Altered gut microbial diversity has been associated with several chronic disease states, including heart failure. Stimulation of the vagus nerve, which innervates the heart and abdominal organs, is proving to be an effective therapeutic in heart failure. We hypothesized that cervical vagus nerve stimulation (VNS) could alter fecal flora and prevent aberrations observed in fecal samples from heart failure animals. To determine whether microbial abundances were altered by pressure overload (PO), leading to heart failure and VNS therapy, a VNS pulse generator was implanted with a stimulus lead on either the left or right vagus nerve before creation of PO by aortic constriction. Animals received intermittent, open-loop stimulation or sham treatment, and their heart function was monitored by echocardiography. Left ventricular end-systolic and diastolic volumes, as well as cardiac output, were impaired in PO animals compared with baseline. VNS mitigated these effects. Metagenetic analysis was then performed using 16S rRNA sequencing to identify bacterial genera present in fecal samples. The abundance of 10 genera was significantly altered by PO, 8 of which were mitigated in animals receiving either left- or right-sided VNS. Metatranscriptomics analyses indicate that the abundance of genera that express genes associated with ATP-binding cassette transport and amino sugar/nitrogen metabolism was significantly changed following PO. These gut flora changes were not observed in PO animals subjected to VNS. These data suggest that VNS prevents aberrant gut flora following PO, which could contribute to its beneficial effects in heart failure patients.

Orientador: Silméia Garcia Zanati Silméia Garcia Bazan / Resumo: Fundamento: A hipertensão arterial sistêmica (HAS) é um dos principais fatores de risco para o desenvolvimento de doença cardiovascular. Quando a mulher hipertensa engravida, ocorre uma nova condição hemodinâmica, com adição da situação de sobrecarga crônica de pressão à situação de sobrecarga crônica de volume. Essa nova condição hemodinâmica pode propiciar maior hipertrofia miocárdica (HVE), sendo que sua evolução após o parto ainda é pouco estudada na literatura. Suspeita-se que as mulheres hipertensas que apresentaram HVE durante gestação mantenham essa alteração cardíaca após o parto. Objetivos: Avaliar a hipertrofia miocárdica em mulheres hipertensas no terceiro trimestre da gestação e após seis meses do parto e estabelecer quais variáveis clínicas estão associadas com risco aumentado de hipertrofia miocárdica. Métodos: Estudo prospectivo longitudinal incluindo 41 mulheres gestantes com idade gestacional acima de 35 semanas e com diagnóstico prévio de HAS, acompanhadas no Ambulatório de Pré-Natal de Hipertensão Arterial do Serviço de Obstetrícia do Hospital das Clínicas da Faculdade de Medicina de Botucatu - UNESP. Foram submetidas às avaliações clínica e ecocardiográfica em dois momentos, período gestacional e período de seis meses após o parto. A HVE foi definida para índice de massa do ventrículo esquerdo indexada pela altura (IMVE) ≥ 45g/m2,7. Análise estatística: regressão logística multivariada com as exposições mais fortemente associadas com a manutenção da HVE n... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Systemic arterial hypertension (SAH) is one of the principal risk factors for developing cardiovascular disease. When a hypertensive woman becomes pregnant, a new hemodynamic condition is installed, with addition from chronic pressure overload to chronic volume overload. This new hemodynamic condition can provides greater myocardial hypertrophy (LVH), whose postpartum evolution has been little studied in the literature. It is suspected that hypertensive women who presented LVH during pregnancy maintain this cardiac alteration after delivery. Objectives: To evaluate myocardial hypertrophy in hypertensive women in the third trimester of pregnancy and six months after delivery and to establish which clinical variables are associated with elevated risk of myocardial hypertrophy. Methods: Prospective longitudinal study including 41 pregnant women beyond 35 gestational weeks and with previous SAH diagnosis, monitored at the Hypertension Clinic of the Obstetrics Unit of the Botucatu School of Medicine - UNESP. They were submitted to clinical and echocardiographic evaluation at two moments, the gestational period and six months postpartum. LVH was defined for the left ventricular mass index as (LVMI) ≥ 45g/m2.7. Statistical analysis: multivariate logistic regression with the exposures most strongly associated with maintenance of hypertrophy in univariate analysis. Significance level: p<0.05. Results: The mean age was 29±6.2 years; mean gestacional age was 36.7±1.18 weeks;... (Complete abstract click electronic access below) / Mestre

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23060号 / 医博第4687号 / 新制||医||1048(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 齊藤 博英, 教授 湊谷 謙司, 教授 萩原 正敏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Heart failure contributes to nearly 60,000 deaths per year in the USA and is often caused by hypertension and preceded by the development of left ventricular hypertrophy (LVH). LVH is usually accompanied by intensive interstitial and perivascular fibrosis which may contribute to arrhythmogenic sudden cardiac death. Emerging evidence indicates that LV dysfunction in patients and animal models of cardiac hypertrophy is closely associated with perivascular inflammation. To investigate the role of perivascular inflammation in coronary artery remodeling and cardiac fibrosis during hypertrophic ventricular remodeling, we used a well-established mouse model of pressure-overload-induced LVH: transverse aortic constriction (TAC). Early perivascular inflammation was indicated by accumulation of macrophages and T lymphocytes 24 hours post-TAC and which peaked at day 7. Coronary luminal platelet deposition was observed along with macrophages and lymphocytes at day 3. Also, LV protein levels of VEGF and MCP-1 were significantly increased. Consistent with lymphocyte accumulation, cardiac expression of IL-10 mRNA was elevated. Furthermore, circulating platelet-leukocyte aggregates tended to be higher after TAC, compared to sham controls. Platelets have been shown to modulate perivascular inflammation and may facilitate leukocyte recruitment at sites of inflamed endothelium. Therefore, we investigated the impact of thrombocytopenia in the response to TAC. Immunodepletion of platelets decreased early perivascular accumulation of T lymphocytes and IL-10 mRNA expression, and altered subsequent coronary artery remodeling. The contribution of lymphocytes was examined in Rag1-/- mice, which displayed significantly more intimal hyperplasia and perivascular fibrosis compared to wild-type mice following TAC. Collectively, our studies support a role of early perivascular accumulation of platelets and T lymphocytes in pressure overload-induced inflammation which will contribute to long-term LV remodeling. One potential mechanism for inflammatory cells to modulate their environment and affect surrounding cells is through release of cargo stored in granules. To determine the contribution of granule release from inflammatory cells in the development of LVH, we used Unc13dJinx (Jinx) mice, which contain a single point mutation in Unc13d gene resulting in defects in Munc13-4. Munc13-4 is a limiting factor in vesicular priming and fusion during granule secretion. Therefore, Jinx mice have defects in degranulation of platelets, NK cells, cytotoxic T lymphocytes, neutrophils, mast and other cells. With the use of bone marrow transplantation, Jinx chimeric mice were created to determine whether the ability of hematopoietic cells to secrete granule contents affects the development of LVH. Wild-type mice (WT) that were transplanted with WT bone marrow (WT>WT) and WT mice that received Jinx bone marrow (Jinx>WT) developed LVH and a classic fetal reprogramming response early after TAC (7 days), but at later times (5 weeks), Jinx>WT mice failed to sustain the cardiac hypertrophic response observed in WT>WT mice. No difference in cardiac fibrosis was observed at early or late times. Repetitive injection of WT platelets or platelet releasate restored cardiac hypertrophy in Jinx>WT mice. These results suggest that sustained LVH in the setting of pressure overload depends on factor(s) secreted, likely from platelets. In conclusion, our studies demonstrate that platelets and lymphocytes are involved in early perivascular inflammation post-TAC, which may contribute to later remodeling in the setting of LVH. Factors released from hematopoietic cells, including platelets, in a Munc13-4-dependent manner are required to promote cardiac hypertrophy. These findings focus attention on modulating perivascular inflammation and targeting granule cargo release to prevent the development and consequences of LVH.

Tumor necrosis factor (TNF) is upregulated in a number of cardiomyopathies. This thesis investigates TNF in triggering the expression and activation of matrix metalloproteinases (MMPs) in pressure overload cardiac disease, and explores the role of superoxide. Cardiac pressure overload was generated in adult wild-type and TNF-/- mice by transverse aortic constriction. Isolated cardiomyocytes and cardiofibroblasts from neonatal mice ventricles were treated with recombinant TNF (rTNF), and MMP induction and activation were assessed, with and without apocynin (a NADPH-oxidase inhibitor). TNF-/- mice showed less superoxide production and MMP activation, compared to wild-type mice, following pressure overload. rTNF upregulated the production of NADPH-dependent superoxide in cardiomyocytes as early as 1 hour (24 hours in cardiofibroblasts). rTNF also increased the expression of MMP-9 and MMP-12 in cardiomyocytes more than in cardiofibroblasts, and MMP-8 and MMP-13 more in cardiofibroblasts. This induction in both cardiac cell types was concomitant with superoxide production.

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Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15–20%) aortic constriction. Of the 31 animals surviving PO induction, 10 were randomized to RCV VNS, 9 to LCV VNS, and 12 to sham VNS. VNS was delivered at 20 Hz and 1.14 ± 0.03 mA at a 22% duty cycle. VNS commenced 10 days after PO induction and was maintained for 40 days. Time-matched controls (n = 9) were evaluated concurrently. Echocardiograms were obtained before and 50 days after PO. At termination, intracellular current-clamp recordings of intrinsic cardiac (IC) neurons were studied in vitro to determine effects of therapy on soma characteristics. Ventricular cardiomyocyte sizes were assessed with histology along with immunoblot analysis of selected proteins in myocardial tissue extracts. In sham-treated animals, PO increased cardiac output (34%, P < 0.004), as well as systolic (114%, P < 0.04) and diastolic (49%, P < 0.002) left ventricular volumes, a hemodynamic response prevented by VNS. PO-induced enhancements of IC synaptic efficacy and muscarinic sensitivity of IC neurons were mitigated by chronic VNS. Increased myocyte size, which doubled in PO (P < 0.05), was mitigated by RCV. PO hypertrophic myocardium displayed decreased glycogen synthase (GS) protein levels and accumulation of the phosphorylated (inactive) form of GS. These PO-induced changes in GS were moderated by left VNS. Chronic VNS targets IC neurons accompanying PO to obtund associated adverse cardiomyocyte remodeling.

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