Koki Nakanishi

Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells

The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been exploited for the treatment of diseases. For example, EVs secreted by therapeutic cells injected into infarcted hearts can induce recovery through the delivery of cell-specific microRNAs. However, retention of the EVs and the therapeutic effects are short-lived. Here, we show that an engineered hydrogel patch capable of slowly releasing EVs secreted from cardiomyocytes (CMs) derived from induced pluripotent stem cells reduced arrhythmic burden, promoted ejection-fraction recovery, decreased CM apoptosis 24 h after infarction, and reduced infarct size and cell hypertrophy 4 weeks post-infarction when implanted onto infarcted rat hearts. We also show that EVs are enriched with cardiac-specific microRNAs known to modulate CM-specific processes. The extended delivery of EVs secreted from induced-pluripotent-stem-cell-derived CMs into the heart may help us to treat heart injury and to understand heart recovery.A hydrogel patch for the sustained delivery of extracellular vesicles from cardiomyocytes derived from induced pluripotent stem cells improves tissue regeneration in infarcted rat hearts.

Left ventricular mass-geometry and silent cerebrovascular disease: The Cardiovascular Abnormalities and Brain Lesions (CABL) study

Background Although abnormal left ventricular geometric patterns have prognostic value for morbidity and mortality, their possible association with silent cerebrovascular disease has not been extensively evaluated. Methods We examined 665 participants in the CABL study who underwent transthoracic echocardiography and brain magnetic resonance imaging. Participants were divided into 4 geometric patterns: normal geometry (n = 397), concentric remodeling (n = 89), eccentric hypertrophy (n = 126), and concentric hypertrophy (n = 53). Subclinical cerebrovascular disease was defined as silent brain infarcts (SBIs) and white matter hyperintensity volume (WMHV; expressed as log‐transformed percentage of the total cranial volume). Results Silent brain infarcts were observed in 94 participants (14%). Mean log‐WMHV was −0.97 ± 0.93. Concentric hypertrophy carried the greatest risk for both SBI (adjusted odds ratio [OR] 3.39, P < .001) and upper quartile of log‐WMHV (adjusted OR 3.35, P < .001), followed by eccentric hypertrophy (adjusted ORs 2.52 [P = .001 for SBI] and 1.96 [P = .004] for log‐WMHV). Concentric remodeling was not associated with subclinical brain disease. In subgroup analyses, concentric and eccentric hypertrophies were significantly associated with SBI and WMHV in both genders and nonobese participants, but differed for SBI by age (all ages for eccentric hypertrophy, only patients ≥70 years for concentric hypertrophy) and by race‐ethnicity (Hispanics for eccentric hypertrophy, blacks for concentric hypertrophy; no association in whites). Conclusions Left ventricular hypertrophy, with both eccentric and concentric patterns, was significantly associated with subclinical cerebrovascular disease in a multiethnic stroke‐free general population. Left ventricular geometric patterns may carry different risks for silent cerebrovascular disease in different sex, age, race‐ethnic, and body size subgroups.

Patent foramen ovale and cryptogenic stroke

The presence of a patent foramen ovale (PFO) has been found to be associated with an increased risk of cryptogenic stroke in many case-control studies. This paper reviews the current understanding of the pathophysiology and diagnosis of PFO, and therapeutic options of patients with PFO and cryptogenic stroke.

Role of echocardiography in patients with stroke

Investigation of potential embolic source is an important diagnostic step in treating patients with ischemic stroke and transient ischemic attack. Cardiogenic embolism has been estimated to be the causative factor in 15-30% of all cases of ischemic stroke. Cardioembolic strokes are generally severe and recurrence and mortality rate high. Various cardiac disorders including atrial fibrillation, ventricular thrombus, valvular heart disease, cardiac tumors, and structural heart defects can cause cardioembolic stroke. Although the aortic arch is not a cardiac structure, it is usually considered under source of cardiac embolism (cardioaortic source) and is reviewed in this article. Echocardiography (both transthoracic and transesophageal) is a widely used and versatile technique that can provide comprehensive information of thromboembolic risk in patients with stroke. This article reviews potential cardiac sources of stroke and discusses the role of echocardiography in clinical practice.

Association of chronic kidney disease with impaired left atrial reservoir function: A community-based cohort study

Background Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation, although the pathophysiological mechanisms remain unclear. This study investigated the relationship between CKD and left atrial (LA) volume and function in a sample of the general population without overt cardiac disease. Design and methods We examined 358 participants from the Cardiovascular Abnormalities and Brain Lesions study. The LA minimum volume index (LAVImin), LA maximum volume index (LAVImax), and LA emptying fraction (LAEF) were assessed by real-time three-dimensional echocardiography. Based on their estimated glomerular filtration rate (eGFR), the participants were divided into a CKD group (eGFR <60 ml/min/1.73 m2) and a non-CKD group (eGFR ≥60 ml/min/1.73 m2). Results Of the 358 participants, 69 (19%) were classified as having CKD and 289 (81%) as non-CKD. Participants with CKD were older, had a greater prevalence of hypertension and use of antihypertensive drugs, a larger left ventricular (LV) mass index, and a higher prevalence of diastolic dysfunction than those without CKD (all p < 0.05). There was no significant difference in LAVImax between the CKD and non-CKD groups (23.4 ± 7.1 vs. 22.8 ± 5.8 ml/m2, p = 0.47), whereas significant differences were observed for LAVImin (13.6 ± 5.5 vs. 12.0 ± 4.6 ml/m2, p = 0.01) and LAEF (42.7 ± 11.4 vs. 47.8 ± 11.5%, p = 0.001). Multivariate regression analysis revealed that the eGFR was significantly associated with LAEF independent of age, LV mass index, and diastolic dysfunction (all p < 0.05). Conclusions Participants with CKD in an unselected community-based cohort had significantly impaired LA reservoir function. Assessment of LA function may add important information in the prognostic assessment of patients with CKD even in the absence of overt cardiac disease.

Atherosclerotic Plaques in the Aortic Arch and Subclinical Cerebrovascular Disease

Background and Purpose— Aortic arch plaque (AAP) is a risk factor for ischemic stroke, but its association with subclinical cerebrovascular disease is not established. We investigated the association between AAP and subclinical cerebrovascular disease in an elderly stroke-free community-based cohort. Methods— The CABL study (Cardiovascular Abnormalities and Brain Lesions) was designed to investigate cardiovascular predictors of silent cerebrovascular disease in the elderly. AAPs were assessed by suprasternal transthoracic echocardiography in 954 participants. Silent brain infarcts and white matter hyperintensity volume (WMHV) were assessed by brain magnetic resonance imaging. The association of AAP thickness with silent brain infarcts and WMHV was evaluated by logistic regression analysis. Results— Mean age was 71.6±9.3 years; 63% were women. AAP was present in 658 (69%) subjects. Silent brain infarcts were detected in 138 participants (14.5%). In multivariate analysis adjusted for potential confounders, AAP thickness and large AAP (≥4 mm in thickness) were significantly associated with the upper quartile of WMHV (WMHV-Q4; odds ratio =1.17; 95% confidence interval, 1.04–1.32; P=0.009 and odds ratio =1.79; 95% confidence interval, 1.40–3.09; P=0.036, respectively), but not with silent brain infarcts (odds ratio =1.08; 95% confidence interval, 0.94–1.23; P=0.265 and odds ratio =1.46; 95% confidence interval, 0.77–2.77; P=0.251, respectively). Conclusions— Aortic arch atherosclerosis was associated with WMHV in a stroke-free community-based elderly cohort. This association was stronger in subjects with large plaques and independent of cardiovascular risk factors. Aortic arch assessment by transthoracic echocardiography may help identify subjects at higher risk of subclinical cerebrovascular disease, who may benefit from aggressive stroke risk factors treatment.

Prevalence, Predictors, and Prognostic Value of Residual Tricuspid Regurgitation in Patients With Left Ventricular Assist Device

Background Although implantation of a left ventricular assist device (LVAD) generally improves tricuspid regurgitation (TR) in short‐term follow‐up, the clinical significance of residual TR in patients with mid‐ to long‐term LVAD support is unknown. This study aimed to identify the prevalence, predictors, and prognostic value of residual TR in LVAD patients in association with tricuspid valve (TV) deformation. Methods and Results The study cohort consisted of 127 patients who underwent LVAD implantation without TV procedure and were supported with LVAD at least 1 year. All patients underwent echocardiographic examination preoperatively and 1 year after LVAD implantation. TR was quantitatively assessed by ratio of TR color jet area/right atrial area, and significant residual TR was defined as ≥20% of %TR at follow‐up echocardiographic examination. Detailed echocardiographic measurements were also performed, including TV annulus diameter, TV leaflet displacement, and left ventricular and right ventricular systolic function. LVAD implantation significantly improved ratio of TR color jet area/right atrial area as well as left ventricular and right ventricular systolic function and tethering distance (all P<0.05), whereas it enlarged TV annulus diameter (P=0.002). Significant residual TR was observed in 30 (23.6%) patients. Age, preoperative TV annulus diameter, and residual mitral regurgitation were significantly associated with significant residual TR (all P<0.05), whereas TV tethering was not. During a mean follow‐up of 21±17 months, patients with residual TR had significantly higher mortality than those without residual TR (log‐rank P<0.001). Conclusions Significant residual TR was observed in ≈25% patients supported with LVAD over 1 year and was associated with unfavorable outcome.

Association of body size metrics with left atrial phasic volumes and reservoir function in the elderly

Aims General obesity, defined by increased body mass index (BMI), is associated with left atrial (LA) enlargement, a marker of cardiovascular risk in the general population. The association between abdominal adiposity, defined by increased waist circumference (WC) or waist-to-hip ratio (WHR), and LA phasic volumes and reservoir function is not well known. The aim of this study was to evaluate the association between different body size metrics and LA phasic volumes and reservoir function in the elderly. Methods and results Participants from the CABL (Cardiovascular Abnormalities and Brain Lesions) study underwent measurement of BMI, WC, and WHR. The LA maximum (LAVmax) and minimum (LAVmin) volumes, and LA reservoir function, measured as total emptying volume index (LAEVI), total emptying fraction (LAEF), and expansion index (LAEI), were assessed by real-time 3D echocardiography. The study population included 629 participants (mean age 71 ± 9 years, 61% women). Mean BMI was 27.9 ± 4.6 kg/m2, WC was 95.0 ± 11.7 cm, WHR was 0.91 ± 0.08. After adjusting for multiple potential confounders (demographics, cardiovascular risk factors, left ventricular mass index, and diastolic function), higher WC was significantly associated with higher LA phasic volumes (LAVmax, β = 0.10, P = 0.007 and LAVmin, β = 0.12, P = 0.002) and reduced reservoir function (LAEVI, β = -0.15, P = 0.001 and LAEI, β = -0.09, P = 0.027). WHR was significantly associated only with reduced reservoir function (LAEVI, β = -0.11, P = 0.012), whereas BMI was not associated with either LA phasic volumes or reservoir function. Conclusion In the elderly, WC may have more impact on LA phasic volumes and reservoir function, and therefore risk for cardiovascular events, than WHR and BMI.

Heart Failure Severity and Quality of Warfarin Anticoagulation Control (From the WARCEF Trial)

Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.

Usefulness of Tricuspid Annular Diameter to Predict Late Right Sided Heart Failure in Patients With Left Ventricular Assist Device

Although late-onset right-sided heart failure is recognized as a clinical problem in the treatment of patients with left ventricular assist devices (LVADs), the mechanism and predictors are unknown. Tricuspid valve (TV) deformation leads to the restriction of the leaflet motion and decreased coaptation, resulting in a functional tricuspid regurgitation that may act as a surrogate marker of late right-sided heart failure. This study aimed to investigate the association of preoperative TV deformation (annulus dilatation and leaflet tethering) with late right-sided heart failure development after continuous-flow LVAD implantation. The study cohort consisted of 274 patients who underwent 2-dimensional echocardiography before LVAD implantation. TV annulus diameter and tethering distance were measured in an apical 4-chamber view. Late right-sided heart failure was defined as right-sided heart failure requiring readmission and medical and/or surgical treatment after initial LVAD implantation. During a mean follow-up of 25.1 ± 19.0 months after LVAD implantation, late right-sided heart failure occurred in 33 patients (12.0%). Multivariate Cox proportional hazard analysis demonstrated that TV annulus diameter (hazard ratio 1.221 per 1 mm, p <0.001) was significantly associated with late right-sided heart failure development, whereas leaflet tethering distance was not. The best cut-off value of the TV annular diameter was 41 mm (area under the curve 0.787). Kaplan-Meier analysis showed that patients with dilated TV annulus (TV annular diameter ≥41 mm) exhibited a significantly higher late right-sided heart failure occurrence than those without TV annular enlargement (log-rank p <0.001). In conclusion, preoperative TV annulus diameter, but not leaflet tethering distance, predicted the occurrence of late right-sided heart failure after LVAD implantation.