Study Protocol of Cardiac Rehabilitation for Acute Myocardial Infarction From the JROAD/JROAD-DPC Database　- JROAD-CR.

Background: Although cardiac rehabilitation (CR) has been reported to be effective for improving the prognosis of acute myocardial infarction (AMI), more patients must participate in CR during admission and as outpatients. Factors contributing to, and countermeasures against, the low CR participation rate need to be identified. Here we describe the protocol for a study designed to evaluate the effectiveness and problems of CR for AMI from the Japanese Registry of All Cardiac and Vascular Diseases (JROAD) and the JROAD-Japanese Diagnosis Procedure Combination system (JROAD-DPC) database. Methods and Results: This is a multicenter retrospective cohort study that will use the JROAD/JROAD-DPC database to evaluate the effectiveness of CR for AMI (JROAD-CR). Five thousand patients with AMI who were admitted to hospitals registered in the JROAD database in 2014 will be investigated with regard to their baseline characteristics, AMI severity and treatment, examination results, history of CR, and prognosis up to 5 years. We will also investigate the presence, quantity, and quality of CR, and evaluate the effectiveness of CR with respect to cost, exercise tolerance, and prognosis during admission and follow-up. Conclusions: The JROAD-CR study will seek to reveal the effectiveness of CR for AMI in the era of early reperfusion therapy and shortened hospitalization.

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.

Efficacy of Early Cardiac Rehabilitation After Cardiac Surgery　- Verification Using Japanese Diagnosis Procedure Combination Data.

Background: The current status of cardiac rehabilitation (CR) after cardiac surgery and the introduction of early CR (E-CR) in Japan are not fully understood. In this study, the current status of E-CR and its efficacy were investigated by the Academic Committee of the Japanese Association of Cardiac Rehabilitation. Methods and Results: We examined the rate of introduction of E-CR and its effects among 220,122 patients who underwent major cardiac and thoracic vascular surgery, as registered in the Diagnosis Procedure Combination (DPC) classification system, between April 2012 and March 2018. In this study, E-CR was defined as CR starting within 1 day after surgery. Patients with and without E-CR were propensity score matched and analyzed for clinical outcomes. Of all patients participating in CR after surgery, E-CR was initiated in 52.1%, 56.9%, 47.4%, and 54.1% of patients undergoing coronary artery bypass grafting, valve surgery, aortic surgery, and other cardiovascular surgery, respectively. After propensity score matching, outcomes for E-CR were significantly superior to non-E-CR in terms of in-hospital deaths, Barthel Index score at discharge, length of hospital stay, and hospitalization costs. Conclusions: E-CR after cardiac surgery was effective in terms of prognosis, hospital stay, and medical costs. This study is the first report using big data in Japan. The results indicate that further introduction of E-CR needs to be recommended in the future.

Trends and Factors Associated With Cardiac Rehabilitation Participation　- Data From Japanese Nationwide Databases.

BACKGROUND: Few studies have comprehensively evaluated the trends and factors associated with CR participation across major cardiovascular diseases in Japan.Methods and Results: This study performed a nationwide cross-sectional study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan and the Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination database. This study described the nationwide trends and evaluated patient- and hospital-level associated factors of CR participation for patients with acute heart failure (AHF), acute coronary syndrome (ACS), acute aortic dissection (AAD), peripheral artery disease (PAD), and after cardiovascular surgery using mixed-effect logistic regression analysis. Although the annual number of patients who underwent CR has increased during the study period, the total number of patients participating in outpatient CR was lower than that of inpatient CR. The outpatient CR participation rate was lower for patients with AHF (3.5%), AAD (3.2%), and PAD (1.7%), compared with ACS (7.9%) and after surgery (9.4%). Age, sex, body mass index, Barthel index, Charlson comorbidity index, and institutional capacity were identified as significant associated factors of CR participation in inpatient and outpatient settings. CONCLUSIONS: Participation in outpatient CR was still low, and higher age, multi-comorbidity, and low institutional capacity contributed to the lower outpatient CR participation rate. Identification of the associated factors may help cardiologists to increase CR participation.

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.

Clinical backgrounds and the time course of sleep-disordered breathing in patients after myocardial infarction.

INTRODUCTION: Previous studies have suggested that sleep-disordered breathing (SDB) frequently develops after myocardial infarction (MI) and leads to a poor prognosis. However, the details remain unclear. Therefore, we examined the clinical backgrounds and the time course of SDB in patients after MI. METHODS: The subjects were 92 consecutive patients (mean age, 65 ± 12 years) who had MI without decompensated heart failure or uncontrolled myocardial ischemia. All subjects underwent overnight sleep studies, and we investigated baseline clinical characteristics. Among the patients with confirmed SDB, the 38 patients who agreed underwent nighttime multichannel respiratory monitoring at both 14 days and 2 months after the onset of MI, and we investigated their clinical features. RESULTS: The percentage of patients with SDB 14 days after MI was high (93.5%). Among all patients, 6.5% had no SDB, 39.1% had mild SDB, 29.3% had moderate SDB, and 25.0% had severe SDB. The clinical features of patients with moderate-to-severe SDB (apnea-hypopnea index [AHI] ≥15 times/hour) did not differ significantly from those of patients with mild SDB or patients without SDB (AHI <15 times/hour). In patients with central SDB and AHI ≥10 times/hour, there was a significant improvement in AHI from 14 days to 2 months after MI. Multiple regression analysis showed that central SDB and nighttime onset of MI were associated with a decrease in AHI. CONCLUSION: These findings suggest that SDB after MI should be managed on the basis of the type of SDB and the time of MI onset.

Prognostic value of depression, anxiety, and anger in hospitalized cardiovascular disease patients for predicting adverse cardiac outcomes.

Although attention has recently been focused on the role of psychosocial factors in patients with cardiovascular disease (CVD), the factors that have the greatest influence on prognosis have not yet been elucidated. The aim of this study was to evaluate the effects of depression, anxiety, and anger on the prognosis of patients with CVD. Four hundred fourteen consecutive patients hospitalized with CVD were prospectively enrolled. Depression was evaluated using the Patient Health Questionnaire, anxiety using the Generalized Anxiety Disorder Questionnaire, and anger using the Spielberger Trait Anger Scale. Cox proportional-hazards regression was used to examine the individual effects of depression, anxiety, and anger on a combined primary end point of cardiac death or cardiac hospitalization and on a combined secondary end point of all-cause death or hospitalization during follow-up (median 14.2 months). Multivariate analysis showed that depression was a significant risk factor for cardiovascular hospitalization or death after adjusting for cardiac risk factors and other psychosocial factors (hazard ratio 2.62, p = 0.02), whereas anxiety was not significantly associated with cardiovascular hospitalization or death after adjustment (hazard ratio 2.35, p = 0.10). Anger was associated with a low rate of cardiovascular hospitalization or death (hazard ratio 0.34, p <0.01). In conclusion, depression in hospitalized patients with CVD is a stronger independent risk factor for adverse cardiac events than either anxiety or anger. Anger may help prevent adverse outcomes. Routine screening for depression should therefore be performed in patients with CVD, and the potential effects of anger in clinical practice should be reconsidered.

Baroreflex mechanisms and response to exercise in patients with heart disease.

BACKGROUND: Past reports showed that the baroreflex continuously regulates hemodynamics during exercise. However, it is still clinically unclear. If baroreflex mechanism is able to influence actually exercise cardiovascular control, baroreflex sympathetic and/or parasympathetic function relates to response to exercise. Therefore, we examined the relationship of heat rate changes to both blood pressure increment and decrement with tolerance and chronotropic response to peak exercise in patients with heart disease. METHODS: In 25 male heart disease patients (60 ± 9 years) without decompensated heart failure, baroreceptor reflex sensitivity (BRS ms mmHg(-1) ) was measured by reflex heart rate responses to changes in blood pressure after phenylephrine (P-BRS) and nitroglycerin (N-BRS) injection, respectively. Symptom-limited treadmill exercise test was performed according to Bruce's protocol. RESULTS: (i) The absolute values of blood pressure change after the administrations were similar between the agents because the dosages of nitroglycerin and phenylephrine were set to equalize absolute changes in blood pressure. (ii) In this study population, the ratio of N-BRS to P-BRS was not significantly correlated with hypertension and diabetes mellitus. (iii) Exercise capacity (METs) (r= -0.626) and heart rate response to exercise per METs (r=0.670) was significantly related to N-BRS but not to P-BRS. CONCLUSION: We found that the abnormality of baroreflex function in the presence of blood pressure decrements can lead to insufficient capacity and easy sympathetic activation during exercise.

Sleep-disordered breathing with nighttime hypocapnia relates to daytime enhanced ventilatory response to exercise in patients with heart disease.

BACKGROUND: Sleep-disordered breathing (SDB) induces nighttime disturbance of arterial gases, such as carbon dioxide. However, it is still unclear whether nighttime SDB-related gas abnormality is related to respiratory dysregulation in daytime. Therefore, we examined the relationship between the arterial partial pressure of carbon dioxide (PaCO(2)) at nighttime and the respiratory response to exercise in daytime. METHODS: Eighteen men (age, mean ± SD; 55 ± 11 years) with heart disease underwent multichannel respiratory monitoring through the night with transdermal measurement of PaCO(2) (PtcCO(2)) reflecting PaCO(2) and a cardiopulmonary exercise test in daytime. The ventilatory equivalent (VE)/carbon dioxide production (VCO(2)) slope as an index of ventilatory response to exercise and peak oxygen consumption (VO(2)) were obtained with a cardiopulmonary exercise test. RESULTS: Of the 18 patients, 10 patients had obstructive SDB, 5 had central SDB, and 3 patients did not have SDB. The mean apnea-hypopnea index was 21 ± 17. Minimum nighttime saturation of O(2) was positively correlated with peak VO(2), but not with VE/VCO(2). Nighttime PtcCO(2) was not correlated with peak VO(2) but was negatively correlated with the VE/VCO(2) slope of the daytime cardiopulmonary exercise test (r=-0.53). CONCLUSION: Nighttime lowering of PaCO(2) in SDB is related to an abnormal ventilatory response to exercise testing in the daytime. This finding suggests that nighttime hyperventilation in SDB alters both nighttime and daytime pathophysiological conditions in patients with heart disease.

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.

Relationship between plasma norepinephrine at peak exercise and 123I-MIBG imaging of the heart and lower limbs in heart failure.

BACKGROUND: Past studies suggested that plasma norepinephrine during exercise originates in sympathetic nerve endings and that the main origin differs among pathophysiological conditions. AIMS: This study investigated the most important site of sympathetic terminals as an origin of plasma norepinephrine during exercise in patients with heart failure using (123)I- metaiodobenzylguanidine (MIBG) scintigraphy. METHODS AND RESULTS: Twenty patients with organic heart disease underwent exercise testing and (123)I-MIBG scintigraphy. Systemic (123)I-MIBG uptake was measured 4 hours after (123)I-MIBG injection, and the heart-to-brain (H/B) and lower limb-to-brain ratios (L/B) were calculated. Plasma norepinephrine concentration was measured at rest and at peak exercise. Subjects were divided into two groups: those with preserved left ventricular ejection fraction (LVEF> or =45%, n=8) and those with reduced LVEF (<45%, n=12). Plasma norepinephrine at rest did not correlate with H/B or L/B. In the preserved LVEF group, plasma norepinephrine at peak exercise was correlated with H/B (r=0.722), but not with L/B. In the reduced LVEF group, the norepinephrine response to peak exercise correlated with L/B (r=0.642), but not with H/B. CONCLUSION: The present findings suggest that norepinephrine concentration is regulated by sympathetic terminal function of working muscles in patients with impaired LVEF and by that of the heart in patients with preserved LVEF.

Analysis of alteration of blood pressure response to exercise through baroreflex.

BACKGROUND: The baroreflex has been reported to play an important role in hemodynamic regulation during exercise. Therefore, impairment of baroreflex function can induce an abnormal response of systolic blood pressure (SBP) to exercise, including exercise-induced hypertension. To clarify whether baroreflex function alters SBP response, we examined the relationship of baroreflex sensitivity (BRS) with SBP response to exercise. METHODS: In 22 subjects without cardiac dysfunction, BRS (ms/mmHg) was measured by the phenylephrine method, and a treadmill exercise test was administered according to Bruce's protocol. RESULTS: 1) The chronotropic response to exercise was higher in the normal BRS group than in the reduced BRS group (p<0.01). The SBP at the initial phase of exercise (1 min after the start of exercise) showed a smaller increase in the normal BRS group than in the reduced BRS group (p<0.01). During the initial phase of exercise, BRS had negative correlation with the SBP increment from rest (r=-0.408, p<0.05). During submaximal exercise (6 min after the start of exercise), a positive correlation between BRS and SBP response (r=0.422, p<0.05) was shown. 2) Subjects were divided into 2 groups: 12 subjects with normal BRS (> or =5 ms/mmHg) and 10 subjects with reduced BRS (<5 ms/mmHg). During the initial exercise phase, the negative correlation between BRS and SBP response was stronger in the normal BRS group (r=-0.398) than in the reduced BRS group (r= -0.126). During submaximal exercise, BRS had a positive correlation with BP response to exercise in subjects with normal BRS (r=0.462). CONCLUSION: Preserved baroreflex function is thought to be related to the pressor response to submaximal exercise, although the baroreflex is thought to be associated with the stabilization of blood pressure change during the initial exercise phase. These findings suggest that exercise-induced hypertension develops through the baroreflex mechanism.

[Recent advance of exercise test in clinical cardiology concerning heart failure].

Present review focused on the recent advance and clinical application of exercise test in cardiology. Exercise intolerance is considered as one of clinical essential feature in patients with heart failure. Cardiac dysfunction induces systemic disorders including motor muscle and vasculature, and then limits exercise performance through direct and indirect pathway. Parameters of exercise test consist of subjective indexes such as NYHA functional class, and objective evaluations such as cardiopulmonary exercise test(CPX). Especially, we discussed the parameters of CPX provided many indexes, for example peak VO2, VE/VCO2 slope and deltaVO2/Work rate. These various indexes have different clinical meanings among each other. Low value of peak VO2, which reflected both disturbances of central and peripheral factors, is reported to result in poor survival rate. Although VE/VCO2 slope similarly predicts the prognosis, it thought to be mediated through a different way. We concluded that exercise test is important to understand the pathophysiological feature of heart failure as a systemic disease.

Improvement of sympathetic response to exercise by oral administration of ascorbic acid in patients after myocardial infarction.

BACKGROUND: Recent studies indicated that excessive oxidative stress in an animal heart failure model injures both the sympathetic nerve endings and receptors, resulting in disturbance of norepinephrine release and sensitivity to norepinephrine. However, it has not been clarified whether this phenomenon is expressed clinically in patients with heart disease. Therefore, we examined the efficacy of ascorbic acid administration as an antioxidant vitamin in relation to the heart rate and norepinephrine response to exercise in patients after myocardial infarction. METHODS: In this randomized crossover trial, 21 male patients who had had myocardial infarction underwent symptom-limited ergometer cardiopulmonary exercise testing twice, that is, without and with ascorbic acid (2 g) administration. Plasma norepinephrine concentrations were assessed at rest and at peak exercise, and heart rate responsiveness to the norepinephrine increment from rest to peak exercise (DeltaHR/logDeltaNE) was calculated. RESULTS: In the exercise test after ascorbic acid administration, peak oxygen consumption (VO(2)) improved over baseline. Ascorbic acid administration significantly increased the change in heart rate and norepinephrine from rest to peak exercise and DeltaHR/logDeltaNE. The increment in heart rate was significantly correlated with peak VO(2) in each test. CONCLUSION: Ascorbic acid intake before exercise improved exercise capacity through enhancement of the heart rate and norepinephrine response to exercise in patients after myocardial infarction. These findings suggest that ascorbic acid intake improves sympathetic dysfunction resulting from injury by excessive oxidative stress after myocardial infarction.

Sudden death in a case of cardiac amyloidosis immediately after pacemaker implantation for complete atrioventricular block.

We report a patient with cardiac involvement associated with primary amyloidosis presenting marked left ventricular (LV) wall thickening, severely decreased systolic and diastolic function, and complete atrioventricular block (CAVB), who died suddenly of cardiac arrest caused by electro-mechanical uncoupling occurring immediately after permanent pacemaker implantation. Post mortem examination showed no procedural complications such as cardiac or venous perforation. The heart was densely infiltrated with amyloid fibrils, especially in the extracellular tissues surrounding the papillary vessels.

Impaired baroreflex as a cause of chronotropic incompetence during exercise via autonomic mechanism in patients with heart disease.

PURPOSE: It is thought that the mechanisms responsible for impaired chronotropic response to exercise are related to disturbance of cardiovascular autonomic regulation such as the baroreflex. However, it is still unclear whether the baroreflex mechanisms modulate heart rate (HR) responses to exercise via vagal and/or sympathetic alteration. We therefore investigated the effects of baroreflex sensitivity (BRS) on the exercise HR response in the early phase of vagal deactivation and in the later phase of sympathetic excitation via metabolic stimulation. METHODS: Twenty-four patients (18 males and 6 females, age 59+/-9 years) with heart disease underwent symptom-limited treadmill exercise testing according to the Bruce protocol, and BRS was measured utilizing the phenylephrine method. Subjects were grouped by their resting BRS value: 12 with normal BRS (> or =6 ms/mmHg) and 12 with depressed BRS (<6 ms/mmHg). The HR response to exercise was assessed using two parameters: the increment in HR during exercise and the ratio of HR response to the metabolic reserve (chronotropic index). RESULTS: (1) In the patients with depressed BRS, the HR responses within 1 min after the start of exercise and from 1 min to peak exercise were attenuated compared with those having a normal BRS (15+/-8 vs. 24+/-8 bpm and 36+/-9 vs. 47+/-15 bpm, respectively). (2) The chronotropic index in the patients with depressed BRS was lower than in those with normal BRS (0.50+/-0.14 vs. 0.64+/-0.08). CONCLUSION: These findings suggest that impaired BRS modulates both the parasympathetic influence in early exercise and sympathetic effects in the later phase on HR response to exercise.

[Detection of myocardial ischemia by analysis of the shape of exercise-induced ST elevation in infarct-related leads].

OBJECTIVES: Possible mechanisms of exercise-induced ST elevation in infarct-related leads include ventricular dyskinesis, and myocardial ischemia in the infarct region. Detection of ischemia in viable myocardium in the infarct region is important to determine the therapeutic strategy. This study evaluated whether the analysis of the shape of exercise-induced ST elevation(convex or concave type) is useful to detect myocardial ischemia in the infarct region. METHODS: Ninety-eight patients (78 males, 20 females, mean age 59 +/- 10 years) with prior Q wave myocardial infarction underwent the treadmill exercise test. Patients were divided into three groups according to the exercise-induced ST changes: No ST-E group, 27 patients without ST changes; Concave ST-E group, 52 patients with concave type ST elevation; Convex ST-E group, 19 patients with convex type ST elevation. Coronary arteriography was evaluated in all patients. Dobutamine stress echocardiography was performed in 38 patients, including 28 patients in the Concave ST-E group and 10 patients in the Convex ST-E group. Biphasic or worsening response on dobutamine stress echocardiography was defined as ischemic response. RESULTS: Coronary arteriography revealed significant stenosis of the infarct-related artery in 30% of the No ST-E group, 47% in the Convex ST-E and 86% in the Concave ST-E groups (p < 0.05). Dobutamine stress echocardiography revealed myocardial ischemia in the infarct region in 30% in the Convex ST-E group and 75% in the Concave ST-E group(p < 0.05). CONCLUSIONS: The Concave ST-E group had a higher incidence of stenosis of the infarct-related artery and myocardial ischemia in the infarct region. Analysis of the shape of exercise-induced ST elevation in infarct-related leads is useful for the detection of ischemia of viable myocardium.