Cardiac Rehabilitation for Patients With Stable Ischemic Heart Disease Without Revascularization　- Rationale and Design of a Single-Arm Pilot Study.

Background: Clinical practice guidelines strongly recommend optimal medical therapy (OMT), including lifestyle modification, pharmacotherapy, and exercise-based cardiac rehabilitation (CR), in patients with stable ischemic heart disease (SIHD). However, the efficacy and safety of CR in patients with SIHD without revascularization remain unclear. Methods and Results: The Prospective Registry of STable Angina RehabiliTation (Pre-START) study is a multicenter, prospective, single-arm, open-label pilot study to evaluate the efficacy and safety of CR on health-related quality of life (HRQL), exercise capacity, and clinical outcomes in Japanese patients with SIHD without revascularization. In this study, all patients will undergo guideline-based OMT and are encouraged to have 36 outpatient CR sessions within 5 months after enrollment. The primary endpoint is the change in the Seattle Angina Questionnaire-7 summary score between baseline and the 6-month visit; an improvement of ≥5 points will be defined as a clinically important change. Secondary endpoints include changes in other HRQL scores and exercise capacity between baseline and the 6-month visit, as well as clinical outcomes between enrollment and the 6-month visit. Conclusions: The Pre-START study will provide valuable evidence to elucidate the efficacy and safety of CR in patients with SIHD and indispensable information for a subsequent randomized controlled trial. The study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (ID: UMIN000045415) on April 1, 2022.

A model for predicting the time of early symptomatic restenosis after infrapopliteal angioplasty in patients with critical limb ischemia.

The objective of this study is to develop a model for predicting the time of early symptomatic (delayed or nonhealing wound) restenosis after infrapopliteal angioplasty in patients with critical limb ischemia (CLI). This is a single-center retrospective cohort study evaluating 60 de novo infrapopliteal lesions of 38 limbs in 35 patients with CLI, who underwent successful endovascular treatment (EVT) from October 2016 to December 2018 and follow-up angiography within 3 months from the procedure. Outcome measures were binary restenosis at follow-up angiography and clinical outcome at 3 months. Patient/limb/lesion characteristics were compared between the restenosis and non-restenosis groups. Angiographic restenosis predictors were assessed to develop a model for predicting the time of restenosis using multinomial logistic regression. The restenosis rate at follow-up angiography (median time, 41 days [IQR 27-58 days]) was 38% (23/60). After adjustment for covariables, longer period between EVT and follow-up angiography and lower C-reactive protein (CRP) were the predictors of angiographic restenosis. We developed a model for predicting the time of early symptomatic restenosis with a probability of 70%: "Days = 200 - 2.1 age - 13 CTO + 3.3 CRP" (R2 = 0.81, RMSE = 0.27), e.g., 80 years old, CTO (+), CRP 4.4 mg/dl: 32.2 days. The predictive model including age, CTO, and CRP might allow estimation of the period for the angiographic restenosis development.

Brachial-Ankle Pulse Waves Reflect the Hemodynamics of Valvular Heart Disease.

BACKGROUND: Brachial-ankle pulse wave (ba-PW) analysis is an established technique for assessing arterial stiffness and cardiovascular risk. The peripheral arterial pulse wave configuration may be useful for valvular heart disease (VHD) detection because it is closely related to the physical signs of VHD; however, few reports have been made assessing the efficacy of ba-PW analysis for VHD screening. METHODS: Consecutive VHD patients scheduled for valve surgery were enrolled in the study. These included 58 patients with aortic stenosis (AS) (mean age 74 ± 1.1 years), 67 with aortic regurgitation (AR) (mean age 59 ± 1.9 years), and 65 with mitral regurgitation (MR) (mean age 62 ± 1.6 years). Ba-PW analysis was conducted using the VaSera VS-1500 screening system before and after surgery. Upstroke time (UT), ejection time (ET), pre-ejection period (PEP), PEP/ET ratio, mean arterial pressure (%MAP), and cardio-ankle vascular index (CAVI) were compared with a control group (n = 65; mean age 69 ± 1.5 years) without VHD. RESULTS: The UT was significantly shorter in the AR group (132.9 ± 4.0 ms) and MR group (134.5 ± 2.5 ms), but significantly longer in the AS group (178.2 ± 2.8 ms) compared to controls (149.6 ± 3.6 ms; all p <0.01). The ET was significantly longer in the AS group (318.5 ± 7.4 ms) and AR group (320.0 ± 4.6 ms), but significantly shorter in the MR group (289.0 ± 3.8 ms) compared to controls (305.3 ± 3.4 ms; all p <0.05). In ROC analyses of each group compared to controls, areas under the curve of UT, corrected (c)UT, ET and cET in the AS group, UT/ET ratio in the AR group, and PEP/UT ratio in the MR group were all >0.7. CONCLUSIONS: Multiple pulse wave parameters reflect VHD hemodynamics and may be useful for screening for the condition.

Usefulness of peripheral arterial signs in the evaluation of aortic regurgitation.

BACKGROUND: Early diagnosis and optimal timing of surgical repair for chronic aortic regurgitation (AR) are topics of interest, because left ventricular compensation delays the clinical signs of the early stages of left ventricular dysfunction. Various physical signs have been described as indicators of chronic AR, but AR screening can be difficult depending on the proficiency of primary care providers. The recent use of the cardio-ankle vascular index (CAVI) measurement to assess peripheral atherosclerosis may detect AR objectively and simply because its arterial pulse wave configuration is closely related to the physical signs of AR. METHODS: CAVI measurements include pulse pressure (PP), the difference in blood pressures between upper and lower limbs (ABD), ankle-brachial index (ABI), ejection time (ET), and upstroke time (UT). We evaluated the differences in CAVI parameters between AR group and age-matched control group, the relationships between CAVI parameters and the echocardiographic semi-quantitative measurements of AR severity such as left ventricular dimensions (Dd, Ds) and vena contracta (VC), and between the changes in CAVI parameters before and after aortic valve replacement. RESULTS: ABD, PP, ET, ankle systolic pressure and ABI in the AR group were significantly higher than that in the control group. Brachial diastolic pressure and CAVI in the AR group were significantly lower than that in the control group. UT was lower than that in the control group (p=0.05). PP did not correlate with the semi-quantitative AR severity, but ABD was correlated with Dd, Ds, and VC and was negatively correlated with UT. The exaggerated ABD, PP, ET, and ABI were moderated after surgery. CONCLUSIONS: CAVI parameters could be useful in the screening and serial follow-up of AR patients.

Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system.

Prorenin is an enzymatically inactive precursor of renin, and its biological function in endothelial cells (ECs) is unknown despite its relevance with the incidence of diabetic microvascular complications. Recently, (pro)renin receptor was identified, and the receptor-associated prorenin system has been discovered, whereas its expression as well as function in ECs remain unclear. In the present study, we found that ECs express the (pro)renin receptor, and that prorenin provoked ERK activation through (pro)renin receptor independently of the renin-angiotensin system (RAS). Prorenin stimulated the proliferation, migration and tube-formation of ECs, while it inhibited endothelial apoptosis induced by serum and growth factor depletion. MEK inhibitor abrogated these proangiogenic effects of prorenin, while AT1 receptor antagonist or angiotensin-converting enzyme inhibitor failed to block them. In vivo neovascularization in the Matrigel-plugs implanted into mouse flanks was significantly enhanced by prorenin, in which significant ERK activation was detected in ECs. Furthermore, tumor xenografts stably transfected with prorenin demonstrated the significantly accelerated growth rate concomitantly with enhanced intratumoral neovascularization. Our data demonstrated that the RAS-independent (pro)renin receptor-mediated signal transduction plays a pivotal role in the regulation of ECs function as well as in the neovascularization, and thus prorenin is potentially involved in the pathophysiology of diabetic microvascular complications as well as cancers.

Replicative senescence of vascular smooth muscle cells enhances the calcification through initiating the osteoblastic transition.

Medial artery calcification, which does not accompany lipid or cholesterol deposit, preferentially occurs in elderly population, but its underlying mechanisms remain unclear. In the present study, we investigated the potential role of senescent vascular smooth muscle cells (VSMCs) in the formation of senescence-associated medial calcification. Replicative senescence was induced by the extended passages (until passages 11-13) in human primary VSMCs, and cells in early passage (passage 6) were used as control young cells. VSMC calcification was markedly enhanced in the senescent cells compared with that in the control young cells. We identified that genes highly expressed in osteoblasts, such as alkaline phosphatase (ALP) and type I collagen, were significantly upregulated in the senescent VSMCs, suggesting their osteoblastic transition during the senescence. Knockdown of either ALP or type I collagen significantly reduced the calcification in the senescent VSMCs. Of note, runt-related transcription factor-2 (RUNX-2), a core transcriptional factor that initiates the osteoblastic differentiation, was also upregulated in the senescent VSMCs. Knockdown of RUNX-2 significantly reduced the ALP expression and calcification in the senescent VSMCs, suggesting that RUNX-2 is involved in the senescence-mediated osteoblastic transition. Furthermore, immunohistochemistry of aorta from the klotho(-/-) aging mouse model demonstrated in vivo emergence of osteoblast-like cells expressing RUNX-2 exclusively in the calcified media. We also found that statin and Rho-kinase inhibitor effectively reduced the VSMC calcification by inhibiting P(i)-induced apoptosis and potentially enhancing matrix Gla protein expression in the senescent VSMCs. These findings strongly suggest an important role of senescent VSMCs in the pathophysiology of senescence-associated medial calcification, and the inhibition of osteoblastic transition could be a new therapeutic approach for the prevention of senescence-associated medial calcification.