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Agradecemos a compreensão. on 2017-07-26T19:10:07Z (GMT) / Submitted by JULIANE ROSA POIATI null (jpoiati@yahoo.com.br) on 2017-07-27T00:19:47Z No. of bitstreams: 1 Tese Pronta recente.pdf: 1203025 bytes, checksum: 3f33e46e228494eaa8c4c9ba0d1246d1 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-07-31T14:34:20Z (GMT) No. of bitstreams: 1 poiati_jr_dr_bot.pdf: 1203025 bytes, checksum: 3f33e46e228494eaa8c4c9ba0d1246d1 (MD5) / Made available in DSpace on 2017-07-31T14:34:20Z (GMT). No. of bitstreams: 1 poiati_jr_dr_bot.pdf: 1203025 bytes, checksum: 3f33e46e228494eaa8c4c9ba0d1246d1 (MD5) Previous issue date: 2017-05-26 / Objetivo: Determinar o valor da concentração do BNP que se associa à presença de hipertrofia do ventrículo esquerdo (VE) em mulheres com pré-eclâmpsia (PE). Métodos: Realizou-se estudo observacional, descritivo e transversal em gestantes com diagnóstico de pré-eclâmpsia, que receberam assistência obstétrica no Hospital das Clínicas da Faculdade de Medicina de Botucatu - Unesp. Foram excluídas do estudo gestantes portadoras de patologia clínica ou gestacional associada a alterações cardiovasculares (diabetes, hipertensão arterial crônica, cardiopatias, colagenoses, nefropatias). Considerando a prevalência de hipertrofia concêntrica do VE nessa população de 27% e assumindo a margem de erro de 10% e confiabilidade de 95%, o tamanho amostral calculado foi de 76 gestantes. No momento do diagnóstico de PE as gestantes selecionadas foram submetidas à coleta de sangue venoso para determinação da concentração sérica de BNP e ao exame de ecocardiograma para identificação de hipertrofia concêntrica do VE. As correlações entre o índice de massa do VE (iMVE) e entre a espessura relativa da parede (ER) e o BNP foram realizadas pelo teste de Spearman. O ponto de corte da concentração do BNP, que identifica hipertrofia concêntrica do VE, foi estabelecido pela curva ROC, utilizando-se o programa estatístico SPSS for Windows. Resultados: A hipertrofia concêntrica do ventrículo esquerdo foi diagnosticada em 48,7% das gestantes. O ponto de corte do valor da concentração do BNP, que identifica a hipertrofia concêntrica do VE, foi 203pg/mL (sensibilidade de 88%, especificidade de 80%, valor preditivo positivo de 69%, valor preditivo negativo de 93% e acurácia de 83%). A área sob a curva foi 0,87 (IC 95%= 0,79 – 0,95). A correlação entre o iMVE e a ER com a concentração do BNP foi significativa (iMVE: r=0,49; p<0,0001; ER: r=0,50; p<0,0001). Conclusões: O presente estudo encontrou correlação positiva entre os valores de BNP e hipertrofia do VE, além de determinar o ponto de corte (203 pg/ml) para o diagnóstico dessa condição. Utilizar o BNP como rastreamento de hipertrofia do VE pode ajudar na racionalização da indicação do ecocardiograma para confirmação diagnóstica. / Objective: To determine BNP concentration value associated with the presence of left ventricular hypertrophy (LV) in women with pre-eclampsia (PE). Methods: An observational, descriptive and cross-sectional study was performed in pregnant women diagnosed with preeclampsia, who have received obstetric care at Botucatu Medical School Clinical Hospital - Unesp. Pregnant women with clinical or gestational pathology associated with cardiovascular alterations such as diabetes, chronic hypertension, heart diseases, collagenosis, nephropathies were excluded from the study. Considering the prevalence of LV concentric hypertrophy in this population of 27% and assuming the margin of error of 10%, as well as reliability of 95%, the calculated sample size was of 76 pregnant women. At the moment of PE diagnosis the selected pregnant women were submitted to both venous blood collection (in order to determine BNP serum concentration) and to echocardiogram examination (to identify LV concentric hypertrophy). Correlations between LV mass index (iMVL), relative wall thickness (WT) and BNP were performed with Spearman test. The cut off of BNP concentration, which identifies LV concentric hypertrophy, was established with ROC curve, using the statistical program SPSS for Windows. Results: Left ventricular concentric hypertrophy was diagnosed in 48.7% of the pregnant women. The cut off value of BNP concentration, which identifies LV concentric hypertrophy, was 203pg / mL (sensitivity 88%, specificity 80%, positive predictive value 69%, negative predictive value 93%, and accuracy 83%). The area under the curve was 0.87 (95% CI = 0.79-0.95). The correlation between iMVL and WT with BNP concentration was significant (iMVE: r=0,49; p<0,0001; ER: r=0,50; p<0,0001). Conclusions: The present study found a positive correlation between BNP values and LV hypertrophy. Moreover, it determined the cut off (203 pg / ml) for the diagnosis of this condition. Therefore, using BNP as a screening method for LV hypertrophy may help to rationalize echocardiographic indication for diagnosis confirmation.

O remodelamento cardíaco é uma sequela da hipertensão. Receptores do tipo Toll (TLRs) pertencem a imunidade inata e sua ativação produz moléculas inflamatórias. O objetivo do trabalho foi avaliar a participação do TLR4 no remodelamento cardíaco de ratos espontaneamente hipertensos (SHR). Utilizamos SHR e Wistar de 6 e 21 semanas. O nível do RNAm do TLR4 de SHR de 21 semanas é maior em relação aos outros grupos. Outros grupos de Wistar e SHR de 19 semanas foram tratados com anticorpo anti-TLR4, os controles receberam anticorpo IgG inespecífico. Observamos redução no nível do RNAm do TLR4 e MyD88 e expressão protéica do TLR4, MyD88, TNF-<font face=\"symbol\">a e IL-1<font face=\"symbol\">b de SHR anti-TLR4 em relação aos SHR controle. Não houve alteração nos valores pressóricos. Verificamos redução no nível do RNAm de colágenos I e III, de metaloproteinases 2 e 9, de ANP, BNP e <font face=\"symbol\">a-actina esquelética e de deposição de colágeno, área e diâmetro de cardiomiócitos de SHR anti-TLR4 em relação aos SHR controle. Nossos resultados sugerem que o TLR4 participa do processo de remodelamento cardíaco de SHR adultos. / The cardiac remodeling is a sequel of hypertension. Toll-Like Receptors (TLR) are innate immunity receptor and its activation produces inflammatory molecules. The objective of this study was to evaluate the involvement of TLR4 in cardiac remodeling of spontaneously hypertensive rats (SHR). We used male Wistar and SHR with 6 and 21 weeks. The level of TLR4 mRNA in SHR with 21 weeks is higher than the other groups. Wistar and SHR with 19 weeks were treated with anti-TLR4 or nonspecific IgG antibody (control group). We observed a reduction in the level of TLR4 and MyD88 mRNA and protein expression of TLR4, MyD88, TNF-<font face=\"symbol\">a and IL-1<font face=\"symbol\">b in anti-TLR4 SHR compared to control SHR. There was no change in blood pressure values in SHR after anti-TLR4 treatment. We observed reduction in mRNA level of collagens I and III, metalloproteinases 2 and 9, ANP, BNP, <font face=\"symbol\">a-skeletal actin, collagen deposition, cardiomyocyte area and diameter in anti-TLR4 SHR compared to control SHR. Our results suggest that TLR4 participates of cardiac remodeling process in adults SHR.

Orientador: Heitor Moreno Junior / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-20T00:15:25Z (GMT). No. of bitstreams: 1 Ludovico_NelsonDinamarco_D.pdf: 11127350 bytes, checksum: fac2a775e3c6969068fdbd9ca7d14542 (MD5) Previous issue date: 2012 / Resumo: A hipertrofia ventricular esquerda caracterizada como lesão de órgão alvo aumenta o risco de morbi-mortalidade de 5 a 9 vezes quando presente. A detecção precoce da HVE permite a identificação de pacientes com risco, além de permitir a intervenção de forma precoce, melhorando o planejamento estratégico para o seu manejo. A hipertensão arterial resistente é caracterizada pelo paciente, que mesmo em uso de três medicações em doses otimizadas, sendo um deles diurético, ainda se mantém fora das metas preconizadas. Vários métodos diagnósticos de hipertrofia estão disponíveis para o diagnóstico da HVE, entre eles se destaca o ecocardiograma com elevada sensibilidade, especificidade e acurácia, o eletrocardiograma, com elevada especificidade, porém baixa sensibilidade e acurácia, em contrapartida com excelente reprodutibilidade e baixo custo operacional, e fácil realização, inclusive em locais afastados dos grandes centros, em contraposição ao ecocardiograma. Outro método, não muito usado na prática clínica, o vetorcardiograma, pode atualmente, ser realizado no mesmo equipamento do eletrocardiograma, justificando assim a sua empregabilidade na prática clínica diária. Apresentou em nosso estudo a mesma baixa sensibilidade e acurácia que o eletrocardiograma, compatíveis com estudos publicados recentemente, porém a associação de dois critérios, um eletrocardiográfico e outro vetorcardiográfico melhorou a sensibilidade e acurácia na detecção da hipertrofia ventricular esquerda, sem prejuízo para a especificidade, com valores próximos ao ecocardiograma / Abstract: Left ventricular hypertrophy characterized as target-organ damage increases the risk of morbidity and mortality 5-9 times when present. Early detection of LVH allows the identification of patients at risk, and allows intervention at an early stage, improving strategic planning for its management. The resistant hypertension is characterized by the patient, even taking three medications in doses optimized, one being a diuretic, is still outside of the recommended goals. Several diagnostic methods are available to hypertrophy the diagnosis of LVH, including echocardiography stands out with high sensitivity, specificity and accuracy, the electrocardiogram, with high specificity but low sensitivity and accuracy, in contrast with excellent reproducibility and low operating cost, and easy to perform, even in places far from the large centers, in contrast echocardiography. Another method, not widely used in clinical practice, the vectorcardiogram, can now be performed on the same equipment on the electrocardiogram, thereby justifying their employability in daily clinical practice. In our study vectorcardiography presented the same low sensitivity and accuracy than electrocardiography, consistent with recently published studies, but the combination of two criteria, an electrocardiogram and other vetorcardiográfico improved sensitivity and accuracy in detecting left ventricular hypertrophy, without prejudice to the specificity, with values close to echocardiography / Doutorado / Farmacologia / Doutor em Farmacologia

Introduction : Le diagnostic de cardiomyopathie hypertrophique (CMH) est difficile chez l’athlète. En effet, le remodelage physiologique induit par l’entraînement physique intense entraîne des modifications électriques et morphologiques qui peuvent mimer une cardiomyopathie. Or il est indispensable de poser le diagnostic de cardiomyopathie avec certitude chez un athlète. Ne pas contre-indiquer un athlète avec une cardiomyopathie l’expose à un risque de mort subite, mais poser un diagnostic par excès l’expose à de lourdes répercussions tant professionnelles que sociales. Méthodes : (1) Nous avons cherché à améliorer les critères ECG actuels de détection de cardiomyopathie chez l’athlète à partir d’une cohorte multicentrique d’athlètes et de CMH. (2) Nous avons cherché à déterminer quel bilan complémentaire réaliser en cas d’anomalie ECG par un suivi longitudinal d’athlètes avec ondes T négatives. (3) Nous avons essayé de mieux caractériser le phénotype des athlètes atteints de CMH par rapport aux CMH sédentaires dans une cohorte multicentrique. (4) Nous avons tenté de déterminer si l’utilisation des nouvelles techniques d’imagerie de déformation myocardique permettait d’améliorer la pertinence diagnostique et pronostique en cas de CMH dans une cohorte de CMH et d’athlètes rennais. Résultats : Nous avons proposé une nouvelle classification ECG permettant de mieux identifier les athlètes avec modifications ECG non pathologiques sans diminuer pour autant la capacité à détecter les CMH. En cas d’ondes T négatives chez l’athlète, nous avons démontré qu’il était indispensable de réaliser une IRM myocardique. En effet l’échocardiographie peut être prise en défaut dans près de 35% des cas. Néanmoins, les critères diagnostiques actuels de CMH peuvent être pris en défaut; en effet les athlètes avec une CMH ont un phénotype différent des CMH sédentaires avec une meilleure fonction systolique, notamment longitudinale, et diastolique. L’évaluation de la fonction longitudinale à l’effort et l’évaluation de la dispersion mécanique sont des paramètres qui semblent prometteurs en terme de diagnostic. En effet l’altération la fonction longitudinale semble être en lien avec la fibrose myocardique. L’échocardiographie d’effort, notamment la présence d’une insuffisance mitrale à l’effort, semble être un facteur pronostic important dans les CMH. Conclusions : les travaux réalisés ont permis de développer des outils pour mieux différencier une hypertrophie ventriculaire gauche (HVG) pathologique d’une HVG physiologique mais également pour mieux caractériser cette HVG et déterminer avec plus de précision le pronostic des CMH . / Introduction: the diagnosis of hypertrophic cardiomyopathy (HCM) in athlete is difficult. Indeed, intense sports practice induces an electrical and morphological physiological remodeling which can be difficult to differentiate from the changes induced in pathology. However, it is essential to diagnose an athlete with a cardiomyopathy. Indeed, in case of underlying cardiomyopathy the athlete will be at risk of sudden cardiac death, but an excessive over diagnosis has strong professional and social consequences. Methods: (1) we have tried to improve the ECG criteria’s, which enable the differentiation between ECG changes induced by exercise and the ECG changes induced by an underlying cardiomyopathy. (2) We tried to define the best investigation algorithm in case of abnormal ECG changes in athletes. (3) We tried to improve the characterization of the phenotype of athletes with HCM as compared to sedentary HCM. (4) We tried to investigate if the use of new imaging technics, i.e. speckle tracking, might improve the diagnostic accuracy and enable a better prognostic evaluation in HCM. Results: We have proposed a new classification of ECG in athletes enabling to decrease the rate of false positive ECG in athletes without decreasing its diagnostic accuracy in HCM. In case of pathological T wave inversion (PTWI) in athletes, we demonstrated that a CMR is mandatory, as echocardiography missed a diagnosis of pathology in 35% of PTWI athletes. Nevertheless, the diagnosis of HCM with current criteria’s of HCM can be challenging. Indeed, HCM athletes have a different phenotype from HCM sedentary, with a better systolic and diastolic function; they also have a better longitudinal function. The assessment of longitudinal function during exercise and mechanical dispersion are promising tool for the diagnosis of HCM in athletes. Indeed, the alteration of longitudinal strain is related to myocardial fibrosis. Exercise echocardiography, i.e. exercise mitral insufficiency, seems to be a prognostic factor in HCM patients. Conclusions: Ours results enabled to develop tools which might help to better differentiate pathological and physiological left ventricular hypertrophy (LVH); but also to better characterize LVH and the prognosis in HCM patients.

No presente estudo, duas importantes situações foram abordadas no intuito de se melhor entender os mecanismos homeostáticos dos pressorreceptores na gênese da hipertrofia cardíaca em resposta à hipertensão renovascular: o efeito do tempo de clipe na artéria renal e o efeito dos níveis pressóricos e da variabilidade da pressão arterial. O curso temporal mostrou que, antes mesmo da instalação da hipertensão, há alteração da morfologia cardíaca, qual seja o desenvolvimento de uma hipertrofia ventricular excêntrica e, como forma de mecanismo compensatório, um aumento da expressão de algumas proteínas da homeostase do cálcio (fosfolambam fosforilada pela serina-16 e corrigido pelo fosfolambam total em 100% e fosfolambam fosforilado pela treonina-17 e corrigido pelo fosfolambam total em 54%). Uma vez instalada a hipertensão, observou-se um remodelamento ventricular esquerdo para o tipo concêntrico, com prejuízo da função diastólica e um desbalanço do sistema nervoso autonômico, com aumento da atividade simpática, observado pelo aumento da razão dos componentes de baixa freqüência (LF) e alta freqüência (HF) no tacograma (0,44 ± 0,10 vs. 0,20 ± 0,03 nos controles). A análise do efeito da pressão arterial e da variabilidade da pressão arterial mostrou uma correlação positiva com o grau de hipertrofia ventricular esquerda (r=0,76, p<0,01). A secção cirúrgica dos pressorreceptores somada à implantação do clipe na artéria renal mostrou adaptações cardiovasculares em níveis semelhantes (mesmo nível de hipertensão) e, por vezes maiores (modulação simpática para o coração e para os vasos, hipertrofia ventricular esquerda e disfunção diastólica), ao grupo cuja artéria renal foi estenosada e que permaneceu com os barorreceptores intactos. Estas respostas aconteceram num período de tempo três vezes menor na ausência do barorreflexo. Tais observações ressaltam o importante efeito homeostático do barorreflexo na gênese das respostas cardíacas adaptativas à hipertensão arterial / In the present study, two important situations were observed to evaluate the role of the baroreceptors in the genesis of cardiac hypertrophy in response to hypertension: the effect of the time-course of the clip in the renal artery and the effect of the level of arterial blood pressure (ABP) and blood pressure variability (ABPV). The time-course evaluation showed that even before hypertension was installed, cardiac alterations could be observed, as a left ventricular eccentric hypertrophy. Compensatory mechanisms, such as an increase in some calcium homeosthatic proteins, could also be noticed (increase in phosphorilated phospholmaban at threonin-17 corrected by total phospholamban in 54% and increase in phosphorilated phospholmaban at serine-16 corrected by total phospholamban in 100%). However, once hypertension was established, left ventricle morphology changed to a concentric hypertrophy, accompanied by a diastolic dysfunction and enhanced sympathetic modulation, observed by relation between low-frequency component (LF) and high-frequency component (HF) at tachogram (0,44 ± 0,10 vs. 0,20 ± 0,03 in control group). ABP and ABPV analyses showed an important positive correlation with the degree of left ventricular hypertrophy (r=0,76, p<0,01). However, the absence of baroreceptors in one of the hypertensive groups, evoked the same cardiovascular alterations (same level of hypertension) or even worse (sympathetic modulation for heart and vessels, left ventricular hypertrophy and diastolic dysfunction) reached by the hypertensive baroreceptors-preserved group. These cardiovascular responses were observed in a period that correspond one third of time to the group with intact baroreflex. These observations lead us to conclude the importance of homeosthatic effects of the baroreflex in the genesis of cardiac responses to hypertension

Activation of NF-κB contributes to cardiac hypertrophy and the interleukin-1 receptor (IL-1R)-mediated MyD88-dependent signaling pathway predominately activates NF-κB. Recent studies have shown that the TIR/ BB-Loop mimetic (AS-1) disrupted the interaction of MyD88 with the IL-1R, resulting in blunting of NF-κB activation. We have examined the effects of AS-1 on the IL-1b-induced hypertrophic response using cultured neonatal cardiac myocytes in vitro and transverse aortic constriction (TAC) pressure overload-induced cardiac hypertrophy in vivo. Neonatal cardiac myocytes were treated with AS-1 15 min prior to IL-1β stimulation for 24 h. AS-1 treatment significantly attenuated IL-1β-induced hypertrophic responses of cardiac myocytes. In vivo experiments showed that AS-1 administration prevented cardiac hypertrophy and dysfunction induced by pressure overload. AS-1 administration disrupted the interaction of IL-1R with MyD88 in the pressure overloaded hearts and prevented activation of NF-κB. In addition, AS-1 prevented increases in activation of the MAPK pathway (p38 and p-ERK) in TAC-induced hypertrophic hearts. Our data suggest that the IL-1R-mediated MyD88-dependent signaling pathway plays a role in the development of cardiac hypertrophy and AS-1 attenuation of cardiac hypertrophy is mediated by blocking the interaction between IL-1R and MyD88, resulting in decreased NF-κB binding activity and decreased MAPK activation.

Background: Resistant hypertension (RH) is defined as blood pressure (BP) that remains elevated (>140/90mmHg) despite being treated with an antihypertensive regimen of 3 or more medications from different classes, including a long-acting calcium channel blocker, an angiotensin converting enzyme inhibitor or angiotension receptor blocker and a diuretic. The prevalence of RH in South Africa is currently unknown, however, clinical reports suggest that it is not rare. Patients with RH are significantly predisposed to cardiovascular (CV) diseases compared to patients with controlled BP. Consequences of RH include left ventricular hypertrophy, heart failure, ischaemic heart disease, chronic kidney disease leading to end-stage renal disease, stroke, vascular dementia, CV death and peripheral arterial disease. A proportion of patients with RH who never achieve BP control despite maximal medical treatment, represent a potentially novel and distinctive phenotype which is different from RH patients whose BP canbe controlled. Recognising and categorising such patients becomes the initial and crucial step in stratifying phenotypes and defining mechanisms of treatment resistance. Objectives: The aim of this study was to identify patients with resistant uncontrolled hypertension (RUH) and compare phenotypes in these patients to resistant controlled hypertensives (RCH). Methods: We enrolled 50 patients from the Groote Schuur Hospital Hypertension Clinic: a teriary referral hospital for RH. Patients on 4 or more antihypertensive medication including a diuretic, with BP< 140/90mmHg were considered RCH, and those with BP ≥ 140/90 considered RUH. Assessments included clinical examination, electrocardiography, echocardiography, applanation tonometry, serum biomarkers and cardiovascular magnetic resonance (CMR - which included biventricular volumes and function, myocardial strain, tissue characteristics and late gadolinium enhancement - LGE). Results: Thirty were diagnosed with RUH and twenty with RCH. Patients with RUH were more likely to have a longer duration since diagnosis of hypertension (10.5±10.7 vs. 3.6±3.4, p=0.02) and more likely to be on treatment that included an ACE-inhibitor (90% vs. 58%, p=0.01). As expected, patients with RUH had significantly higher systolic BP (155.6±21.6 vs. 137.8±16.5 mmHg, p< 0.001), diastolic BP (88.4±14.5 vs. 77.5±13.6 mmHg, p= 0.03), mean arterial BP (115.4±17.2 vs 101±15.3 mmHg, p= 0.004) and pulse pressure (67.3±14.2 vs. 60.1±12.4 mmHg, p=0.001). Further, RUH patients had significantly lower large artery elasticity (12.5±4 vs 14.7±3.8ml/mmHgx100, p=0.08) and lower small artery elasticity (4.1±2.1 vs. 6.9±3.6ml/mmHgx100, p< 0.001). RUH patients also had a higher systemic vascular resistance (1754±418.4 vs. 1363±371.5dyneXsecXcm-5, p=0.002). On CMR, RUH patients had lower right ventricular (RV) end-systolic and end-diastolic volumes (p=0.02), as well as higher indexed left ventricular mass (LVMI) (61.6±17.6 vs 52.9±13.9 g/m2 , p= 0.06). There were no differences in native T1, extracellular volume quantification and LGE volume fraction between RUH and RCH patients. Conclusions: Patients with RUH have a greater involvement and more severe CV phenotype, that is likely to result in increased CV morbidity and mortality, including greater target end organ damage as a result of vascular adaptations and concentric remodeling.

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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.

Background Coarctation of the aorta (CoA) constitutes 5-8 % of all congenital heart disease (CHD) and is associated with long-term complications such as hypertension (HTN) and left ventricular hypertrophy (LVH). Factors associated with HTN, LVH, and diffuse myocardial fibrosis, are not yet fully explored in this population. Methods Papers I-III: The Swedish national register of congenital heart disease (SWEDCON) was used to identify adult patients with repaired CoA. Paper IV: Data on 2,424 adult patients with CHD was extracted from SWEDCON and compared to controls (n = 4,605) regarding height, weight and body mass index (BMI). Paper V: Adults with CoA (n = 21, age 28.5 (19.1-65.1) years, 33.3 % female) referred for CMR were investigated with T1 mapping to determine left ventricular extracellular volume fraction (ECV). Results Papers I-II: Out of 653 patients, 344 (52.7 %) had HTN. In a multivariable model, age (years) (OR 1.07, CI 1.05-1.10), sex (male) (OR 3.35, CI 1.98-5.68) and BMI (kg/m2) (OR 1.09, CI 1.03-1.16) were associated with having HTN, and so was systolic arm-leg blood pressure (BP) gradient where an association was found at the ranges (10, 20] mmHg (OR 3.58, CI 1.70-7.55) and &gt; 20 mmHg (OR 11.38, CI 4.03-32.11), in comparison to the range [0, 10] mmHg. When investigating 243 patients with diagnosed HTN, 127 (52.3 %) had elevated BP (≥ 140/90 mmHg). Age (years) (OR 1.03, CI 1.01-1.06) was associated with elevated BP, and so was systolic arm-leg BP gradient in the ranges (10, 20] mmHg (OR 4.92, CI 1.76-13.79), and &gt; 20 mmHg (OR 9.93, CI 2.99-33.02), in comparison to the reference interval [0, 10] mmHg. Patients with elevated BP had more classes of anti-hypertensive medication classes prescribed (1.9 vs 1.5, p = 0.003). Paper III: Out of 506 patients, 114 (22.5 %) were found to have LVH. Systolic BP (mmHg) (OR 1.02, CI 1.01-1.04), aortic valve disease, (OR 2.17, CI 1.33–3.53), age (years) (OR 1.03, CI 1.01–1.05), and HTN (OR 3.02, CI 1.81-5.02), were associated with LVH, while sex (female) (OR 0.41, CI 0.24-0.72) was negatively associated with LVH. Paper IV: There was no difference in height, weight, or BMI between patients with CoA (n = 414) and the reference population. Paper V: In the population of 21 patients, an increased left ventricular myocardial ECV was found in 6 cases (28.6 %). Of the patients with increased ECV, 5/6 (83.3 %) were female (p = 0.002). Patients with increased ECV did not otherwise differ from the rest of the study population. iv Conclusions In adults with repaired CoA, HTN and LVH were common, and many patients with HTN had elevated BP despite treatment. The potentially modifiable factors BMI and systolic arm-leg BP gradient were associated with HTN, and the gradient was also associated with elevated BP among patients with diagnosed HTN. The gradient’s significance remained even within what the current guidelines consider acceptable ranges. Potentially modifiable factors associated with LVH were systolic BP and aortic valve disease. We found no general difference in height, weight, or BMI between patients with CoA and the reference population. While LVH was more common among men, increased myocardial ECV was more common among women.