20±0.18 m/sec, p<0.001; 21.7 ± 5.5 vs. 23.6 ± 6.3 kg, p<0.01; 0.37±0.09 vs. 0.43±0.11 kgf/kg, p = 0.001, respectively), but peak VO2 did not change after CR (15.9 ± 3.1 vs. 16.2 ± 3.8 ml/min/kg, NS). In the non-frailty group, all these parameters were significantly improved after CR (1.24±0.19 vs. 1.29±0.23 m/sec, p<0.05, 28.7 ± 7.0 vs. 30.2 ± 7.3 kg, p<0.001, 0.50±0.18 vs. 0.54±0.13 kgf/kg, p<0.05, 17.7 ± 4.7 vs 18.5 ± 4.2 ml/min/kg, p<0.01, respectively). CONCLUSION: Short-term CR could obtain the improvement of the physical function, providing the prerequisite step for possibly following improvement of exercise capacity in elderly CVD patients with frailty. It may be inferred that longer duration of CR would be needed to obtain the improvement of exercise capacity in these patients, being the future consideration to be determined.

Effects of Phase II Comprehensive Cardiac Rehabilitation on Risk Factor Modification and Exercise Capacity in Patients With Acute Coronary Syndrome　- Results From the JACR Registry.

Background: Cardiac rehabilitation (CR) is categorized as a Class I recommendation in guidelines for the management of patients with acute coronary syndrome (ACS); however, nationwide studies on CR in patients with ACS remain limited in Japan. Methods and Results: The Japanese Association of Cardiac Rehabilitation (JACR) Registry is a nationwide, real-world database for patients participating in CR. From the JACR Registry database, we analyzed 924 patients participating in Phase II CR in 7 hospitals between September 2014 and December 2016. The mean age of patients was 65.9±12.0 years, and 80% were male. The prevalence of ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina pectoris (UAP) was 58%, 9%, and 33%, respectively. The prevalence of hypertension, diabetes, dyslipidemia, current smoking, and a family history was 55%, 27%, 67%, 21%, and 10%, respectively. Among the entire CR cohort at baseline, 96%, 78%, and 92% were treated with aspirin, ß-blockers, and statins, respectively. After CR, the values of body mass index, the lipid profile, and exercise capacity significantly improved in the STEMI, NSTEMI and UAP groups. Conclusions: In the JACR Registry, a high rate of guideline-recommended medications at baseline and improvements in both coronary risk factors and exercise capacity after CR were observed in patients with ACS.

Sympathetic excitation during exercise as a cause of attenuated heart rate recovery in patients with myocardial infarction.

BACKGROUND: Heart rate recovery (HRR) after exercise is known as a predictor of cardiac death in patients with heart disease. The mechanism is not fully understood, although a parasympathetic mechanism has been reported. To elucidate the factors that influence HRR, we evaluated the relationship of HRR with exercise performance and plasma norepinephrine (NE), lactic acid and B-type natriuretic peptide (BNP) responses to exercise testing. METHODS: The study population consisted of 52 male patients (age 58 +/- 9.6 years) who had experienced myocardial infarction without residual ischemia, uncompensated heart failure or atrial fibrillation. All subjects underwent a symptom-limited cardiopulmonary exercise test without a cool-down period and echocardiography. NE, lactic acid and BNP were measured at rest and at peak exercise. RESULTS: HRR did not correlate with the left ventricular ejection fraction, peak VO(2), lactic acid and BNP. HRR significantly correlated with the increment in heart rate (HR) from rest to peak exercise (DeltaHR) (r=0.30, p<0.05). When we divided DeltaHR into two phases at the anaerobic threshold (AT), HRR significantly correlated with DeltaHR (peak-AT) (r=0.409, p<0.01), but not with DeltaHR (AT-rest). There was a significant negative correlation between HRR and NE both at rest and at peak exercise (r=-0.286, p<0.05, r=-0.310, p<0.05). HRR was also correlated significantly with DeltaHR/logDeltaNE as an index of sensitivity to NE (r=0.421, p<0.01). Based on multiple regression analysis, DeltaHR and logDeltaNE predicted HRR (R(2)=0.467, p=0.0027). CONCLUSIONS: Present findings suggest that enhanced sympathetic excitation at maximum exercise suppresses parasympathetic reactivation and results in attenuation of HRR.

Effect of cardiac rehabilitation on the renal function in chronic kidney disease - Analysis using serum cystatin-C based glomerular filtration rate.

BACKGROUND: Whether an individually determined appropriate level of cardiac rehabilitation (CR) has a favorable effect on the renal function still remains unclarified. The aim of this study was to confirm the effect of CR on the estimated glomerular filtration rate (eGFR) using cystatin C, which is known to be unaffected by physical exercise. METHODS: The study population was comprised of 86 patients (61 males; average age 74 y/o) with a lower-moderate level of chronic kidney disease (CKD) who was admitted to our hospital for treatment of cardiovascular disease (CVD) and who participated in our 3-month CR program. The exercise capacity was assessed by cardiopulmonary exercise testing (CPX) and the eGFR was measured by a formula based on the serum cystatin C concentration (eGFRcys) in each patient both at the beginning and end of the CR. RESULTS: In the CVD patients with CKD, both the peak oxygen uptake (VO2) and peak work rate (WR) improved significantly after CR (15.0 ±â€¯3 to 15.8 ±â€¯3 ml/min/kg, p = 0.002. 65.5 ±â€¯21 to 70.2 ±â€¯25 W, p = 0.001). Regarding the renal function, the eGFRcys improved (45.2 ±â€¯11 to 47.3 ±â€¯13 ml/min/1.73 m2, p = 0.023), however, the eGFR assessed by the serum creatinine (eGFRcr) did not improve after CR (45.1 ±â€¯12 to 44.9 ±â€¯13 ml/min/1.73 m2, p = 0.834). CONCLUSIONS: In CVD patients, a novel CR program significantly improved the exercise capacity. Further, CR was shown to have a favorable effect on the renal function when it was estimated by the eGFRcys.