Efficacy and Safety of Acute Phase Intensive Electrical Muscle Stimulation in Frail Older Patients with Acute Heart Failure: Results from the ACTIVE-EMS Trial.

As frailty in older patients with acute heart failure (AHF) has an adverse effect on clinical outcomes, the addition of electrical muscle stimulation (EMS) to exercise-based early rehabilitation may improve the effects of treatment. Post hoc analysis was performed on a randomized controlled study for clinical outcomes and prespecified subgroups (ACTIVE-EMS: UMIN000019551). In this trial, 31 AHF patients aged ≥ 75 years with frailty (Short Physical Performance Battery [SPPB] score 4-9) were randomized 1:1 to receive treatment with an early rehabilitation program only (n = 16) or early rehabilitation with add-on EMS therapy (n = 15) for 2 weeks. Changes in physical function and cognitive function between baseline and after two weeks of treatment were assessed. There were no adverse events during the EMS period. The EMS group showed significantly greater changes in quadriceps' isometric strength and SPPB compared to the control group, and EMS therapy showed uniform effects in the prespecified subgroups. There were no significant differences in the changes in other indexes of physical function and cognitive function between groups. There was no significant difference in the rate of heart failure hospitalization at 90 days between groups. In conclusion, older AHF patients with frailty showed greater improvement in lower extremity function with the addition of EMS therapy to early rehabilitation without adverse events.

D-dimer levels in patients with nonvalvular atrial fibrillation and acute heart failure treated with edoxaban.

BACKGROUND: D-dimer levels can predict ischemic stroke in patients with acute heart failure (AHF). However, the effects of direct oral anticoagulants on D-dimer levels have not been investigated during admission for AHF in patients with atrial fibrillation (AF). This study examined D-dimer levels immediately after admission and following edoxaban initiation as a sub-analysis of a multi-center study that investigated the pharmacokinetics and pharmacodynamics of edoxaban in patients with nonvalvular AF (NVAF) and AHF. METHODS: Hospitalized patients with NVAF and AHF received edoxaban according to the label. The primary measure was the change in D-dimer levels on 7 consecutive days after admission for AHF. We also investigated differences according to prior edoxaban use (de novo at the time of admission or continuation). RESULTS: In 10/13 (76.9%) de novo patients, D-dimer levels exceeded the reference value (1.0 µg/mL) at admission (mean, 2.12 µg/mL) and subsequently decreased in 9 patients (at final blood sampling: mean, 1.12 µg/mL); 1 patient did not fall below the reference value due to stasis dermatitis. In the continuation group, most patients had D-dimer levels below the reference value from Day 1 (mean, 0.93 µg/mL), and levels remained stable or decreased (at final blood sampling: mean, 0.49 µg/mL). No events of stroke were observed. CONCLUSIONS: D-dimer levels may be elevated in patients with NVAF and AHF, particularly in those without prior anticoagulant treatment. Edoxaban may be effective for lowering and keeping D-dimer levels, a biomarker for predicting ischemic stroke, below the reference value in patients with NVAF and AHF.

Plasma Concentration and Pharmacodynamics of Edoxaban in Patients with Nonvalvular Atrial Fibrillation and Acute Heart Failure.

OBJECTIVE: The objective of this study was to assess the pharmacokinetic and pharmacodynamic profiles and safety of edoxaban in patients with nonvalvular atrial fibrillation (NVAF) who were hospitalized with acute heart failure (AHF). METHODS: The trough plasma concentrations of edoxaban, and the coagulation biomarkers prothrombin fragments 1 and 2 (F1+2) and D-dimer, were determined. Twenty-six patients received edoxaban 60 mg (30 mg when dose adjustment was required) and blood samples were collected immediately before oral edoxaban administration for 7 consecutive days after hospitalization and on the day of discharge. RESULTS: The mean observation period was 13 (range 7-46) days. Trough plasma concentrations of edoxaban were constant from day 2 onwards. On day 1, the variation was greater owing to the differing intervals between the last edoxaban dose and day 1 blood collection. Trough plasma concentrations were higher in patients with reduced creatinine clearance (≤ 50 mL/min). Median values for F1+2 and D-dimer remained within normal ranges throughout the study. There were no drug discontinuations, and no serious adverse events were reported. CONCLUSIONS: This is the first study of edoxaban pharmacokinetics and pharmacodynamics in patients with NVAF and AHF, and shows that the pharmacokinetic and pharmacodynamic profiles of edoxaban were constant during hospitalization. Thus, even in patients with NVAF and AHF, edoxaban anticoagulation therapy with guided dose adjustment is considered to be a safe and appropriate intervention. In particular, patients with reduced creatinine clearance should adhere to dose adjustment criteria. CLINICAL TRIAL REGISTRATION: jRCTs031190006 (Japan Registry of Clinical Trials), 5 April, 2019 retrospectively registered.

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

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

Effects of Acute Phase Intensive Electrical Muscle Stimulation in Frail Elderly Patients With Acute Heart Failure (ACTIVE-EMS): Rationale and protocol for a multicenter randomized controlled trial.

In elderly patients with acute heart failure (AHF), clinical outcome is adversely affected by frailty. Although a number of potentially effective interventions for frailty have been reported, little is known about the effects of rehabilitation programs in frail elderly AHF patients. We postulated that addition of electrical muscle stimulation (EMS), which induces muscle contraction without requiring patient volition, to early rehabilitation would be efficacious in frail elderly AHF patients. The ACTIVE-EMS (Effects of Acute Phase Intensive Electrical Muscle Stimulation in Frail Elderly Patients With AHF; UMIN000019551) trial is a multicenter, randomized controlled trial that will enroll 80 patients from 3 hospitals in Japan. AHF patients age ≥ 75 years positive for frailty, defined as Short Physical Performance Battery score 4 to 9, will be randomly assigned to receive early rehabilitation program only or EMS add-on therapy for 2 weeks. The primary endpoint of the trial is the change in quadriceps isometric strength between baseline and 2 weeks, with changes in physical function and cognitive function, and clinical safety and feasibility of EMS therapy as secondary outcomes. ACTIVE-EMS is the first randomized trial to evaluate the clinical effectiveness of adding EMS therapy to early rehabilitation in frail elderly AHF patients. The results of this study will provide insight for the development of appropriate rehabilitation programs for this high-risk population.

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

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

Two-week interval optical coherence tomography: imaging evidence on neointimal coverage completion after implantation of the Endeavor zotarolimus-eluting stent.

OBJECTIVE: To obtain imaging evidence by 2-week optical coherence tomography (OCT) on the completion of neointimal coverage (NIC; the percentage of stent strut coverage and thickness of the formed neointima) completion after implantation of the Endeavor zotarolimus-eluting stent (E-ZES). BACKGROUND: Despite the fact that NIC is a cardinal process in the pathomechanism of late stent thrombosis, little imaging information is available on morphological changes thereof on a short-time interval basis. METHODS: 27 Japanese patients with stable angina pectoris and de novo native coronary artery lesions were enrolled, and 27 lesions (30 implantations) were examined. OCT was performed at weeks 2, 4, 6, 8, and 10 after E-ZES implantation. NIC was examined using cross-sectional OCT images obtained at the 1.0-mm intervals. RESULTS: In total, 621 cross-sectional OCT images, which depicted 7,747 stent struts, were analyzed. The mean percentages of stent strut coverage at weeks 2, 4, 6, 8, and 10 after E-ZES implantation were 12.3, 70.4, 67.9, 86.0, and 99.2%, respectively; a marked increase was found between weeks 2 and 4. The mean thicknesses of the formed neointima were 40.2, 52.1, 48.1, 86.5, and 146.2 µm at respective weeks, with the high-signal and thick neointima (146 µm) at week 10. An intracoronary thrombus was detected in only one stent at week 4. CONCLUSIONS: The full circumferential coverage of the vessel wall by the high-signal neointima was found at as early as week 10 after E-ZES implantation, imparting a surrogate index for vascular healing by NIC.

Long-term outcome of acute myocardial infarction patients treated with stents versus balloon angioplasty: results from randomized trials.

AIM: To examine the impact of primary stent implantation versus balloon angioplasty on long-term outcome (median 8 years) in 117 patients with ST-elevation myocardial infarction (STEMI) from randomized trials. METHODS: Enrolled patients were those presenting with STEMI within 12 h of symptom onset. Patients were randomized to either Palmaz-Schatz stent implantation (N=25) or balloon angioplasty (N=23) between January and November 1996; or Palmaz-Schatz (N=26), or Cordis coil stent implantation (N=24) or balloon angioplasty (N=19) between February 1998 and March 1999. RESULTS: Patients (67+/-11 years) arrived to the hospital within median 2.5 h of symptom onset with Killip 1/2/3/4 grade (72/19/7/2%, respectively). The culprit lesion was located in the left anterior descending (50%), right (39%), or left circumflex coronary artery (11%) with TIMI 0/1/2/3 flow (81/5/12/2%, respectively). Clinical/angiographic features were comparable between the 2 groups. During follow-up, there was a significant reduction in cardiac mortality in the stent group (5%) compared to the angioplasty group (17%, log-rank test p=0.04). In addition, the stent group had a lower target lesion revascularization rate (28% versus 52%, p=0.008), and a significantly lower major adverse cardiac event rate (37% versus 67%, p=0.005), than the angioplasty group. CONCLUSION: Compared to balloon angioplasty, primary stenting resulted in a sustained beneficial effect on cardiac mortality at 8 years.

Percutaneous coronary intervention using a novel 4-French coronary accessor.

BACKGROUND: Percutaneous coronary intervention (PCI) using a guiding catheter with small diameters may have a favorable impact on vascular access complications and patient morbidity. Here, we report the initial results of PCI using a 4-Fr coronary accessor. METHODS: A total of 31 patients underwent 4-Fr PCI. Exclusion criteria for 4-Fr PCI were (1) lesions associated with large side branches requiring wire protection or kissing balloon technique and (2) planned use of angioplasty devices which were not compatible with 4-Fr catheter. RESULTS: A total of 36 lesions, including 4 chronic total occlusions (CTO), were treated. Access sites included radial artery in 19 patients (61%), brachial artery in 8 (26%), and femoral artery in 4 (13%). Four-Fr PCI was successful in 34 of 36 lesions (94%) in 29 of 31 patients (94%). One of the two unsuccessful patients was a case of CTO, and the other a case of tortuous right coronary artery. In both, crossover to a 6-Fr PCI was necessary. Among successfully treated 34 lesions of the 29 patients, coronary stents were deployed in 30 lesions (88%). There were no stent dislodgements or inadequate contrast opacification. No access-site related complications including radial artery occlusion were observed. CONCLUSIONS: PCI with a 4-Fr coronary accessor is a viable alternative to the use of larger guide catheters. The advent of 4-Fr stent delivery system may afford a less invasive approach for the treatment of patients with coronary artery disease.

[Qualitative and quantitative evaluation of coronary plaques with 64-slice computed tomography in comparison with intravascular ultrasound].

OBJECTIVE: To explore the diagnostic feasibility of noninvasive assessment of coronary atherosclerotic plaques with MSCT in comparison with IVUS. METHODS: Contrast-enhanced MSCT angiography (Sensation 64, Siemens Medical Solutions) was performed before percutaneous coronary intervention (PCI), and three-vessel IVUS (Boston Scientific, Natick, MA) was performed during procedure in 12 patients with stable angina pectoris. Complete investigation was digitally stored, and assessed offline with EchoPlaque (Indec Systems, Mountain View, CA). The comparison of MSCT with IVUS was performed based on segment at plaque site (American Heart Association 15-segment model). RESULTS: A total of 88 segments in 31 vessels (left anterior descending: 12, left circumflex: 10, and right coronary artery: 9) were investigated by both IVUS and MSCT. Among 68 assessable segments (54 proximal-middle segments and 14 distal segments) by MSCT (20 segments were excluded for poor image quality: 16 for severe calcification, 2 for motion artifact, 2 for poor opacification), MSCT correctly detected 47 of the 51 segments with plaques (sensitivity: 92%), and correctly evaluated 16 of 17 segments without plaques (specificity: 94%). Concerning plaque quantification, MSCT correlated well with IVUS in grading whether the vessel obstruction was less or more than 50% (simple kappa: 0.63, 95% CI: from 0.47 to 0.78). Plaque area by MSCT also correlated with that by IVUS (r = 0.53, P < 0.01), but overestimated plaque area [(9.09 +/- 3.89) mm(2) vs. (6.80 +/- 2.81) mm(2), P < 0.01]. In addition, 30 of 43 hypoechoic compositions were detected as low-density compositions by MSCT with average CT number as 67.39 HU. CONCLUSIONS: In segments without severe calcification, contrast-enhanced 64-slice CT angiography could detect plaques in coronary artery with high accuracy. Plaque area quantification by MSCT correlated with that of IVUS though with limited accuracy.

Late angiographic stent thrombosis after sirolimus-eluting stent implantation.

BACKGROUND: Although drug-eluting stents dramatically reduce revascularization after percutaneous coronary intervention (PCI), it is still unclear whether they increase the risk of stent thrombosis. Late stent thrombosis (>30 days) was a very rare complication after bare metal stent implantation. Four cases of confirmed late angiographic stent thrombosis (LAST) after sirolimus-eluting stent (SES) implantation are presented and the incidence, promoting factors and outcomes of such cases in Japan, where clopidogrel has not been approved, are described. METHODS AND RESULTS: Between September 2004 and March 2006, 725 patients underwent PCI with SES implantation and 679 patients (94%) were clinically followed up (median 271 days). There were 4 cases (0.6%) of LAST (at 60, 180, 215, and 508 days, respectively) after elective SES implantation resulting in myocardial infarction. Three cases occurred soon after antiplatelet therapy discontinuation 3 patients died after LAST events. The incidence of LAST was 0.6%. CONCLUSIONS: LAST is a rare complication, even after SES implantation, at least in patients with appropriate antiplatelet therapy. However, as it can lead to fatal complications, it must be taken into account, especially when antiplatelet therapy is discontinued.

A serious complication of a power injector for coronary angiography.

Recently several contrast delivery systems for coronary angiography have been introduced to provide adequate artery opacification through small catheters, which are thought to facilitate patient comfort and reduce hemorrhagic/vascular complications. However, the safety profile of a specific system has not been fully examined. In this case report, we present patients who underwent angiography using a contrast delivery system and suffered from massive air embolism necessitating mechanical support. We discuss the potential mechanism and the prevention of this complication.

New method to increase a backup support of a 6 French guiding coronary catheter.

A 6 Fr guiding catheter is commonly used in the percutaneous coronary intervention (PCI). However, one of the limitations of the 6 Fr guiding catheter is its weak backup support compared to a 7 or an 8 Fr guiding catheter. In this article, we present a new system for PCI called the five-in-six system. Between March 2003 and September 2003, this system was tried on eight chronic total occlusion cases. The advantage of the five-in-six system is that it increases backup support of a 6 Fr guiding catheter.

Analysis of postextrasystolic relaxation response in the human heart.

Postextrasystolic potentiation is the phenomenon in which ventricular contractile force is strengthened by a preceding premature beat. However, the response of diastolic function after an extrasystole is unknown. We studied 58 patients with chronic heart failure (CHF) and two control subjects to evaluate the response of relaxation following extrasystole. At cardiac catheterization, from the derivative of the left ventricular (LV) pressure, the ratio of LV peak negative dP/dt (-dP/dt) of a postextrasystole to a basal beat was calculated and defined as the postextrasystolic relaxation response (PRR). PRR was compared with parameters of left ventriculography: LV end-diastolic volume index (EDVI), LV end-systolic volume index (ESVI), and LV ejection fraction (EF). The PRRs of the two control subjects were 0.80 and 0.84. The mean PRR of the CHF patients was 0.99 +/- 0.15. In all subjects, including patients and controls, correlation analysis between (EDVI, ESVI, and EF) and PRR yielded the following: (a) EDVI vs. PRR: R = 0.273, p = 0.036; (b) ESVI vs. PRR: R = 0.446, p < 0.001; and (c) EF vs. PRR: R = -0.520, p < 0.001. Thus, normal or non-failing human hearts showed a decline of -dP/dt in postextrasystole compared with the basal beats, but failing hearts had potentiated relaxation following an extrasystole.

Time course of gene expression in rat experimental autoimmune myocarditis.

Genetic responses that characterize experimental autoimmune myocarditis (EAM) have not yet been determined. To investigate gene expression in the myocardium of EAM, absolute copy numbers of 44 mRNA species [calcium-handling proteins, contractile proteins, natriuretic peptides (NPs), cytokines, chemokines, growth factors, renin-angiotensin-aldosterone (RAA) system, endothelins (ETs) and extracellular matrix] in synthesized cDNA from a fixed quantity of total heart RNA were assessed using real-time reverse-transcriptase PCR at days 0, 14, 21 and 28 after immunization. alpha-Cardiac myosin showed a 26.3-fold decrease and beta-cardiac myosin a 3.75-fold increase at day 14. Atrial NP and brain NP increased 47.7- and 6.35-fold at days 21 and 14 respectively. Angiotensin II type 1 receptor, angiotensin-converting enzyme and ET1 increased 22.3-fold at day 21, 6.30-fold at day 21 and 16.8-fold at day 14 respectively. Aldosterone receptor decreased 2.15-fold at day 14, but aldosterone synthetase was detected only at days 14 and 21. Interleukin (IL)-2, IL-10, interferon-gamma and monocyte chemo-attractant protein-1 increased 9.08-fold at day 14, 398-fold at day 21, 43.1-fold at day 14 and 142-fold at day 14 respectively. Collagen type 3, collagen type 1 and fibronectin increased 34.6-, 1.74- and 44.4-fold respectively at day 21. Interestingly, osteopontin showed a 4540-fold increase and it was the highest mRNA of all at day 14. An isoform of cardiac myosin and NP are dramatically changed in EAM. RAA system and ET expressions are changed differently during the EAM time course. Cytokine, chemokine and extracellular matrix greatly increase and, in particular, large numbers of osteopontin mRNA are expressed in early EAM.