Introdução. Pacientes com insuficiência cardíaca submetidos à ventriculectomia parcial esquerda apresentam melhora na função sistólica do ventrículo esquerdo em repouso, porém continuam apresentando limitação funcional. Objetivo. Para melhor compreender os mecanismos desta limitação funcional, estudamos a função sistólica e diastólica do ventrículo esquerdo em repouso e durante exercício submáximo em pacientes submetidos a ventriculectomia parcial esquerda e em pacientes com insuficiência cardíaca não operados, pareados para capacidade funcional máxima e submáxima. Métodos. Foram estudados 9 pacientes submetidos previamente a ventriculografia parcial esquerda (VPE) e 9 pacientes com insuficiência cardíaca não operados previamente (IC). Todos os pacientes foram submetidos inicialmente a um teste cardiopulmonar para determinação do consumo de oxigênio no limiar anaeróbio (LA) e de pico (VO2 pico). Após, foram estudados através da ventriculografia radioisotópica e analisadas a fração de ejeção (FE) e a taxa máxima de enchimento (TME) do ventrículo esquerdo, em repouso e exercício na intensidade do LA. Resultados. Os grupos apresentaram capacidade funcional semelhante avaliada pelo VO2 pico (VPE: [média ± DP] 13,1 ± 3,3 ml/kg.min; IC: 14,1 ± 3,6 ml/kg.min; P > 0,05) e LA (VPE: 7,9 ± 1.3 ml/kg.min; IC: 8,5 ± 1,6 ml/kg.min; P > 0,05). A frequência cardíaca máxima foi maior no grupo IC em comparação ao grupo da VPE (VPE: 119 ± 20 bpm; IC: 149 ± 21 bpm; P < 0.05) A FE em repouso era mais elevada no grupo VPE (VPE: 40 ± 12 %; IC: 32 ± 9 %; P < 0,0125), entretanto a FE elevou-se do repouso ao LA apenas no grupo IC (VPE: 44 ± 17 %; IC: 39 ± 11 %; P < 0,0125). A TME foi semelhante em repouso (VPE: 1,41 ± 0,55 VDF/s; IC: 1,39 ± 0,55 VDF/s; P > 0,05) e aumentou na intensidade do LA similarmente em ambos os grupos (VPE: 2,28 ± 0,55 VDF/s; IC: 2,52 ± 1,07 VDF/s; P < 0,0125). Conclusão. Pacientes submetidos a ventriculectomia parcial esquerda apresentam uma o limiar anaeróbio (LA) resposta anormal da função sistólica do ventrículo esquerdo ao exercício na intensidade do LA e uma resposta cronotrópica diminuida ao exercício máximo. Essas respostas anormais podem contribuir para a limitada capacidade ao exercício destes pacientes, a despeito da melhora na função ventricular sistólica em repouso. / Background. Patients with heart failure who have undergone partial left ventriculectomy improve resting left ventricular systolic function, but maintain limited functional capacity. Objective. In order to better understand the mechanisms associated with this limitation, we studied the systolic and diastolic left ventricular function at rest and during submaximal exercise in patients with previous partial left ventriculectomy and in patients with heart failure who had not been operated, matched for maximal and submaximal exercise capacity. Methods: Nine patients with heart failure who were previously submitted to partial left ventriculectomy (PLV) were compared with a group of 9 patients with heart failure who had not been operated. All patients performed a cardiopulmonary exercise testing with measurement of peak oxygen uptake (VO2 peak) and anaerobic threshold (AT). In a second evaluation, radionuclide left ventriculography was performed to analyze ejection fraction (EF) and peak filling rate (PFR) at rest and during exercise at the intensity corresponding to the AT. Results: Groups presented similar exercise capacity evaluated by VO2peak (PLV: [mean ± SD] 13.1 ± 3.3 mL/Kg.min; HF: 14.1 ± 3.6 mL/Kg.min; P > 0.05) and AT (PLV: 7.9 ± 1.3 mL/Kg.min; HF: 8.5 ± 1.6 mL/Kg.min; P > 0.05). Maximal heart rate was higher in the HF group when compared to the PLV group (PLV: 119 ± 20 bpm; HF: 149 ± 21 bpm; P < 0.05). EF at rest was higher in the PLV group (PLV: 40 ± 12 %; HF: 32 ± 9 %; P < 0.0125), however EF increased from rest to AT only in the HF group (PLV: 44 ± 17 %; HF: 39 ± 11 %; P < 0.0125). PFR was similar at rest (PLV: 1.41 ± 0.55 EDV/sec; HF: 1.39 ± 0.55 EDV/sec; P > 0.05) and increased in both groups at the AT intensity (PLV: 2.28 ± 0.55 EDV/sec; HF: 2.52 ± 1.07 EDV/sec; P < 0,0125). Conclusion: Patients who had partial left ventriculectomy present an abnormal response of left ventricular systolic function to exercise at the AT intensity and an impaired chronotropic response to maximal exercise. These abnormal responses may contribute to the limited exercise capacity of these patients, despite the improvement in resting left ventricular systolic function.

Introdução. Pacientes com insuficiência cardíaca submetidos à ventriculectomia parcial esquerda apresentam melhora na função sistólica do ventrículo esquerdo em repouso, porém continuam apresentando limitação funcional. Objetivo. Para melhor compreender os mecanismos desta limitação funcional, estudamos a função sistólica e diastólica do ventrículo esquerdo em repouso e durante exercício submáximo em pacientes submetidos a ventriculectomia parcial esquerda e em pacientes com insuficiência cardíaca não operados, pareados para capacidade funcional máxima e submáxima. Métodos. Foram estudados 9 pacientes submetidos previamente a ventriculografia parcial esquerda (VPE) e 9 pacientes com insuficiência cardíaca não operados previamente (IC). Todos os pacientes foram submetidos inicialmente a um teste cardiopulmonar para determinação do consumo de oxigênio no limiar anaeróbio (LA) e de pico (VO2 pico). Após, foram estudados através da ventriculografia radioisotópica e analisadas a fração de ejeção (FE) e a taxa máxima de enchimento (TME) do ventrículo esquerdo, em repouso e exercício na intensidade do LA. Resultados. Os grupos apresentaram capacidade funcional semelhante avaliada pelo VO2 pico (VPE: [média ± DP] 13,1 ± 3,3 ml/kg.min; IC: 14,1 ± 3,6 ml/kg.min; P > 0,05) e LA (VPE: 7,9 ± 1.3 ml/kg.min; IC: 8,5 ± 1,6 ml/kg.min; P > 0,05). A frequência cardíaca máxima foi maior no grupo IC em comparação ao grupo da VPE (VPE: 119 ± 20 bpm; IC: 149 ± 21 bpm; P < 0.05) A FE em repouso era mais elevada no grupo VPE (VPE: 40 ± 12 %; IC: 32 ± 9 %; P < 0,0125), entretanto a FE elevou-se do repouso ao LA apenas no grupo IC (VPE: 44 ± 17 %; IC: 39 ± 11 %; P < 0,0125). A TME foi semelhante em repouso (VPE: 1,41 ± 0,55 VDF/s; IC: 1,39 ± 0,55 VDF/s; P > 0,05) e aumentou na intensidade do LA similarmente em ambos os grupos (VPE: 2,28 ± 0,55 VDF/s; IC: 2,52 ± 1,07 VDF/s; P < 0,0125). Conclusão. Pacientes submetidos a ventriculectomia parcial esquerda apresentam uma o limiar anaeróbio (LA) resposta anormal da função sistólica do ventrículo esquerdo ao exercício na intensidade do LA e uma resposta cronotrópica diminuida ao exercício máximo. Essas respostas anormais podem contribuir para a limitada capacidade ao exercício destes pacientes, a despeito da melhora na função ventricular sistólica em repouso. / Background. Patients with heart failure who have undergone partial left ventriculectomy improve resting left ventricular systolic function, but maintain limited functional capacity. Objective. In order to better understand the mechanisms associated with this limitation, we studied the systolic and diastolic left ventricular function at rest and during submaximal exercise in patients with previous partial left ventriculectomy and in patients with heart failure who had not been operated, matched for maximal and submaximal exercise capacity. Methods: Nine patients with heart failure who were previously submitted to partial left ventriculectomy (PLV) were compared with a group of 9 patients with heart failure who had not been operated. All patients performed a cardiopulmonary exercise testing with measurement of peak oxygen uptake (VO2 peak) and anaerobic threshold (AT). In a second evaluation, radionuclide left ventriculography was performed to analyze ejection fraction (EF) and peak filling rate (PFR) at rest and during exercise at the intensity corresponding to the AT. Results: Groups presented similar exercise capacity evaluated by VO2peak (PLV: [mean ± SD] 13.1 ± 3.3 mL/Kg.min; HF: 14.1 ± 3.6 mL/Kg.min; P > 0.05) and AT (PLV: 7.9 ± 1.3 mL/Kg.min; HF: 8.5 ± 1.6 mL/Kg.min; P > 0.05). Maximal heart rate was higher in the HF group when compared to the PLV group (PLV: 119 ± 20 bpm; HF: 149 ± 21 bpm; P < 0.05). EF at rest was higher in the PLV group (PLV: 40 ± 12 %; HF: 32 ± 9 %; P < 0.0125), however EF increased from rest to AT only in the HF group (PLV: 44 ± 17 %; HF: 39 ± 11 %; P < 0.0125). PFR was similar at rest (PLV: 1.41 ± 0.55 EDV/sec; HF: 1.39 ± 0.55 EDV/sec; P > 0.05) and increased in both groups at the AT intensity (PLV: 2.28 ± 0.55 EDV/sec; HF: 2.52 ± 1.07 EDV/sec; P < 0,0125). Conclusion: Patients who had partial left ventriculectomy present an abnormal response of left ventricular systolic function to exercise at the AT intensity and an impaired chronotropic response to maximal exercise. These abnormal responses may contribute to the limited exercise capacity of these patients, despite the improvement in resting left ventricular systolic function.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-02-04T11:32:50Z No. of bitstreams: 1 Carolina Thé Macedo Avaliação da acuracia...2015.pdf: 2036804 bytes, checksum: 926f70b1e7ec1709b317e04842607c6a (MD5) / Approved for entry into archive by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-02-04T11:33:56Z (GMT) No. of bitstreams: 1 Carolina Thé Macedo Avaliação da acuracia...2015.pdf: 2036804 bytes, checksum: 926f70b1e7ec1709b317e04842607c6a (MD5) / Made available in DSpace on 2016-02-04T11:33:56Z (GMT). No. of bitstreams: 1 Carolina Thé Macedo Avaliação da acuracia...2015.pdf: 2036804 bytes, checksum: 926f70b1e7ec1709b317e04842607c6a (MD5) Previous issue date: 2015 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Um dos principais desafios na miocardiopatia chagásica é a detecção de alterações precoces na função ventricular esquerda. A avaliação do strain pelo speckle tracking na ecocardiografia bidimensional (2-D ST) é um novo método com aplicações em diversas doenças cardíacas, tendo sido validado para pacientes com infarto do miocárdio em comparação à ressonância magnética cardíaca (RMC). Neste estudo, avaliamos a hipótese de que o strain global longitudinal (SGL) possui um valor incremental à fração de ejeção (FE) pelo método de Simpson para predição de fibrose miocárdica na RMC, em pacientes portadores de doença de Chagas (DC). Métodos: Estudo observacional, com um total de 58 pacientes portadores de DC. Todos os pacientes foram submetidos à realização de ecocardiograma convencional e com strain pelo speckle tracking, além de RMC. Resultados: A análise da curva ROC mostrou que tanto a SGL (área sob a curva: 0,78, p = 0,001) quanto a fração de ejeção (área sob a curva: 0,82, p < 0,001) tiveram significância estatística na detecção de fibrose. Em relação á porcentagem de fibrose, uma alta correlação foi observada tanto com a FE pela ecocardiografia (r = - 0,70, p < 0,001) quanto com o SGL (r = 0,64, p < 0,001). Contudo, quando ajustado pela regressão linear múltipla, o SGL perdeu a significância estatística como preditor independente de fibrose miocárdica (p = 0.111). Conclusões: SGL não possui valor incremental em relação à FE na predição de fibrose miocárdica em pacientes portadores de DC. / One of the most challenging issues of chronic Chagas disease is to provide earlier detection of heart involvement. Two-dimensional speckle tracking (2-D ST) echocardiography, a new imaging modality with useful applications in several cardiac diseases, has been validated for subjects with myocardial infarction against cardiac magnetic resonance (CMR). Here we hypothesize that the longitudinal global strain (LGS) has an incremental value to ejection fraction for predicting myocardial fibrosis in subjects with Chagas disease. Methods: This observational study comprised 58 subjects with Chagas disease, confirmed by two positive serologic tests. All subjects underwent conventional Doppler echocardiogram plus speckle tracking strain, and cardiac magnetic resonance. Results: The ROC curve analysis revealed that both LGS (Area under the curve: 0.78, p = 0.001) and ejection fraction (Area under the curve: 0.82, p < 0.001) were significant predictors of myocardial fibrosis. Regarding the percentage of fibrosis, a high correlation was observed with both ejection fraction assessed by echocardiography (r = - 0.70, p < 0.001) and LGS (r = 0.64, p < 0.001). However, when adjusted through multiple linear regression, the LGS lost statistical significance as a predictor of myocardial fibrosis (p = 0.111). Conclusions: LGS has no incremental value to conventional ejection fraction measurement in the prediction of myocardial fibrosis in subjects with Chagas disease.

Introdução. Pacientes com insuficiência cardíaca submetidos à ventriculectomia parcial esquerda apresentam melhora na função sistólica do ventrículo esquerdo em repouso, porém continuam apresentando limitação funcional. Objetivo. Para melhor compreender os mecanismos desta limitação funcional, estudamos a função sistólica e diastólica do ventrículo esquerdo em repouso e durante exercício submáximo em pacientes submetidos a ventriculectomia parcial esquerda e em pacientes com insuficiência cardíaca não operados, pareados para capacidade funcional máxima e submáxima. Métodos. Foram estudados 9 pacientes submetidos previamente a ventriculografia parcial esquerda (VPE) e 9 pacientes com insuficiência cardíaca não operados previamente (IC). Todos os pacientes foram submetidos inicialmente a um teste cardiopulmonar para determinação do consumo de oxigênio no limiar anaeróbio (LA) e de pico (VO2 pico). Após, foram estudados através da ventriculografia radioisotópica e analisadas a fração de ejeção (FE) e a taxa máxima de enchimento (TME) do ventrículo esquerdo, em repouso e exercício na intensidade do LA. Resultados. Os grupos apresentaram capacidade funcional semelhante avaliada pelo VO2 pico (VPE: [média ± DP] 13,1 ± 3,3 ml/kg.min; IC: 14,1 ± 3,6 ml/kg.min; P > 0,05) e LA (VPE: 7,9 ± 1.3 ml/kg.min; IC: 8,5 ± 1,6 ml/kg.min; P > 0,05). A frequência cardíaca máxima foi maior no grupo IC em comparação ao grupo da VPE (VPE: 119 ± 20 bpm; IC: 149 ± 21 bpm; P < 0.05) A FE em repouso era mais elevada no grupo VPE (VPE: 40 ± 12 %; IC: 32 ± 9 %; P < 0,0125), entretanto a FE elevou-se do repouso ao LA apenas no grupo IC (VPE: 44 ± 17 %; IC: 39 ± 11 %; P < 0,0125). A TME foi semelhante em repouso (VPE: 1,41 ± 0,55 VDF/s; IC: 1,39 ± 0,55 VDF/s; P > 0,05) e aumentou na intensidade do LA similarmente em ambos os grupos (VPE: 2,28 ± 0,55 VDF/s; IC: 2,52 ± 1,07 VDF/s; P < 0,0125). Conclusão. Pacientes submetidos a ventriculectomia parcial esquerda apresentam uma o limiar anaeróbio (LA) resposta anormal da função sistólica do ventrículo esquerdo ao exercício na intensidade do LA e uma resposta cronotrópica diminuida ao exercício máximo. Essas respostas anormais podem contribuir para a limitada capacidade ao exercício destes pacientes, a despeito da melhora na função ventricular sistólica em repouso. / Background. Patients with heart failure who have undergone partial left ventriculectomy improve resting left ventricular systolic function, but maintain limited functional capacity. Objective. In order to better understand the mechanisms associated with this limitation, we studied the systolic and diastolic left ventricular function at rest and during submaximal exercise in patients with previous partial left ventriculectomy and in patients with heart failure who had not been operated, matched for maximal and submaximal exercise capacity. Methods: Nine patients with heart failure who were previously submitted to partial left ventriculectomy (PLV) were compared with a group of 9 patients with heart failure who had not been operated. All patients performed a cardiopulmonary exercise testing with measurement of peak oxygen uptake (VO2 peak) and anaerobic threshold (AT). In a second evaluation, radionuclide left ventriculography was performed to analyze ejection fraction (EF) and peak filling rate (PFR) at rest and during exercise at the intensity corresponding to the AT. Results: Groups presented similar exercise capacity evaluated by VO2peak (PLV: [mean ± SD] 13.1 ± 3.3 mL/Kg.min; HF: 14.1 ± 3.6 mL/Kg.min; P > 0.05) and AT (PLV: 7.9 ± 1.3 mL/Kg.min; HF: 8.5 ± 1.6 mL/Kg.min; P > 0.05). Maximal heart rate was higher in the HF group when compared to the PLV group (PLV: 119 ± 20 bpm; HF: 149 ± 21 bpm; P < 0.05). EF at rest was higher in the PLV group (PLV: 40 ± 12 %; HF: 32 ± 9 %; P < 0.0125), however EF increased from rest to AT only in the HF group (PLV: 44 ± 17 %; HF: 39 ± 11 %; P < 0.0125). PFR was similar at rest (PLV: 1.41 ± 0.55 EDV/sec; HF: 1.39 ± 0.55 EDV/sec; P > 0.05) and increased in both groups at the AT intensity (PLV: 2.28 ± 0.55 EDV/sec; HF: 2.52 ± 1.07 EDV/sec; P < 0,0125). Conclusion: Patients who had partial left ventriculectomy present an abnormal response of left ventricular systolic function to exercise at the AT intensity and an impaired chronotropic response to maximal exercise. These abnormal responses may contribute to the limited exercise capacity of these patients, despite the improvement in resting left ventricular systolic function.

Abstract Stem cell therapy has several mechanisms for repairing damaged myocardium and improving functional capacity of the left ventricle reduced by myocardial infarction. Despite the increase in scientific data, details of these mechanisms are still partly unexplained. The optimal number and type of stem cells as well as timing and route of transplantation are unclear. The purpose of this study was to clarify therapeutic potential of bone marrow-derived stem cells (BM-MNCs) using experimental porcine acute myocardial infarction model. Myocardial infarction was caused by occluding the circumflex coronary artery for 90 minutes. Immediately after reperfusion BM-MNCs were injected directly into the damaged myocardium or by angioplastic catheter into the infarct-related coronary artery. Left ventricular ejection fraction (LVEF) improved 3 weeks after infarction in animals that received BM-MNCs intramyocardially whereas in animals that received intracoronary transplantation or saline LVEF failed to recover. Radionuclide imaging and histological analysis showed intramyocardially transplanted cells remaining in the infarcted myocardium, whereas after intracoronary transplantation a major fraction of cells flushed into the lungs. In histological analysis minor fraction of BM-MNCs showed differentiation towards myocyte form and proliferation. Significantly lower collagen density and higher levels of smooth muscle actin and skeletal muscle actin were detected in the infarcted myocardium after intramyocardial or intracoronary BM-MNC transplantation compared with animals that received saline. Proteomic screening indicated that mitochondrial energy metabolism recovered after BM-MNC transplantation. Additionally, two proteins showed elevated levels after BM-MNC transplantation, which indicates that they are actively involved in the pathological mechanisms. BM-MNCs appear to enhance recovery of the infarcted myocardium by restoring the reduced LVEF after infarction. Intramyocardial stem cell therapy showed best results in recovery. Stem cell therapy moulds the infarct scar by reducing collagen density and by increasing components typical for muscle cells. The effects of stem cell therapy are mainly paracrine. / Tiivistelmä Kantasoluterapian on havaittu korjaavan infarktissa vaurioitunutta sydänlihasta toimintakykyisemmäksi usealla mekanismilla sekä parantavan sydänlihaksen pumppaustoimintaa. Huolimatta lisääntyneestä tutkimustiedosta näiden monimutkaisten mekanismien yksityiskohdat ovat edelleen paljolti selvittämättä. Samoin käytettävien kantasolujen tyypin, määrän, siirtotekniikan ja siirron ajoituksen optimointi on vielä epäselvää. Tämän tutkimuksen tavoitteena oli selvittää kokeellista sian infarktimallia käyttäen luuytimen kantasolujen kykyä tehostaa vaurioituneen sydänlihaksen toipumista akuutin infarktin jälkeen. Mallissa aiheutettiin sydäninfarkti sulkemalla vasemman sepelvaltimon kiertävähaara 90 minuutiksi. Välittömästi verenkierron uudelleen avaamisen jälkeen luuytimen soluja ruiskutettiin infarktialueelle joko suoraan sydänlihakseen tai sepelvaltimoon. Kolmen viikon kuluttua infarktista kantasoluja suoraan sydänlihakseen saaneiden eläinten vasemman kammion ejektiofraktio (LVEF) parani tilastollisesti merkitsevästi verrattuna kantasoluja sepelvaltimoon saaneisiin eläimiin ja keittosuolaa saaneisiin eläimiin, joiden LVEF pysyi infarktin jälkeisellä alentuneella tasolla. Isotooppitutkimus ja histologinen analyysi osoittivat, että suoraan sydänlihakseen ruiskutetuista kantasoluista valtaosa säilyy infarktialueella kun taas sepelvaltimoon siirretyt solut pääasiassa ajautuvat keuhkoihin. Histologisessa analyysissa sydänlihakseen ruiskutettujen solujen todettiin vähäisessä määrin erilaistuvan lihassolujen suuntaan ja jakautuvan. Kantasoluja saaneiden eläinten ryhmissä todettiin infarktialueella merkitsevästi alhaisempi kollageenipitoisuus sekä enemmän sileälihassolujen aktiinia ja poikkijuovaisten lihassolujen aktiinia kuin keittosuolaa saaneilla eläimillä. Proteomiikka-analyysin tulokset viittaavat kantasoluterapian saaneilla eläimillä mitokondrioiden energiatalouden tehostumiseen. Lisäksi esille tuli kaksi kantasoluterapian jälkeen aktiivista proteiinia, joilla todennäköisesti on keskeinen tehtävä infarktin patogeneesissä. Tutkimuksen perusteella luuytimen kantasolut tehostavat sydänlihaksen toipumista infarktista palauttamalla sydämen alentunutta pumppaustehoa. Suoraan sydänlihakseen annettu kantasoluterapia vaikuttaa tehokkaimmalta menetelmältä. Kantasoluterapia muovaa infarktiarpea vähentämällä kollageenin ja lisäämällä lihassoluille tyypillisten komponenttien määrää. Kantasoluterapian vaikutukset ovat pääasiassa parakriinisiä.

No description available.

Cardiovascular diseases (CVD) have been the leading cause of death worldwide for many years, making it a devasting and increasing concern across the globe. The risk factors of CVD include postnatal factors and prenatal factors. For the prenatal CVD risk factors study, we focused on maternal hypothyroidism (MH), which is a common clinical condition. Studies have shown MH progeny have increased susceptibility to both acquired cardiovascular disease in adulthood and congenital heart disease, but the underlying mechanisms are not well understood. The goal of the present experiments was to test the hypothesis that MH reduces early postnatal cardiac myocyte proliferation in the progeny so that their adult hearts have a smaller complement of cardiac myocytes, which leads to adverse cardiac disease responses. MH model was induced by thyroidectomy (TX) with total thyroxine (TT4) under 1ng/dl after surgery. The progeny from mice that underwent Sham or TX surgery was termed WT (wild type) or MH (maternal hypothyroidism) progeny, respectively. Hearts were collected from WT and MH progeny to determine heart weight (HW), CM size, CM proliferation, and cell culture. RNA-seq was performed on heart tissue at postnatal day 5 (P5) and P60. Transverse Aortic Constriction (TAC) was performed to cause pressure overload-induced cardiac hypertrophy and/or heart failure (HF) in adult WT and MH progeny. ECHO (in-vivo) and histological (ex-vivo) studies were performed at specific times after TAC. Thyroid hormone treatment (levothyroxine, T4) for MH mother was administered. The results showed that the Heart weight (HW) to body weight (BW) ratio at P60 was no difference between groups, but the MH progeny had a larger CM size, consistent with fewer CM numbers. MH progeny had lower EdU+, Ki67+, and PH3+ CMs, and fewer mononucleated CMs, which shows they had a decreased CM proliferation capacity. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH progeny, including Bmp10. Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation in the presence of thyroid hormone. In adult progeny, RNA-seq data showed that MH mice had genes upregulated in the inflammatory response before TAC surgery. Six weeks after TAC, the MH progeny had a greater HW/BW ratio, larger CM size, and more severe LV fibrosis consistent with more severe cardiac pathological remodeling compared with WT progeny. T4 supplemented treatment for MH mothers preserved progeny’s early postnatal CM proliferation capacity and the excessive pathological remodeling after TAC. Concluding, CM proliferation during the early postnatal development stage was significantly attenuated in MH progeny, which results in fewer CMs and CM hypertrophy in adult MH progeny. These changes are associated with worse cardiac disease responses under pressure overload in adult MH progeny. For the postnatal CVD risk factors study, we focused on calcium overload and metabolic disorder, which play a critical role in heart failure with preserved ejection fraction (HFpEF). HFpEF is defined as HF with an EF ≥50% and elevated cardiac diastolic filling pressures. The underlying causes of HFpEF are multifactorial and not well-defined. A transgenic mouse with low levels of cardiomyocyte (CM)-specific inducible Cavβ2a expression (β2a-Tg mice) showed increased cytosolic CM Ca2+, and modest levels of CM hypertrophy and fibrosis. This study aimed to determine if β2a-Tg mice develop an HFpEF phenotype when challenged with two additional stressors, a high-fat diet (HFD) and L-NAME (LN). Four-month-old wild-type (WT) and β2a-Tg mice were given either normal chow (WT-N, β2a-N) or HFD and/or L-NAME (WT-HFD, WT-LN, WT-HFD-LN, β2a-HFD, β2a-LN, and β2a-HFD-LN). Some animals were treated with the HDAC (hypertrophy regulators) inhibitor suberoylanilide hydroxamic acid (SAHA) (β2a-HFD-LN-SAHA). Echocardiography was performed monthly. After four months of treatment, terminal studies were performed, including invasive hemodynamics and organ weight measurements. Cardiac tissue was collected. Our results showed that four months of HFD plus L-NAME treatment did not induce a profound HFpEF phenotype in FVB WT mice. β2a-HFD-LN (3-Hit) mice developed features of HFpEF, including increased natriuretic peptide (ANP) levels, preserved EF, diastolic dysfunction, robust CM hypertrophy, increased M2 macrophage population, and myocardial fibrosis. SAHA reduced the HFpEF phenotype in the 3-Hit mouse model by attenuating these effects. Concluding, the 3-Hit mouse model induced a reliable HFpEF phenotype with CM hypertrophy, cardiac fibrosis, and an increased M2 macrophage population. This model could be used for identifying and preclinical testing of novel therapeutic strategies. / Biomedical Sciences

Medical-grade ultrasound devices are now pocket sized and can be easily transported to underserved parts of the world, allowing health care providers to have the tools to optimize diagnoses, inform management plans, and improve patient outcomes in remote locations. Other great advances in technology have recently occurred, such as artificial intelligence applied to mobile health devices and cloud computing, as augmented reality instructions make these devices more user friendly and readily applicable across health care encounters. However, broader awareness of the impact of these mobile health technologies is needed among health care providers, along with training on how to use them in valid and reproducible environments, for accurate diagnosis and treatment. This article provides a summary of a Mayo International Health Program journey to Bwindi, Uganda, with a portable mobile health unit. This article shows how point-of-care ultrasonography and other technologies can benefit remote clinical diagnosis and management in underserved areas around the world.

<p>Oxygen (O2) plays a crucial role in the energy metabolism of complex multicellular life on earth. Due to the small and finite energy stores in the body, fine-tuned changes within the body are required to meet metabolic demand during skeletal muscle contractions, such as during exercise and activities of daily living. The skeletal muscle microcirculation is one of the last steps in the O2 transport pathway from the lungs to muscle cells and represents the largest surface area for O2 and substrate exchange. When skeletal muscle O2 uptake increases during contractions to meet metabolic demand, there must be an increase in muscle O2 delivery. To achieve these elevations in O2 delivery, vessel (arteriole) diameter in the microcirculation is increased, known as vasodilation. This process in the skeletal muscle microcirculation is regulated by several factors, such as neurohumoral, mechanical, endothelial, paracrine, and metabolic influences, which are imperative in properly regulating O2 delivery at rest and during muscular contractions. Two vasodilatory pathways of interest in this dissertation are the cyclooxygenase (COX) and nitric oxide (NO) vasodilatory pathways.</p> <p>The primary aim of my dissertation studies was to determine the mechanisms that modulate skeletal muscle oxygenation in health and to define the impact of a potentially effective intervention, whole-body chronic heat therapy (HT), to treat heart failure with preserved ejection fraction (HFpEF). In Chapter 2, we report that acute selective COX-2 inhibition had no effect on resting or exercising skeletal muscle microvascular oxygenation, pulmonary oxygen uptake, or exercise tolerance in healthy young humans. In Chapter 3, we report that NO, via phosphodiesterase type 5 inhibition, regulates myocyte O2 transport at rest and during recovery from muscle contractions in healthy young rats. In Chapter 4, we show that whole-body chronic HT promotes central and peripheral adaptations, which impact positively exercise tolerance in a pre-clinical rat model of HFpEF. Specifically, whole-body chronic HT had beneficial influences on exercise tolerance, skeletal muscle oxygenation from rest to contractions (driven, at least in part, by enhanced NO bioavailability), body composition, and cardiac function. Chapter 5 is a summary of the results and limitations of the projects presented in Chapters 2-4, with a brief discussion of potential future research directions. </p>

Aims In heart failure with preserved ejection fraction (HFpEF), the reduction of nitric oxide (NO)-bioavailability and consequently endothelial dysfunction leads to LV stiffness and diastolic dysfunction of the heart. Besides shear stress, high-density lipoprotein (HDL) stimulates endothelial cells to increased production of NO via phosphorylation of endothelial nitric oxide synthase (eNOS). For patients with heart failure with reduced ejection fraction, earlier studies demonstrated a positive impact of exercise training (ET) on HDL-mediated eNOS activation. The study aims to investigate the influence of ET on HDL-mediated phosphorylation of eNOS in HFpEF patients. Methods and results The present study is a substudy of the OptimEx-Clin trial. The patients were randomized to three groups: (i) HIIT (high-intensity interval training; (ii) MCT (moderate-intensity continuous training); and (iii) CG (control group). Supervised training at study centres was offered for the first 3 months. From months 4–12, training sessions were continued at home with the same exercise protocol as performed during the in-hospital phase. Blood was collected at baseline, after 3, and 12 months, and HDL was isolated by ultracentrifugation. Human aortic endothelial cells were incubated with isolated HDL, and HDL-induced eNOS phosphorylation at Ser1177 and Thr495 was assessed. Subsequently, the antioxidative function of HDL was evaluated by measuring the activity of HDL-associated paraoxonase-1 (Pon1) and the concentration of thiobarbituric acid-reactive substances (TBARS). After 3 months of supervised ET, HIIT resulted in increased HDL-mediated eNOS-Ser1177 phosphorylation. This effect diminished after 12 months of ET. No effect of HIIT was observed on HDL-mediated eNOS-Thr495 phosphorylation. MCT had no effect on HDL-mediated eNOS phosphorylation at Ser1177 and Thr495. HIIT also increased Pon1 activity after 12 months of ET and reduced the concentration of TBARS in the serum after 3 and 12 months of ET. A negative correlation was observed between TBARS concentration and HDL-associated Pon1 activity in the HIIT group (r = −0.61, P < 0.05), and a trend was evident for the correlation between the change in HDL-mediated eNOS-Ser1177 phosphorylation and the change in peak V̇O2 after 3 months in the HIIT group (r = 0.635, P = 0.07). Conclusions The present study documented that HIIT but not MCT exerts beneficial effects on HDL-mediated eNOS phosphorylation and HDL-associated Pon1 activity in HFpEF patients. These beneficial effects of HIIT were reduced as soon as the patients switched to home-based ET.