Restoring blood flow, improving perfusion, reducing clinical symptoms, and augmenting ventricular function are the goals after acute myocardial infarction. Other than cardiac transplantation, no standard clinical procedure is available to restore damaged myocardium. Since we first reported cellular cardiomyoplasty in 1989, successful outcomes have been confirmed by experimental and clinical studies, but definitive long-term efficacy requires large-scale placebo-controlled double-blind randomized trials. On meta-analysis, stem cell-treated groups had significantly improved left ventricular ejection fraction, reduced infarct scar size, and decreased left ventricular end-systolic volume. Fewer myocardial infarctions, deaths, read-missions for heart failure, and repeat revascularizations were additional benefits. Encouraging clinical findings have been reported using satellite or bone marrow stem cells, but understanding of the benefit mechanisms demands additional studies. Adult mammalian ventricular myocardium lacks adequate regeneration capability, and cellular cardiomyoplasty offers a new way to overcome this; the poor retention and engraftment rate and high apoptotic rate of the implanted stem cells limit outcomes. The ideal type and number of cells, optimal timing of cell therapy, and ideal cell delivery method depend on determining the beneficial mechanisms. Cellular cardiomyoplasty has progressed rapidly in the last decade. A critical review may help us to better plan the future direction.

Claudin-5 is a transmembrane cell junction protein that is a component of tight junctions in endothelial cell layers. We have previously shown that claudin-5 also localizes to lateral membranes of murine cardiomyocytes at their junction with the extracellular matrix. Claudin-5 levels are specifically reduced in myocytes from a mouse model of muscular dystrophy with cardiomyopathy. To establish whether claudin-5 is similarly specifically reduced in human cardiomyopathy, we compared the levels of claudin-5 with other cell junction proteins in 62 cardiomyopathic end-stage explant samples. We show that claudin-5 levels are reduced in at least 60% of patient samples compared with non-failing controls. Importantly, claudin-5 reductions can be independent of connexin-43, a gap junction protein previously reported to be reduced in failing heart samples. Other cell junction proteins including α-catenin, β-catenin, γ-catenin, desmoplakin, and N-cadherin are reduced in only a small number of failing samples and only in combination with reduced claudin-5 or connexin-43 levels. We also show that reduced claudin-5 levels can be present independently from dystrophin alterations, which are known to be capable of causing and resulting from cardiomyopathy. These data are the first to show alterations of a tight junction protein in human cardiomyopathy samples and suggest that claudin-5 may participate in novel mechanisms in the pathway to end-stage heart failure.

Hyperthyroidism may present with signs and symptoms related to dysfunction of a variety of organs. Cardiovascular pathology in hyperthyroidism is common. A few case reports describe isolated right heart failure, tricuspid regurgitation, and pulmonary hypertension as the prominent cardiovascular manifestations of hyperthyroidism. Although most textbooks do not mention hyperthyroidism as a cause of pulmonary hypertension and isolated right heart failure, the literature suggests that some hyperthyroid patients may develop reversible pulmonary hypertension and isolated right heart failure. We report a case of hyperthyroidism presenting with signs and symptoms of isolated right heart failure, tricuspid regurgitation, and pulmonary hypertension, which resolved with treatment of hyperthyroidism.

No description available.

Objective: Aortic stenosis (AS) patients with eccentric hypertrophy (Ecc-LVH) have increased left ventricular (LV) size and possibly reduced ejection fraction (EF). However, previous studies suggest worse outcomes with concentric remodeling and hypertrophy. We hypothesized that Ecc-LVH pattern in AS patients will also be associated with greater heart failure (HF) and all-cause mortality (ACM). Methods: We queried the electronic medical record from a community-based university practice for all AS patients. We included patients with >60 days follow-up and interpretable Doppler echocardiograms. We recorded demographics, Doppler-echo parameters, laboratories, HF readmission and ACM with follow-up to 2083 days. There were 329 patients divided into 4 groups based on the presence of LV hypertrophy (LVH) and relative wall thickness (RWT) by echocardiography. Ecc-LVH had RWT<0.43 and LVH. Results: Patients with severe AS were older, had greater coronary disease prevalence, lower hemoglobin, greater LV mass index, more abnormal diastolic function, greater HF and ACM. Multivariate Cox proportional analysis revealed that valvulo-arterial impedance (p=0.017) and Ecc-LVH (p=0.033) were HF predictors. Brain natriuretic peptide>100 pg/ml (p<0.001) and Ecc-LVH (p=0.019) were ACM predictors. ACM was increased in Ecc-LVH patients with both moderate (HR=3.67-8.18 vs other geometries, p=0.007-0.0007) and severe AS (HR=3.94-9.48 vs normal and concentric remodeling, p=0.0002). In patients with HF, Ecc-LVH was associated with greater HF in moderate AS vs normal geometry (HR=3.28, p=0.0135) and concentric remodeling (HR=2.66, p=0.0472). Conclusions: Patients with AS and Ecc-LVH have greater ACM than other LV geometries with both moderate and severe AS and greater HF in moderate AS.

Chronic heart failure (HF) is estimated to affect 23 million people worldwide, and many patients show minimal improvement after treatment with high-potency medications. HF with reduced left ventricular ejection fraction makes up approximately half of cases and is associated with high mortality: a 5-year survival rate of only 25% after hospitalization. This disease is marked by autonomic and cardiac dysfunction, as well as increased inflammatory markers both in the brain and microbiota of the gastrointestinal tract. As a main component of the autonomic nervous system, the vagus nerve has been identified as a potential treatment target for HF. Vagus nerve stimulation (VNS) is thought to help re-balance the autonomic system and has shown promising results in clinical trials for treatment of HF. Although the mechanism of action for VNS remains partially understood, anti-inflammatory pathways have been shown to play a significant role, and these pathways may be enhanced by microbiota signaling via the vagus nerve. The goal of the current study is to provide insight into VNS treatment for HF with reduced ejection fraction via a pressure overload (PO) model. Male Sprague-Dawley rats were randomly divided into age-matched control (n=7), PO (n=6), and PO+VNS (n=11). PO rats underwent aortic constriction (~40%) to induce HF, and a subset of these had VNS leads implanted around the left cervical vagus nerve. Treatment was initiated for PO+VNS rats after reaching a 20% drop in left ventricular relative ejection fraction (EF, p<0.001). VNS was delivered using 1.0 mA pulses at 20 Hz, with 14 sec on-time followed by 66 sec off-time for 2 months to model settings used in successful clinical studies. Echocardiography to image the heart and fecal samples to assess microbiota were collected at regular intervals for all rats. Hearts were weighed at termination for a final heart to body weight ratio, and brains were processed to assess neuroinflammation. Findings indicate that while PO reduced EF ~40% at termination (p<0.05), VNS treatment restored EF back to control levels (p<0.0001 compared to study midpoint). Further, the heart/body weight ratio was increased for PO rats (p<0.05) compared to controls and PO+VNS rats. These data demonstrate that physiological markers of heart failure can be mitigated using these VNS settings. Notably, 66% of microbiota populations altered by PO were prevented with VNS treatment. Further, prolonged VNS significantly affected microbiota populations involved in inflammatory processes. Neuroinflammation was assessed in two key autonomic nuclei: paraventricular nucleus of the hypothalamus and locus coeruleus. PO displayed increased neuroinflammation as measured by microglial density in both regions, and VNS attenuated this effect (p<0.001). These findings indicate relevant contributions of inflammatory mechanisms and microbiome alterations for beneficial VNS effects leading to improved cardiac function in HF.

Fatigue and exercise intolerance are common symptoms experienced by patients with chronic heart failure (CHF). Historically it has been argued that central cardiopulmonary factors including pulmonary congestion and reduced lung compliance cause dyspnoea that limits the exercise tolerance of such patients. But recent studies have indicated that exercise capacity in patients with CHF may not be limited solely by central cardiorespiratory factors. Rather the focus has shifted to aspects of the peripheral circulation and skeletal muscle function as possible factors limiting the exercise tolerance of patients with CHF. However there are few studies describing both the structural and functional abnormalities in the skeletal muscle of patients with CHF. In the first study of this dissertation, 11 patients with end-stage heart failure (NYHA class Ill-IV) and 10 healthy control subjects (C) underwent i) graded exercise to exhaustion for determination of peak oxygen consumption (VO₂ peak) and peak work load (Wlpeak); ii) isometric and isokinetic tests of skeletal muscle function and iii) radionuclide angiography for determination of ejection fraction (EF%). VO₂ peak (12.5 ± 1.0 vs 34.3 ± 3.5 mlO₂fkg/min; p<0.001), Wlpeak (73 ± 10 vs 224 ± 14 W; p<0.001), total work performed by the quadriceps muscles (TWQ) in a 30 sec isokinetic test (TWQ; 1565 ± 166 vs 2892 ± 345 J; p<0.05), and hamstring muscles (TWH) (TWH; 604 ± 163 vs 2003 ± 326 J; p<0.05), maximum voluntary isometric contraction (MVC) of the quadriceps muscles (MVC; 134 ± 12 vs 194 ± 11 Nm; p<0.001) and isokinetic peak torque of the ~uadriceps (PKTQ) (PKTQ; 133 ± 15 vs 203 ± 23 Nm; p<0.05) and hamstring muscles (PKTH) (PKTH; 60 ± 8 vs 108 ± 16 Nm; p<0.05) and time to fatigue during a test of isometric endurance (68 ± 12 vs 100 ± 10 sec; p<0.05) were all significantly lower in patients with CHF. However when corrected for the reduced lean thigh volume (muscle mass) in patients with CHF, PKTQ, PKTH and MVC were no longer different from control values. But the total work performed by the quadriceps and hamstring muscles in a 30 second isokinetic test was reduced even when corrected for the reduced lean thigh volume in patients with CHF. Furthermore, patients with CHF terminated progressive cycle exercise to exhaustion at heart rates, rates of ventilation, respiratory exchange ratios and blood lactate concentrations that were significantly lower than values achieved by control subjects during maximal dynamic exercise. These data suggest that skeletal muscle functional abnormalities including a decreased resistance to the development of fatigue exist in patients with severe CHF. In the second study of this dissertation, 10 patients with CHF who participated in the first study and eight control subjects underwent a skeletal muscle biopsy of the vastus lateralis muscle for light and electron microscopic analysis. Significant histological and ultrastructural changes were found in all SM biopsies from patients with CHF. These included atrophy and hypertrophy of fibres, fibre splitting, internalized nuclei, nuclear knots, moth-eaten fibres, increased lipid droplets. Electron microscopy showed a large variety of nonspecific abnormalities, including mitochondrial changes, Z-band degeneration and accumulation of intracellular glycogen. Ultrastructural morphometry revealed capillary basement membrane width significantly increased in the SM of patients with CHF, (409 ± 13 vs 121 ± 3 nm; p<0.01). A novel, blinded, impartially scored method for grading SM pathology showed that SM biopsies of patients with CHF had higher scores for myopathic changes compared to C (12.0 ± 1.5 vs 1.6 ± 1.0 arbitrary units; p<0.05). SM pathology score correlated significantly with VO₂ peak, Wlpeak, and TWQ (p<0.05 to p<0.02) but not with EF%. EF% did not correlate with either VO₂ peak, Wlpeak or TWQ. These data support the hypothesis that: i) severe SM structural and functional abnormalities may limit exercise capacity in patients with CHF; ii) the severity of SM pathology but not resting systolic cardiac function, predicts exercise performance in patients with CHF.

INTRODUCTION: Diastolic heart failure (HF) i.e., HF with preserved ejection fraction (HFpEF) accounts for ~50% of all clinical HF presentations; but unlike systolic HF i.e., HF with reduced ejection fraction (HFrEF), there are no evidenced based therapies. Obesity is commonly associated with HFpEF. However, there exist a sub-group of obese patients that exhibit a higher survival rate to HFpEF as compared to average patients. Hypertension is the most important risk factor for HFpEF, with a prevalence of 60-89% reported by large controlled trials, epidemiological studies and HF registries. HFpEF morbidity and mortality rates are staggering: 50-60% 5 year mortality rate, 50% 6 month rehospitalization rate and severe clinical disability. However, there remains an incomplete mechanistic understanding about HFpEF. OBJECTIVES: We wanted to explore new pathways related to HFpEF in order to better understand the mechamisms behind its pathophysiology. To do so, we first wanted to explore the potential crosstalk between the heart and adipose tissue during HFpEF by analyzing the adipose tissue in our HFpEF model. Secondly, we sought to test the hypothesis that chronic ETA/ETB inhibition with macitentan (mac) modulates pathologic cardiac remodeling in hypertension-induced HFpEF. METHODS: Mice (20-25 g) were anesthetized, underwent uninephrectomy and received either a continuous infusion of saline (sham) or d-aldosterone (0.3 ug/hour for 4-weeks via osmotic minipumps). All mice were maintained on standard rodent chow and 1.0% sodium chloride drinking water for 4 weeks and then harvested. Second group of mice underwent the same surgical procedure and infusion. They were maintained on standard chow for 2 weeks and then each group was randomized to chow containing macitentan (30 mg/kg/day, HFpEFmac) or standard rodent chow. After 2 additional weeks, the 4 groups of mice (n=4-8/group) were harvested. Blood pressure (BP) was obtained weekly. Prior to sacrifice, body weight and echocardiography parameters (total wall thickness (TWT) and relative wall thickness (RWT)) were determined. We also obtained diastolic dysfunction parameters including deceleration time (DT), isovolumetric relaxation time (IVRT), and E/A ratio. Furthermore, we measured organ weight after harvesting the mice and obtained histological images for the adipose tissues collected. Glucose tolerance test and acute cold tolerance test were performed on HFpEF mice to determine their metabolic state. RESULTS: HFpEF mice developed hypertension, LV hypertrophy, and diastolic dysfunction. Epididymal and inguinal adipose tissue showed significantly reduced weight and adipocyte size. HFpEF mice displayed regular glucose metabolism but were not able to endure a cold tolerance test as their body temperature dropped too low. After 4 weeks, there was no difference in body weight between sham, HFpEF, shammac and HFpEFmac. As expected HFpEF increased systolic BP (117±14 vs 133±16mmHg; P=NS); macitentan did not lower systolic BP after 2 weeks in either shammac or HFpEFmac. Similarly there was no difference in systolic BP between HFpEF and HFpEFmac. Both kidney and spleen weights were increased in HFpEF but not altered by macitentan therapy. There was no change in lung congestion as measured by wet-dry lung ratio. HFpEF increased TWT (0.998±0.04 vs. 0.79±0.11 mm; P<0.01 vs. sham) and RWT (0.686± 0.10 vs. 0.476±0.05 mm; P<0.001 vs. sham) but were modulated by macitentan (HFpEF vs. HFpEFmac; P<0.05 and P<0.001, respectively). There was no difference in chamber size between HFpEF and HFpEFmac. Similarly, IVRT, DT, left ventricular ejection fraction were no different between HFpEF and and HFpEFmac. Furthermore E/A ratio was increased in HFpEF but was not affected by macitentan CONCLUSIONS: Adipose tissue collected from our HFpEF mice displayed a very different phenotype. This demonstrates that inter-tissue communication is definitely occurring between the adipose tissue and the heart. Further research is required to explore what that communication encompasses and how they can be used to improve HFpEF. Macitentan did not lower systolic BP in sham or mice with HFpEF after the development of hypertension. Diastolic dysfunction, as measured by an increased E/A ratio, was not affected by macitentan. Macitentan significantly modulated TWT and RWT after 2 weeks of therapy. It is thus plausible that macitentan may improve HFpEF by improving adverse cardiac remodeling.

Heart failure (HF) readmissions create a financial burden for healthcare nationwide and speak to the lack of effective discharge preparation for patients to be successful with self-care at home. The 183-bed hospital where this DNP quality initiative will take place currently reports an observed-over-expected (O/E) readmission rate for HF patients (Centers for Medicare and Medicaid [CMS]). Core measures on HF developed by the Joint Commission and the Centers for Medicare and Medicaid Services do not appear to be enough to ensure successful transitions of care from hospital to home. Guided by the LOGIC model, the purpose of this quality improvement initiative was to develop a HF educational module to improve patients' readiness to learn in order to promote self-care and prevent readmission to the hospital within 30 days. The design of the educational program was supported by the evidence-based literature and incorporated best practices promoted by the Joint Commission, the Institute for Healthcare Improvement, and the Agency for Healthcare Research and Quality. Content evaluation of the newly developed HF educational program was conducted by 10 experts using a quantitative Likert-type scale and qualitative narrative feedback. Descriptive findings from the Likert scale showed a range of 3.9 to 4.0 in the content, process, and design of the program. Recommendations for improvement included more detail around pathophysiology, as well as how to initiate the process in the outpatient setting. Positive social change can result from the program which offers a relevant strategy to reduce readmissions for HF and has wide-application options for many chronic illnesses that can be better managed through effective discharge teaching.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第17977号 / 医博第3841号 / 新制||医||1001(附属図書館) / 80821 / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩井 一宏, 教授 稲垣 暢也, 教授 岩田 想 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM