Diabetes causes cardiomyopathy and increases the risk of heart failure independent of hypertension and coronary heart disease. This condition called “Diabetic Cardiomyopathy” (DCM) is becoming a well- known clinical entity. Recently, there has been substantial research exploring its molecular mechanisms, structural and functional changes, and possible development of therapeutic approaches for the prevention and treatment of DCM. This review summarizes the recent advancements to better understand fundamental molecular abnormalities that promote this cardiomyopathy and novel therapies for future research. Additionally, different diagnostic modalities, up to date screening tests to guide clinicians with early diagnosis and available current treatment options has been outlined.

A left ventricular assist device is a mechanical pump implanted in patients with heart failure that continuously takes blood from the left ventricle and delivers it to the aorta, thus decreasing ventricular load. The device is typically considered as a ‘bridge to transplant’, i.e. as a temporary therapy, and involves several risks. Modified ventricular hemodynamics due to a heart pump implantation is studied in-vitro using an elastic ventricle. The ventricle is incorporated into a pulse duplicator setup, which prescribes realistic pulsatile inflow/outflow to mimic a weak ejection fraction. A continuous axial pump mimics a ventricular assist device and its effect on the ventricular hemodynamics is investigated as a function of the pump flow suction. Using particle image velocimetry, pump flow effectiveness at providing unloading on the ventricle and increasing ejection is observed and understanding if proper recirculation of the myocardium down to the apex is restored under varying flow rate.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is poorly understood and therapeutic strategies are lacking. This study aimed to identify plasma proteins with pathophysiological relevance in HFpEF and with respect to spironolactone-induced effects. We assessed 92 biomarkers in plasma samples from 386 HFpEF patients—belonging to the Aldo-DHF trial—before (baseline, BL) and after one-year treatment (follow up, FU) with spironolactone (verum) or a placebo. At BL, various biomarkers showed significant associations with the two Aldo-DHF primary end point parameters: 33 with E/e’ and 20 with peak VO2. Ten proteins including adrenomedullin, FGF23 and inflammatory peptides (e.g., TNFRSF11A, TRAILR2) were significantly associated with both parameters, suggesting a role in the clinical HFpEF presentation. For 13 proteins, expression changes from BL to FU were significantly different between verum and placebo. Among them were renin, growth hormone, adrenomedullin and inflammatory proteins (e.g., TNFRSF11A, IL18 and IL4RA), indicating distinct spironolactone-mediated effects. BL levels of five proteins, e.g., inflammatory markers such as CCL17, IL4RA and IL1ra, showed significantly different effects on the instantaneous risk for hospitalization between verum and placebo. This study identified plasma proteins with different implications in HFpEF and following spironolactone treatment. Future studies need to define their precise mechanistic involvement.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) accounts for half of all clinical heart failure presentations, but unfortunately lacks effective therapies. Therefore, it has become more urgent to elucidate the pathophysiology underlying this disease, both by using patient data and the development of more accurate animal models. With clinical evidence suggesting that skeletal muscle abnormality is a significant factor in the development of exercise intolerance, this thesis investigates whether the salty drinking water, unilateral nephrectomy, and aldosterone (SAUNA) HFpEF mouse model also demonstrates similar skeletal muscle abnormality as seen in patients. METHODS: Eight-weeks old C57BL/6J mice were subjected to a left nephrectomy and given a mini-osmotic pump to deliver a continuous infusion of either saline (Sham) or aldosterone (HFpEF). The mice were then maintained on a standard rodent chow and a 1% sodium chloride solution. After 4 weeks, the soleus and gastrocnemius muscles were harvested. Histological analyses were performed to examine fiber composition, cross-sectional area of fiber, capillary density, and fibrosis. Quantitative PCR (qPCR) and western blot analyses were performed to examine the expression changes in mitochondrial oxidative phosphorylation, vasculature, fibrosis and inflammation. RESULTS: HFpEF mice showed significant increase in systolic and diastolic blood pressure, increased heart/tibia length ratio, increased wet/dry lung ratio, decreased bodyweight as well as decreased weight of soleus and gastrocnemius muscle relative to tibia length. In oxidative soleus muscle, histological analyses showed a reduction in the abundance of type 1 and type 2A oxidative fiber, reduced cross-sectional area of type 2A fiber, decreased capillary density and increased fibrosis. Molecular analyses showed alterations that are consistent with histological data as well as increased gene expression of inflammatory mediators. In glycolytic gastrocnemius muscle, histological analysis indicated cross-sectional area was reduced for type 2B fibers and increased in type 1 fibers, and decreased capillary density. However, no changes in fiber abundance or in fibrosis was observed. Molecular data was consistent with these findings and revealed an increased gene expression of inflammatory mediators CONCLUSION: Skeletal muscle in SAUNA HFpEF mice displayed significant abnormalities relative to their sham counterparts. These results thus support that SAUNA HFpEF mouse model is suitable and relevant to study skeletal muscle abnormalities and could contribute to the development of novel therapies for HFpEF. / 2025-06-21T00:00:00Z

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13585号 / 論医博第2305号 / 新制||医||1070(附属図書館) / (主査)教授 石見 拓, 教授 古川 壽亮, 教授 近藤 尚己 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Echocardiography examination is an important and familiar method for heart`s examination. Echocardiography is used to assess the function of the heart during to check the heart disease. In an echocardiography examination, the heart´s flow rates, contractility (pumping capacity), wall thickness, and inner diameter can be examined. All these examinations are done with the help of evolution of the ultrasonic waves that the ultrasonic transducer sends out and receives. The transducer consists of piezoelectric crystals that can both transmit and receive ultrasonic waves with frequencies exceeding 20 kHz. The purpose of the study is to compare the measurement of the left ventricular ejection fraction (LVEF) between an experienced biomedical scientist (BMA) and a student. In addition to see how the image quality affects the result. The measurement was performed by using the Simpson method. The result was analyzed by using with a static method. The results were analyzed by using a paired t-test to see if there is any significant difference between the performance of a BMA and a student. The measurement was performed on apical 4-chamber and apical 2-chamber image. The study included 30 patients, both heart -healthy and cardiac patients of the genders. The result showed that there is a significant difference in the performance of LVEF- measurements between BMA and student, with lower values measured by the student. / Ekokardiografiundersökning är en viktig och vanlig metod vid undersökning av hjärtat. Ekokardiografi används för att bedöma hjärtats funktion vid utredning av hjärtsjukdomar. Vid en ekokardiografiundersökning kan hjärtats flödeshastigheter, kontraktilitet (pumpförmåga), väggtjocklek, och innerdiameter undersökas. Alla dessa undersökningar görs med hjälp av tolkning av ultraljudsvågorna som ultraljudsgivaren skickar ut och tar emot. Givaren består av piezoelektriska kristaller som kan både sända och tar emot ultraljudsvågor med frekvens på över 20 kHz. Syftet med denna studie är att jämföra mätningen av den vänstra ventrikulära ejektionsfraktion (LVEF) mellan en erfaren biomedicinsk analytiker (BMA) och en student samt att se hur bildkvalitén påverkar resultatet. Mätningen utfördes med Simpsons- metoden. Resultatet analyserades med hjälp av en statistisk metod. Resultatet analyserades med hjälp av parat t-test för att se om det finns någon signifikant skillnad mellan utförandet av en BMA och en student. Mätningen utfördes på apikala 4-kammarbilder och apikala 2-kammarblider. Studien inkluderade 30 patienter, både hjärtfriska och hjärtsjuka patienter av både könen. Resultatet visade att det finns en signifikant skillnad i utförande av LVEF- mätningar mellan BMA och student, med lägre uppmätta värden av studenten.

To this day heart failure with preserved ejection fraction (HFpEF) remains a poorly understood malady. Half of all heart failure (HF) cases are HFpEF, and the prevalence of HF is on the rise. Unlike HF with reduced ejection fraction, HFpEF has no treatment options and is often times difficult to diagnose because victims of HFpEF often have pre-existing conditions. Vascular endothelial growth factor (VEGF) has been implicated in maintaining myocardial health and is thought to play a role in HFpEF. We sought to test the hypothesis that VEGF-A plays a role in HFpEF in a hypertensive murine model of HFpEF. Using Western blot analysis we found that there was an up regulation of VEGF-A in the homogenized left ventricle (LV) of our HFpEF mice. Unexpectedly, there was a down regulation of VEGF-A in the homogenized tissue from the aorta in those mice. To study the circulating levels of VEGF in our HFpEF mice we used an ELISA. We found that our HFpEF mice had similar levels of circulating VEGF as our control. This suggests that VEGF has paracrine/autocrine role in our HFpEF model rather than endocrine, like our human data suggested. To identify the cells responsible for the expression profile we saw in the homogenized tissue data we looked at the response of adult rat ventricular myocytes (ARVM) and vascular smooth muscle cells (VSMC) to aldosterone stimulation at short (1hr) and long (24hr) time points at both physiological (50nm) and pathological (1μm) concentrations. To do this analysis we recruited the help of Western blot, ELISA and RT-PCR techniques to construct a consistent VEGF expression profile. The Western blot ARVM data showed statistically significant (P<0.05) increase in VEGF-A to pathological doses of aldosterone, especially at the longer time point. When we tested the VSMC using Western blot analysis, we found that the trend of our n=1 sample suggested a strong response to the physiological dose of aldosterone in the short term. Using the more sensitive ELISA technique to measure the VEGF content of our VCMS we increasing our sample size to n=4 and found no statistically significant (p=NS) response to aldosterone stimulation from the VSMC. However, looking at the trends in the data it is clear that VSMC increases VEGF in response to long-term physiological doses of aldosterone. This is contrary to what we found using Western blot analysis, so we queried the VEGF mRNA from the VSMC to settle the score. Unfortunately, this too proved fruitless. The RT-PCR data was not significant and the trend was that of the ARVM expression profile. We initially turned to VSMC because we hypothesized that they could contribute to the paracrine/autocrine activity similar to what we saw in the LV from the ARVM. It is unclear if VSMC play a role in HFpEF progression, but their lack of consistent response to aldosterone could potential explain the down regulation of VEGF-A we observed in the aorta of our HFpEF mice. We initially sough to test the hypothesis that VEGF-A plays a role in our HFpEF mouse model, what we found was that ARVM contribute to localized VEGF-A increased production in the LV while in the aorta there is a down regulation of VEGF-A in our HFpEF model, we are unable to make any conclusion about VSMC response to aldosterone because of insufficient sample size. Thus in conclusion, it appears that VEGF-A does play a role in our HFpEF model specifically in a paracrine/autocrine manner in the LV where the ARVM contributes to the increased production of the cytokine.

L'insuffisance cardiaque à fraction d’éjection préservée (IC/FEp) constitue un problème de santé croissant. Elle pourrait devenir la principale cause d'IC d'ici une décennie. C’est une pathologie associée à un taux élevé de morbidité et de mortalité. La prise en charge thérapeutique de l’IC/FEp reste limitée en raison de sa physiopathologie encore mal élucidée. Dans le présent travail, après avoir mis au point un modèle d’IC/FEp sur le rat adulte mâle et l’avoir caractérisé, nous avons évalué le phénotype fonctionnel et l’homéostasie calcique des cardiomyocytes. Les cœurs de ces animaux ont montré une fraction d’éjection supérieure à 50%, associée à une congestion pulmonaire, une hypertrophie concentrique avec une augmentation de la masse du ventricule gauche, une rigidité myocardique, une relaxation et un remplissage ventriculaire passif altérés et une dilatation auriculaire. Au niveau cellulaire, la contraction mesurée sur des cardiomyocytes isolés ainsi que le transitoire calcique sont augmentées. On note, de même, une surcharge en Ca2+ diastolique favorisée par une fuite à travers les canaux Ryanodine 2 et par un dysfonctionnement de l’échangeur Na+ /Ca2+ qui contribuent à générer des événements calciques spontanés. La phosphorylation du phospholamban, régulateur de l’activité de la SERCA2a, a également augmenté, laissant suggérer une compensation adaptative du cycle de Ca2+. Enfin, en présence de Ranolazine, inhibiteur du courant sodique soutenu, les évènements calciques spontanés ont été réprimés. En conclusion, le remodelage cardiaque dans l’IC/FEp semble être diffèrent de celui observé dans l’IC/FEr et ouvre la voie vers de nouveaux acteurs physiopathologiques et thérapeutiques. / Heart failure with preserved ejection fraction (HFpEF) is a growing health problem. It could become the leading cause of HF within a decade. It is a pathology associated with high morbidity and mortality. Therapeutic options are limited due to a lack of knowledge of the pathology and its evolution. In this work, we investigated the cellular phenotype and Ca2+ handling in hearts recapitulating HFpEF criteria. HFpEF was induced in a portion of male Wistar rats four weeks after abdominal aortic banding. These animals had nearly normal ejection fraction and presented elevated blood pressure, lung congestion, concentric hypertrophy, increased LV mass, wall stiffness, impaired active relaxation and passive filling of the left ventricle, enlarged left atrium, and cardiomyocyte hypertrophy. Left ventricular cell contraction was stronger and the Ca2+ transient larger. Ca2+ cycling was modified with a RyR2 mediated Ca2+ leak from the sarcoplasmic reticulum and impaired Ca2+ extrusion through the Na+ /Ca2+ (NCX), which promoted an increase in diastolic Ca2+ and spontaneous Ca2+ waves. PLN phosphorylation which promotes SERCA2a activity, was increased, suggesting an adaptive compensation of Ca2+ cycling. In the presence of Ranolazine, a sustained sodium current inhibitor, spontaneous Ca2+ events were suppressed. Cardiac remodeling in hearts with a HFpEF status differs from that known for HFrEF and opens the way to new pathophysiological and therapeutic actors.

Introduction: Chronic kidney disease (CKD) and congestive heart failure (CHF) patients have higher serum B-type natriuretic peptide (BNP), which alters the test interpretation. We aim to define BNP cutoff levels to diagnose acute decompensated heart failure (ADHF) in CKD according to CHF subtype: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Material and methods: We reviewed 1,437 charts of consecutive patients who were admitted for dyspnea. We excluded patients with normal kidney function, without measured BNP, echocardiography, or history of CHF. BNP cutoff values to diagnose ADHF for CKD stages according to CHF subtype were obtained for the highest pair of sensitivity (Sn) and specificity (Sp). We calculated positive and negative likelihood ratios (LR+ and LR–, respectively), and diagnostic odds ratios (DOR), as well as the area under the receiver operating characteristic curves (AUC) for BNP. Results: We evaluated a cohort of 348 consecutive patients: 152 had ADHF, and 196 had stable CHF. In those with HFpEF with CKD stages 3–4, BNP < 155 pg/ml rules out ADHF (Sn90%, LR– = 0.26 and DOR = 5.75), and BNP > 670 pg/ml rules in ADHF (Sp90%, LR+ = 4 and DOR = 6), with an AUC = 0.79 (95% CI: 0.71–0.87). In contrast, in those with HFrEF with CKD stages 3–4, BNP < 412.5 pg/ml rules out ADHF (Sn90%, LR– = 0.19 and DOR = 9.37), and BNP > 1166.5 pg/ml rules in ADHF (Sp87%, LR+ = 3.9 and DOR = 6.97) with an AUC = 0.78 (95% CI: 0.69–0.86). All LRs and DOR were statistically significant. Conclusions: BNP cutoff values for the diagnosis of ADHF in HFrEF were higher than those in HFpEF across CKD stages 3–4, with moderate discriminatory diagnostic ability. / Revisión por pares