Efficacy and safety of remote cardiac rehabilitation in the recovery phase of cardiovascular diseases (RecRCR study): A multicenter, nonrandomized, and interventional trial in Japan.

Backgrounds: Remote cardiac rehabilitation has proven useful in patients with cardiovascular disease; however, the methodology had not been fully validated. This study aimed to investigate the efficacy and safety of remote cardiac rehabilitation (RCR) with real-time monitoring and an ergometer using a bidirectional communication tool during the recovery phase of cardiovascular diseases. Methods: This multicenter, nonrandomized, interventional study was conducted at 29 institutions across Japan and enrolled patients with cardiovascular diseases who met indications for cardiac rehabilitation (CR) after receiving in-hospital treatment. The RCR group exercised at home using an ergometer and was monitored in real-time using interactive video and monitoring tools for 2-3 months. Educational instructions were provided concurrently through e-learning approaches. The safety of the RCR protocol and the improvement in peak oxygen consumption (VO2) were compared with those of the historical control group that participated in center-based CR. Results: Fifty-three patients from the RCR group were compared with 103 historical controls having similar background characteristics. No patients in RCR experienced significant cardiovascular complications while engaging in exercise sessions. After 2-3 months of RCR, the peak VO2 improved significantly, and the increases in the RCR group did not exhibit any significant differences compared to those in the historical controls. During follow-up, the proportion of patients whose exercise capacity increased by 10% or more was also evaluated; this finding did not indicate a statistically significant distinction between the groups. Conclusions: RCR during the recovery phase of cardiovascular diseases proved equally efficient and safe as center-based CR.

An Autopsy Case of Fulminant Myocarditis with Massive Left Ventricular Calcification.

Myocardial calcification in myocarditis is rare and may be linked to poor outcomes. We herein report a case of fulminant myocarditis with massive myocardial calcification and its pathological outcomes at autopsy. A 49-year-old man experienced chest pain and was diagnosed with acute myocarditis. His cardiac function did not recover despite mechanical circulatory support in combination with V-A extracorporeal membrane oxygenation and IMPELLA CP®. He eventually developed sepsis and gastrointestinal bleeding and died on day 27. Diffuse myocardial calcification was observed on computed tomography at autopsy. The pathological autopsy depicted that calcification filled every myocardial cell in the left ventricle.

Impact of pemafibrate on lipid profile and insulin resistance in hypertriglyceridemic patients with coronary artery disease and metabolic syndrome.

This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24 weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n = 41) and those without MetS (non-MetS group, n = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. Serum TG levels significantly decreased (MetS group, from 266.6 to 148.0 mg/dL, p < 0.001; non-MetS group, from 203.9 to 97.6 mg/dL, p < 0.001); however, a percent change (%Change) was not significantly different between the groups (- 44.1% vs. - 51.6%, p = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, - 25.1% vs. - 11.3%, p = 0.027; gamma-glutamyl transferase, - 45.8% vs. - 36.2%, p = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.

Effects of switching from sacubitril/valsartan to valsartan alone on plasma levels of natriuretic peptides and myocardial remodeling in heart failure with reduced ejection fraction.

BACKGROUND: We examined the effect of switching from angiotensin receptor-neprilysin inhibitor (ARNI) to angiotensin-receptor blocker (ARB) on plasma levels of natriuretic peptides and myocardial remodeling. METHODS: This is a prospective study that included 11 patients with heart failure (HF) treated with ARNI. The patients were divided into two groups: 5 patients who continued treatment with sacubitril/valsartan 194/206 mg/day (ARNI-continue group) and 6 patients who were switched to valsartan 160 mg/day (ARB-switch group). The primary endpoint was percent change (%Change) in plasma A-, B-, and N-terminal pro-B-type natriuretic peptide (ANP, BNP, and NT-proBNP) levels from the baseline to week 24. The secondary endpoint was the change in echocardiographic parameters related to myocardial remodeling from the baseline to week 24. RESULTS: ANP levels in the ARB-switch group significantly decreased (from 1155.7 ± 592.6 pg/mL to 231.6 ± 233.8 pg/mL, p = 0.035), whereas those in the ARNI-continue group were not significant (p = 0.180). The %Change of decrease in ANP levels was significantly greater in the ARB-switch group than the ARNI-continue group (- 76.9% vs. -9.1%, p = 0.009). BNP levels were not significantly different between the baseline and week 24 in both groups. NT-proBNP levels in the ARB-switch group increased from 1185.3 ± 835.6 pg/mL to 1515.2 ± 1213.5 pg/mL, although the changes were not statistically significant (p = 0.345). The %Change of increase in NT-proBNP levels was significantly greater in the ARB-switch group than the ARNI-continue group (57.9% vs. 17.3%, p = 0.016). In the ARB-switch group, there was a significant increase in left ventricular (LV) end-systolic volume (from 41.3 ± 24.1 mL/m2 to 71.4 ± 8.8 mL/m2, p = 0.043) and LV peak-systolic wall stress (from 187.0 ± 42.7 × 103 dynes/cm2 to 279.7 ± 34.1 × 103 dynes/cm2, p = 0.012) from the baseline to week 24 and a trend toward a decrease in LV ejection fraction (p = 0.080). In the ARNI-continue group, no differences in echocardiographic parameters were observed from the baseline to week 24. CONCLUSION: Switching from ARNI to ARB may worsen HF due to returning to myocardial remodeling induced by a sustained decline in ANP levels.

Efficacy and Safety of Pemafibrate Versus Bezafibrate to Treat Patients with Hypertriglyceridemia: A Randomized Crossover Study.

AIM: Pemafibrate is a highly selective agonist for peroxisome proliferator-activated receptor (PPAR)-α, a key regulator of lipid and glucose metabolism. We compared the efficacy and safety of pemafibrate with those of bezafibrate, a nonselective PPAR-α agonist. METHODS: In this randomized crossover study, 60 patients with hypertriglyceridemia (fasting triglyceride [TG] ≥ 150 mg/dL) were treated with pemafibrate of 0.2 mg/day or bezafibrate of 400 mg/day for 24 weeks. The primary endpoint was percent change (%Change) from baseline in TG levels, while the secondary endpoints were %Change in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) levels. RESULTS: The %Change in TG and Apo A-I levels was significantly greater with pemafibrate than with bezafibrate (-46.1% vs. -34.7%, p＜0.001; 9.2% vs. 5.7%, p =0.018, respectively). %Change in HDL-C levels was not significantly different between the two treatments. %Change in liver enzyme levels was markedly decreased with pemafibrate than with bezafibrate. Creatinine levels significantly increased in both treatments; however, its %Change was significantly lower with pemafibrate than with bezafibrate (5.72% vs. 15.5%, p＜0.001). The incidence of adverse events (AEs) or serious AEs did not differ between the two treatments; however, the number of patients with elevated creatinine levels (≥ 0.5 mg/dL and/or 25% from baseline) was significantly higher in the bezafibrate group than in the pemafibrate group (14/60 vs. 3/60, p =0.004) [corrected]. CONCLUSION: Compared with bezafibrate, pemafibrate is more effective in decreasing TG levels and increasing Apo A-I levels and is safer regarding liver and renal function.

Plasma kinetics of mature PCSK9, furin-cleaved PCSK9, and Lp(a) with or without administration of PCSK9 inhibitors in acute myocardial infarction.

BACKGROUND: There are two types of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9), mature and furin-cleaved. Most types of lipoprotein(a) [Lp(a)], an independent risk factor of cardiovascular events, bind to mature PCSK9. OBJECTIVE: This study examined the effects of monoclonal anti-PCSK9 antibody on plasma PCSK9 and Lp(a) levels in acute myocardial infarction (MI). METHODS: Acute MI patients (n=36) were randomly divided into evolocumab (140mg; n=17) and non-evolocumab (n=19) groups. Changes in plasma PCSK9 and Lp(a) levels were monitored before and 1, 3, 5, 10, and 20 days after evolocumab administration. RESULTS: In the non-evolocumab group, plasma levels of mature PCSK9, furin-cleaved PCSK9, and Lp(a) (236.4±57.3ng/mL, 22.4±5.8ng/mL, and 19.2.±16.5mg/dL, respectively) significantly increased by day 3 (408.8±77.1ng/mL, p<0.001; 47.2±15.7ng/mL, p<0.001; and 39.7±21.3mg/dL, p<0.005, respectively) and returned to the baseline by day 10 or 20. In the evolocumab group, mature PCSK9 significantly increased by >1000ng/mL with a simultaneous decline of furin-cleaved PCSK9 below the measurement sensitivity level after day 3. The incremental area under the curve for plasma Lp(a) levels was significantly smaller in the evolocumab group compared with the non-evolocumab group (p=0.038). CONCLUSION: Mature and furin-cleaved PCSK9 are transiently upregulated after MI onset. Evolocumab significantly increases mature PCSK9 and decreases furin-cleaved PCSK9 and might inhibit transient increase of plasma Lp(a) in acute MI.

Treadmill exercise prevents reduction of bone mineral density after myocardial infarction in apolipoprotein E-deficient mice.

AIMS: Recent clinical studies demonstrated the association between myocardial infarction (MI) and osteoporotic fractures. We examined whether MI causes bone loss and the effects of exercise training on bone in mice after MI. METHODS: We created a MI model in 16-week-old male apolipoprotein E-deficient mice (n = 42), which were randomly assigned to exercise group (MI-Ex) and sedentary group (MI-Sed). We also performed sham operations in other mice (n = 10). Treadmill exercise training was performed from one week after operation to eight weeks. At eight weeks, the bone parameters of the femur were measured by quantitative computed tomography, followed by histological analysis (n = 10-17). RESULTS: Bone mineral density (BMD) of the femur was significantly decreased in the MI-Sed group as compared with the sham group (P < 0.001), whereas the BMD was significantly increased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). In histological analysis, Rho-associated coiled-coil kinase 2 and tartrate-resistant acid phosphate positive (bone resorptive) area in distal femur were significantly increased in the MI-Sed group as compared with the sham group (P < 0.05), whereas those parameters were significantly decreased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). In contrast, alkaline phosphatase (ALP)-positive (bone-forming) area was significantly decreased in the MI-Sed group as compared with the sham group (P < 0.05), whereas ALP-positive area was significantly increased in the MI-Ex group as compared with the MI-Sed group (P < 0.05). CONCLUSIONS: The present study demonstrates that MI reduces BMD and treadmill exercise training prevents the reduction of BMD in apolipoprotein E-deficient mice.

Decline of popliteal artery flow-mediated dilation with aging and possible involvement of asymmetric dimethylarginine in healthy men.

PURPOSE: We examined the influences of age and gender on flow-mediated endothelial function and the involvement of the competitive inhibition of L-arginine in endothelial function. METHODS: We measured brachial and popliteal flow-mediated vasodilation (FMD) responses, nitrate/nitrite (NOx) concentrations, and plasma levels of asymmetric dimethylarginine (ADMA) in four healthy, nonsmoking groups: young men (mean 26 ± 2 years, n = 17), middle-aged men (mean 50 ± 3 years, n = 19), young women (mean 27 ± 2 years, n = 16), and middle-aged women (mean 51 ± 2 years, n = 18). RESULTS: In young men, we found no significant differences between brachial and popliteal artery FMDs (10.6 ± 1.5 vs 8.7 ± 1.6%, p = 0.06). However, the popliteal artery FMD was significantly lower than the brachial artery FMD in middle-aged men (11.4 ± 1.5 vs 6.4 ± 1.0%, p < 0.001). In women, we found no significant differences between brachial and popliteal artery FMDs in young and middle-aged individuals (young, p = 0.17; middle-aged, p = 0.08). Popliteal artery FMD correlated with plasma NOx and ADMA levels as well as with the NOx/ADMA ratio in men but not in women (r = 0.485, - 0.544, and 0.672, respectively). CONCLUSION: We concluded that a decrease in flow-mediated endothelial function in arteries of the lower extremities was evident in healthy middle-aged men, but not in middle-aged women. The competitive inhibition of L-arginine may contribute to this decrease in men.

Impact of decreased insulin resistance by ezetimibe on postprandial lipid profiles and endothelial functions in obese, non-diabetic-metabolic syndrome patients with coronary artery disease.

The association between insulin resistance and lipid dysmetabolism after consuming a meal is unclear. We aimed at assessing the effects of ezetimibe on postprandial hyperlipidemia and hyperinsulinemia and to find out whether the medication improves endothelial function in obese metabolic syndrome (MetS) patients with coronary artery disease (CAD). We obtained oral fat loading test results (4 and 6 h after load) and brachial flow-mediated vasodilation (FMD) measurements before and 24 weeks after ezetimibe treatment initiation from 27 MetS patients with CAD and from 68 control patients with CAD alone. Serum triglyceride (TG) and insulin levels (2 h after the loading dose) were significantly higher in MetS patients than in control patients. The incremental areas under the curve (iAUCs) for these levels decreased significantly after ezetimibe treatment in MetS patients but not in control patients. Treatment with ezetimibe resulted in significant FMD changes in MetS patients (from 3.4 to 4.9%, P = 0.002), but not in control patients (from 5.1 to 5.4%, P = 0.216). When MetS patients were divided into two groups based on the median insulin iAUC reduction rate (higher group ≥ 34%, n = 14; lower group < 34%, n = 13), those in the higher group showed a significantly higher rate of change in the iAUCs of TG and FMD than those in the lower group (TG, 31.0% vs. 10.8%; P = 0.033; FMD, 39.2% vs. 9.8%; P = 0.037). These results suggest that ezetimibe may reverse insulin resistance, reducing lipid dysmetabolism after a meal and endothelial dysfunction in MetS patients with CAD.

Percutaneous transradial artery approach for femoro- popliteal artery intervention in the current era in Japan.

The percutaneous transradial artery approach for coronary angiography and intervention has been recognized as a safe and effective method, however, it is limited for endovascular therapy (EVT) for femoro-popliteal artery because of lack of devices with longer shaft. Herein, we report two EVT cases for superficial femoral artery disease treated with a long shaft balloon through the radial artery. Although femoro-popliteal artery intervention with this approach has several limits for available devices and technical issues, it is effective for particular patients who are impossible in EVT with femoral artery approach.

Sudden failure of ventricular pacing and recovery in a patient with cardiac sarcoidosis.

A 76-year-old woman with sarcoidosis who had an implantable pacemaker for complete atrioventricular block was admitted with syncope. Electrocardiogram revealed ventricular pacing failure, and a marked rise in the ventricular pacing threshold. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) indicated increased uptake of FDG in the ventricular septum. Three days after steroid therapy, the ventricular pacing threshold reverted to normal, and FDG-PET showed decreased FDG uptake in the ventricular septum. In this case report, we demonstrate that a sudden deterioration in the ventricular pacing threshold due to worsening cardiac sarcoidosis can be reversed with early steroid therapy.

Comparison of the measured pre-ejection periods and left ventricular ejection times between echocardiography and impedance cardiography for optimizing cardiac resynchronization therapy.

BACKGROUND: The pre-ejection period (PEP) and left ventricular ejection time (LVET) are easily measured by impedance cardiography (ICG). We hypothesized that the PEP/LVET measured by ICG would correlate with that measured by echocardiography, and that PEP/LVET measured by ICG would be useful for cardiac resynchronization therapy (CRT) optimization. METHODS: Newly CRT implanted patients were optimized by echocardiography. The PEP/LVET was measured by echocardiography and ICG in two different settings: optimized setting and right ventricle (RV)-only pacing. RESULTS: The PEP/LVET was significantly decreased in the optimized setting compared with that in RV-only pacing (0.62±0.13 vs 0.75±0.16, p<0.05). The PEP/LVET values calculated by ICG and echocardiography were positively correlated (r=0.553, p=0.003). CONCLUSION: ICG was useful for the optimization of CRT.

Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. METHODS AND RESULTS: Experimental AAA was induced in Apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. CONCLUSIONS: Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.

Reliable ferrocenyloligonucleotide-immobilized electrodes and their application to electrochemical DNase I assay.

A ferrocenyloligonucleotide (FcODN) having contiguous cytosine bases was immobilized effectively and reproducibly on a gold electrode furnished with a self-assembled monolayer (SAM) having an N-hydroxysuccinimide-activated carboxylic acid. The resulting electrode was used as a sensor chip in DNase I assay. Thus, the current response of the modified electrode decreased upon addition of DNase I, demonstrating that the phosphodiester bonds of FcODN were cleaved. The DNase I activity assessed by Deltai defined as (i0-i)/i0, where i0 and i represent the current before and after DNase I treatment, respectively, was found to be reproducible with a standard deviation not greater than 9%. The DNase I can be quantitated in the range of 10(-5) to 10(-3) units microL(-1) with a detection limit of 10(-5) units microL(-1) with this sensor chip. The current signal of the FcODN electrode was stable to storage in Biopak water up to 16 days with a 30% signal decrease over this period. DNase I activity in human sera was also determined successfully with this sensor chip.

Electrochemical assay for deoxyribonuclease I activity.

A thiolated oligonucleotide having three ferrocenes was immobilized on a gold electrode through the sulfur-gold linkage. This electrode showed a current response based on the redox reaction of the ferrocene moieties and this response was decreased after treatment with deoxyribonuclease I (DNase I), suggesting the disappearance of the ferrocene moieties on the electrode by the DNase I digestion. A linear correlation between i(0) and i, which are current peaks before and after DNase I treatment, respectively, was observed and this slope was decreased with increase in the amount of DNase I. No current decrease was observed in the presence of EDTA or RNase A instead of DNase I. These results suggested that the current decrease responded specifically to the amount of DNase I and this electrode could be used for an electrochemical DNase I assay. Under the optimum conditions of DNase I digestion at 37 degrees C for 30 min, a quantitative analysis could be achieved in the range of 10(-4)-10(-2)units/microl of DNase I.

Ferrocenylnaphthalene diimide-based electrochemical ribonuclease assay.

Messenger RNA (mRNA) poly(A)+RNA (from mouse kidney) was immobilized on a N-hydroxysuccinimide(NHS)-activated carboxylic acid modified electrode prepared by the treatment of a gold electrode with 3,3'-dithiodipropionic acid, followed by NHS and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). An electrochemical measurement using this mRNA electrode was carried out in an electrolyte containing ferrocenylnaphthalene diimide (1), and showed an electrochemical signal based on 1 concentrated on immobilized mRNA. After treating this electrode with water containing varied amounts of ribonuclease A (RNase A), the current peak based on 1 decreased with increasing in the amount of RNase A with a linear correlation in the range of 0.2-10 pg of RNase A.

Electrochemical RNase detection using ferrocenylnaphthalene diimide.

To develop a conventional RNase detecting system, an RNA electrode was constructed by the immobilization of poly(A)+RNA from mouse kidney on the glassy carbon electrode. Electrochemical measurement using this RNA electrode in the electrolyte containing ferrocenylnaphthalene diimide (1) was carried out and showed the electrochemical signal depending on the amount of the immobilized RNA. After this electrode was treated with water, the differential pulse voltammetric (DPV) measurement was subsequently conducted in the electrolyte containing 1. When RNase is contained in the water, the electrochemical signal decreased with an increase of the amount of RNase. This is derived from the decreasing amount of RNA on the electrode by RNase. In DPV measurement, the concentration of RNaseA was linear in the range of 10(-10) - 10(-8) M and the amount of RNase in the tap water could be estimated.

Electrochemical detection of DNase I activity.

DNase I in one microl of the water could quantitate electrochemically with the detection limit of 0.01 units (ca. 20 pg) by using the ferrocenyl oligonucleotide-immobilized electrode prepared by thiolated oligonucleotide and ferrocenyl carbodiimide as a simple labeling reagent of redox unit.

Recombinant human serum albumin dimer has high blood circulation activity and low vascular permeability in comparison with native human serum albumin.

PURPOSE: Human serum albumin (HSA) is used clinically as an important plasma expander. Albumin infusion is not recommended for critically ill patients with hypovolemia, burns, or hypoalbuminemia because of the increased leakage of albumin into the extravascular spaces, thereby worsening edema. In the present study, we attempted to overcome this problem by producing a recombinant HSA (rHSA) dimer with decreased vascular permeability and an increased half-life. METHODS: Two molecules of rHSA were genetically fused to produce a recombinant albumin dimer molecule. The pharmacokinetics and biodistribution of the recombinant proteins were evaluated in normal rats and carrageenin-induced paw edema mouse model. RESULTS: The conformational properties of this rHSA dimer were similar to those for the native HSA (the HSA monomer), as evidenced by the Western blot and spectroscopic studies. The biological half-life and area under the plasma concentration-time curve of the rHSA dimer were approximately 1.5 times greater than those of the monomer. Dimerization has also caused a significant decrease in the total body clearance and distribution volume at the steady state of the native HSA. rHSA dimer accumulated to a lesser extent in the liver, skin, muscle, and fat, as compared with the native HSA. Up to 96 h, the vascular permeability of the rHSA dimer was less than that of the native HSA in paw edema mouse models. A prolonged plasma half-life of the rHSA dimer was also observed in the edema model rats. CONCLUSIONS: rHSA dimer has a high retention rate in circulating blood and a lower vascular permeability than that of the native HSA.