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Introdução: A doença falciforme (DF) é a afecção hematológica hereditária de maior prevalência no mundo, sendo que a anemia falciforme (AF) é a forma mais grave com elevada morbidade e mortalidade. Alterações cardíacas são reconhecidamente associadas à AF, como aumento cavitário, hipertensão arterial pulmonar e disfunção diastólica do ventrículo esquerdo. No entanto, ainda não existe consenso quanto à função sistólica ventricular nesses pacientes. O objetivo deste estudo foi o de investigar a função ventricular de pacientes com anemia falciforme utilizando o strain e o twist ventricular obtidos pelo speckle tracking bidimensional, e reconhecer os indivíduos sob maior risco cardiovascular, em que a instituição precoce de tratamento específico poderá beneficiar essa população. Métodos: Foram recrutados 40 pacientes com anemia falciforme (23,5 ± 9,3 anos; 24 homens) e 40 controles saudáveis pareados por sexo e idade, submetidos à entrevista estruturada, ecocardiograma transtorácico, cintilografia pulmonar ventilação perfusão e coleta de amostras de sangue. Todos os indivíduos foram submetidos à avaliação ecocardiográfica convencional padrão e subsequente avaliação offline do strain sistólico biventricular e estudo rotacional do ventrículo esquerdo utilizando speckle-tracking ecocardiográfico. Resultados: Os pacientes com AF apresentaram volume do VE indexado, massa do VE indexado, pressão arterial pulmonar e E/E\' médio superiores aos controles. As medidas de FE do VE, excursão sistólica do plano da tricúspide (TAPSE), Strain Global do VE (longitudinal, circunferencial, radial) e Strain Global do VD (longitudinal) não evidenciaram diferenças entre os grupos. Twist VE se mostrou reduzido em comparação aos controles (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) e Tempo de pico de rotação apical prolongado (366,7 ± 26,1ms vs 344,6 ± 11,7ms , P <0,0001 ). Algumas variáveis se mostraram fortemente relacionadas ao twist VE, como índice de gravidade clínico (Rho= - 0,97, Z value= - 6,05, P < 0,0001), relação E/E\' médio (r = 0,94, F valor= 156.9, p<0,0001), IVDFVE (índice do volume diastólico final do ventrículo esquerdo)(r = 0,81 e p<0,0001) e pressão sistólica arterial pulmonar (r = 0,72 e p<0,0001). Conclusões: Os resultados deste trabalho indicam que o twist ventricular esquerdo derivado do speckle tracking bidimensional encontra-se alterado em pacientes com anemia falciforme e função sistólica ventricular preservada, avaliada pela metodologia convencional, e existe forte correlação entre o twist ventricular esquerdo e o índice clínico de gravidade, relação E/E\', índice do volume diastólico final do ventrículo esquerdo e pressão sistólica arterial pulmonar. / Background: Sickle cell disease (SCD) is the most prevalent hematological condition in the world, with sickle cell anemia (SCA) being its most serious form, displaying a high level of morbidity and mortality. Cardiac changes are known to be associated with SCA, including an increase in cardiac chamber size, pulmonary hypertension and left ventricle diastolic dysfunction. However, there is still no consensus regarding the ventricular systolic function in these patients. The purpose of this study is to investigate the ventricular function of patients with sickle cell anemia utilizing the strain and ventricular twist, obtained by two-dimensional speckle tracking, as well as to identify individuals with higher cardiovascular risk, in which early application of specific treatment could benefit this group of people. Methods: 40 patients were recruited with sickle cell anemia (ages 23.5 ± 9.3 years; 24 males) and 40 healthy control individuals paired by gender and age, submitted to structured interviews, transthoracic echocardiogram, pulmonary scintigraphy and collection of blood samples. All individuals were submitted to a standard echocardiographic evaluation and subsequent off line evaluation of the biventricular systolic strain and rotational study of the left ventricle using echocardiographic speckle-tracking. Results: Patients with SCA presented LV volume indices, LV mass Indices, pulmonary arterial pressure and E/ E\' ratios statistically higher than the control individuals. Measurements of Ejection Fraction (EF) of the left ventricle, tricuspid annular plane systolic excursion (TAPSE), Overall LV Strain (Longitudinal, Circumferential, and Radial) and Overall RV Strain (Longitudinal) did not present differences between the groups. LV twist was significantly lower in relation to the control group (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) and prolonged time to peak apical rotation (366.7 ± 26.1ms vs 344.6 ± 11.7ms , P <0.0001 ). In addition, some variables showed themselves to be strongly related to LV twist such as the clinical severity index ( Rho= - 0.97, Z value= - 6.05, P < 0.0001), E/E\' Ratio (r = 0.94, F value=156.9 e p<0.0001) ), left ventricle end diastolic volume index (LVEDV index) (r = 0,81, p<0,0001) and pulmonary systolic arterial pressure (r = 0.72 e p<0.0001). Conclusions: The results of this study indicate that the left ventricular twist derived from two-dimensional speckle tracking is altered in patients with sickle cell anemia and a preserved ventricular systolic function, evaluated using conventional methodology and that there is a strong correlation between left ventricular twist and the clinical severity index, E/E\' ratio, left ventricle end diastolic volume index and the pulmonary systolic arterial pressure.

<p>Cilj: Cilj ovog istraživanja bio je da se utvrde promene koje arterijska hipertenzija dvojakim mehanizmima (dnevno-noćnim ritmom i svojim trajanjem) ostavlja na funkciju i geometriju leve pretkomore i komore srca. Ispitanici i metode: u ovo istraživanje bilo je uključeno 180 ispitanika koji su bili podeljeni u ispitivane grupe u odnosu na dnevno-noćni ritam arterijskog krvnog pritiska tokom 24-časovnog monitoringa arterijskog krvnog pritiska i to na sledeći način: grupa ispitanika sa očuvanim dnevno-noćnim ritmom arterijskog krvnog pritiska sastojala se od ukupno 90 ispitanika, a grupu onih sa naru&scaron;enim dnevno-noćnim ritmom arterijskog krvnog pritiska takođe je činilo 90 ispitanika. U svakoj od ovih grupa izvr&scaron;ena je dodatna podela ispitanika prema dužini trajanja arterijske hipertenzije na one kod kojih je arterijska hipertenzija trajala do 5 godina, one kod kojih je trajala od 5 do 10 godina i na one sa trajanjem arterijske hipertenzije vi&scaron;e od 10 godina. Svim ispitanicima rađen je incijalno 24-časovni ambulantni monitoring arterijskog krvnog pritiska, a nakon toga i ehokardiografski pregled radi određivanja parametara morfologije leve pretkomore i komore, kao i dijastolne funkcije leve komore. Rezultati i diskusija: nakon statističke obrade podataka dobijeni su rezultati koji ukazuju da se dijastolna disfunkcija stepena većeg od I statistički značajno če&scaron;će (p=0,011) uočava kod onih ispitanika koji nemaju očuvan dnevno-noćni ritam arterijskog krvnog pritiska. Naru&scaron;en dnevno-noćni ritam arterijskog krvnog pritiska takođe dovodi do povećanja indeksirane mase miokarda leve komore prema povr&scaron;ini tela ispitanika (LVM/BSA) &ndash; p=0,001; do zadebljanja zidova leve komore (IVS/PLW) &ndash; p=0,025, kao i do smanjenja sistolne brzine miokarda na nivou septalnog dela mitralnog anulusa (s&rsquo;) - p&lt;0,0005. Pored ovoga, u grupi onih sa naru&scaron;enim dnevno-noćnim ritmom arterijskog krvnog pritiska primećeno je če&scaron;će prisustvo ekscentrične hipertrofije miokarda leve komore (p=0,027). U odnosu na geometriju i funkciju leve pretkomore, naru&scaron;en dnevno-noćni ritam arterijskog krvnog pritiska dovodi do promena u smislu povećanja antero-posteriornog dijametra leve pretkomore (LA)-p=0,003; maksimalnog volumena leve pretkomore u komorskoj sistoli (LAVs) &ndash;p=0,007; indeksiranog LAVs prema povr&scaron;ini tela ispitanika (LAVs/BSA)-p&lt;,0005; E/e&rsquo; odnosa &ndash;p=0,040; rezervoarnog strain-a leve pretkomore (PLAS)- p=0,004; krutosti leve pretkomore (stiffness)-p=0,047, kao i brzine propagacije talasa kroz mitralni otvor (Vp)-p=0,029. Sa povećanjem dužine trajanja arterijske hipertenzije takođe su pokazane promene u morfologiji i funkciji leve pretkomore i leve komore srca. Dijastolna disfunkcija stepena većeg od I retko je bila uočena u grupi onih koji su arterijsku hipertenziju lečili kraće od 5 godina, a njeno prisustvo u ispitivanim grupama trajanja od 5 do 10 godina i duže od 10 godina bilo je statistički značajno če&scaron;će (p&lt;0,0005). Takođe, sa trajanjem arterijske hipertenzije statistički značajno se menjaju i parametri leve komore za koje smo pokazali da su pogor&scaron;ani kada dnevno-noćni ritam arterijskog krvnog pritiska nije očuvan, s tim &scaron;to smo ovde uočili i značajne promene u smislu postojanja lo&scaron;ijih vrednosti strain-a leve komore (LVGS)-p&lt;0,0005. Na sličan način kao i u odnosu na dnevno-noćni ritam arterijskog krvnog pritiska, menjao se predominantni oblik hipertrofije miokarda leve komore, te je uočeno značajno če&scaron;će (p=0,017) prisustvo ekscentrične hipertrofije kod ispitanika koji su duže lečili arterijsku hipertenziju. Uz ove promene, sa trajanjem arterijske hipertenzije, uočene su i promene sledećih ehokardiografskih parametara leve pretkomore (p&lt;0,0005): LA, LAVs, LAVs/BSA, E/e&rsquo;, PLAS, stiffness, Vp. Na kraju, formiran je i model za dijagnostiku dijastolne disfunkcije stepena većeg od I koji je testiran na 30 novih ispitanika i koji se pokazao kao kvalitetan uz visoku senzitivnost i specifičnost. Zaključak: arterijska hipertenzija dnevno-noćnim oscilacijama (ritmom), ali i svojim trajanjem dovodi do promena u funkciji i geometriji leve pretkomore i komore srca. Noviji ehokardiografski parametri (PLAS, LVGS, stiffness) su dobri pokazatelji ranih promena na nivou leve pretkomore i komore srca kod pacijenata sa arterijskom hipertenzijom.</p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>Vukadin Milankov</o:Author> <o:Version>16.00</o:Version> </o:DocumentProperties> <o:OfficeDocumentSettings> <o:AllowPNG/> </o:OfficeDocumentSettings></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> 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Abstract Left ventricular hypertrophy (LVH), a common complication of elevated blood pressure (BP), is a risk factor for cardiovascular (CV) morbidity and mortality. Adiponectin has been shown to have cardioprotective effects and is inversely associated with LVH. BP can be measured at a clinical visit, as a momentary value. Ambulatory blood pressure (APB) measurement (ABPM) is a method of repeated BP measurements through a defined period, targeted to evaluate the circadian BP profile. High BP and ABPM have been shown to be associated with LVH and left ventricular diastolic dysfunction (LVDD). A high sodium intake has been associated with elevated BP and adverse CV outcome. The aim of this study was to investigate the associations between adiponectin and left ventricular mass index (LVMI), a measure of LVH, ABPM and the development of LVDD during long-term follow-up, ABPM and the change in LVMI during long-term follow-up, and the role of dietary sodium intake in the incidence of AF. Adiponectin has been shown to have vasoprotective, anti-inflammatory and cardioprotective effects. Hypoadiponectinemia has been associated with hypertension, coronary artery disease (CAD) and LVH. In this study, adiponectin levels were inversely associated with LVMI, even after adjustment with conventional risk factors of LVH, in a fairly large sample of middle-aged subjects. Elevated BP and pulse pressure (PP) have been associated with echocardiographic measures of LVDD. In this study, the association between APBM and the development of LVDD during a 20-year follow-up was evaluated. Ambulatory PP (APP) was shown to independently associate with the development of LVDD, even after adjustment with conventional risk factors of LVDD. APBM has been associated with LVH in cross-sectional assessments and has also been shown to have predictive value in future LVMI or LVH. In a few studies the predictive value of APP in future LVMI was observed. In the present study, an increase in APP was shown to predict the change in LVMI during long-term follow-up. In this study, the association between dietary sodium intake and the incidence of AF was evaluated. A high sodium intake predicted the occurrence of AF, which is a novel finding. In conclusion, this study offers novel findings about predictive factors in the entity of cardiac remodelling. / Tiivistelmä Vasemman kammion hypertrofia on yleinen kohonneen verenpaineen seuraus ja sen on todettu olevan sydän- ja verisuonitapahtumien riskitekijä. Adiponektiinin on osoitettu suojaavan vasemman kammion hypertrofialta. Ambulatorinen verenpaineen mittaus on menetelmä, jossa verenpaine mitataan määritellyllä ajanjaksolla toistuvasti, mikä antaa kuvan verenpaineesta vuorokauden eri jaksoissa. Kohonneella ambulatorisella verenpaineella on osoitettu olevan yhteys vasemman kammion hypertrofiaan sekä vasemman kammion diastoliseen vajaatoimintaan. Runsas natriumin saanti on yhteydessä kohonneeseen verenpaineeseen sekä sydän- ja verisuonisairauksiin. Tämän tutkimuksen tarkoituksena on selvittää yhteyksiä adiponektiinin ja vasemman kammion massaindeksin välillä, ambulatorisen verenpaineen ja vasemman kammion diastolisen vajaatoiminnan kehittymisen välillä, ambulatorisen verenpaineen ja vasemman kammion massaindeksin muutoksen välillä sekä natriumin saannin ja eteisvärinän ilmaantuvuuden välillä. Adiponektiinilla on todettu olevan suotuisia vaikutuksia verisuonistoon, tulehdusreaktion hillintään sekä sydänlihakseen. Matalan adiponektiinitason on osoitettu olevan yhteydessä verenpainetautiin, sepelvaltimotautiin sekä vasemman kammion hypertrofiaan. Tässä tutkimuksessa adiponektiinihormonilla osoitettiin olevan käänteinen yhteys vasemman kammion massaindeksiin, vaikka perinteiset riskitekijät otettiin huomioon. Kohonneella verenpaineella sekä pulssipaineella on osoitettu olevan yhteys vasemman kammion diastoliseen vajaatoimintaan. Tässä tutkimuksessa arvioitiin ambulatorisen verenpaineen merkitystä vasemman kammion diastolisen vajaatoiminnan kehittymisessä. Ambulatorinen pulssipaine osoittautui riskitekijäksi, vaikka perinteiset riskitekijät otettiin huomioon. Ambulatorisella verenpaineella ja pulssipaineella on osoitettu olevan yhteys vasemman kammion hypertrofiaan poikkileikkaustutkimuksissa ja seurantatutkimuksissa. Tässä tutkimuksessa ambulatorisen pulssipaineen nousun havaittiin ennustavan vasemman kammion massaindeksin kasvua pitkäaikaisseurannassa. Tässä tutkimuksessa korkean natriumin saannin todettiin olevan yhteydessä lisääntyneeseen eteisvärinän ilmaantuvuuteen. Tätä yhteyttä ei ole aiemmin todettu muissa tutkimuksissa. Tässä tutkimuksessa löydettiin uusia riskitekijöitä sydämen patologisiin ilmentymiin liittyen.

Introdução: A doença falciforme (DF) é a afecção hematológica hereditária de maior prevalência no mundo, sendo que a anemia falciforme (AF) é a forma mais grave com elevada morbidade e mortalidade. Alterações cardíacas são reconhecidamente associadas à AF, como aumento cavitário, hipertensão arterial pulmonar e disfunção diastólica do ventrículo esquerdo. No entanto, ainda não existe consenso quanto à função sistólica ventricular nesses pacientes. O objetivo deste estudo foi o de investigar a função ventricular de pacientes com anemia falciforme utilizando o strain e o twist ventricular obtidos pelo speckle tracking bidimensional, e reconhecer os indivíduos sob maior risco cardiovascular, em que a instituição precoce de tratamento específico poderá beneficiar essa população. Métodos: Foram recrutados 40 pacientes com anemia falciforme (23,5 ± 9,3 anos; 24 homens) e 40 controles saudáveis pareados por sexo e idade, submetidos à entrevista estruturada, ecocardiograma transtorácico, cintilografia pulmonar ventilação perfusão e coleta de amostras de sangue. Todos os indivíduos foram submetidos à avaliação ecocardiográfica convencional padrão e subsequente avaliação offline do strain sistólico biventricular e estudo rotacional do ventrículo esquerdo utilizando speckle-tracking ecocardiográfico. Resultados: Os pacientes com AF apresentaram volume do VE indexado, massa do VE indexado, pressão arterial pulmonar e E/E\' médio superiores aos controles. As medidas de FE do VE, excursão sistólica do plano da tricúspide (TAPSE), Strain Global do VE (longitudinal, circunferencial, radial) e Strain Global do VD (longitudinal) não evidenciaram diferenças entre os grupos. Twist VE se mostrou reduzido em comparação aos controles (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) e Tempo de pico de rotação apical prolongado (366,7 ± 26,1ms vs 344,6 ± 11,7ms , P <0,0001 ). Algumas variáveis se mostraram fortemente relacionadas ao twist VE, como índice de gravidade clínico (Rho= - 0,97, Z value= - 6,05, P < 0,0001), relação E/E\' médio (r = 0,94, F valor= 156.9, p<0,0001), IVDFVE (índice do volume diastólico final do ventrículo esquerdo)(r = 0,81 e p<0,0001) e pressão sistólica arterial pulmonar (r = 0,72 e p<0,0001). Conclusões: Os resultados deste trabalho indicam que o twist ventricular esquerdo derivado do speckle tracking bidimensional encontra-se alterado em pacientes com anemia falciforme e função sistólica ventricular preservada, avaliada pela metodologia convencional, e existe forte correlação entre o twist ventricular esquerdo e o índice clínico de gravidade, relação E/E\', índice do volume diastólico final do ventrículo esquerdo e pressão sistólica arterial pulmonar. / Background: Sickle cell disease (SCD) is the most prevalent hematological condition in the world, with sickle cell anemia (SCA) being its most serious form, displaying a high level of morbidity and mortality. Cardiac changes are known to be associated with SCA, including an increase in cardiac chamber size, pulmonary hypertension and left ventricle diastolic dysfunction. However, there is still no consensus regarding the ventricular systolic function in these patients. The purpose of this study is to investigate the ventricular function of patients with sickle cell anemia utilizing the strain and ventricular twist, obtained by two-dimensional speckle tracking, as well as to identify individuals with higher cardiovascular risk, in which early application of specific treatment could benefit this group of people. Methods: 40 patients were recruited with sickle cell anemia (ages 23.5 ± 9.3 years; 24 males) and 40 healthy control individuals paired by gender and age, submitted to structured interviews, transthoracic echocardiogram, pulmonary scintigraphy and collection of blood samples. All individuals were submitted to a standard echocardiographic evaluation and subsequent off line evaluation of the biventricular systolic strain and rotational study of the left ventricle using echocardiographic speckle-tracking. Results: Patients with SCA presented LV volume indices, LV mass Indices, pulmonary arterial pressure and E/ E\' ratios statistically higher than the control individuals. Measurements of Ejection Fraction (EF) of the left ventricle, tricuspid annular plane systolic excursion (TAPSE), Overall LV Strain (Longitudinal, Circumferential, and Radial) and Overall RV Strain (Longitudinal) did not present differences between the groups. LV twist was significantly lower in relation to the control group (7,4 ± 1,2? vs 10,7 ± 1,8? , P <0,0001 ) and prolonged time to peak apical rotation (366.7 ± 26.1ms vs 344.6 ± 11.7ms , P <0.0001 ). In addition, some variables showed themselves to be strongly related to LV twist such as the clinical severity index ( Rho= - 0.97, Z value= - 6.05, P < 0.0001), E/E\' Ratio (r = 0.94, F value=156.9 e p<0.0001) ), left ventricle end diastolic volume index (LVEDV index) (r = 0,81, p<0,0001) and pulmonary systolic arterial pressure (r = 0.72 e p<0.0001). Conclusions: The results of this study indicate that the left ventricular twist derived from two-dimensional speckle tracking is altered in patients with sickle cell anemia and a preserved ventricular systolic function, evaluated using conventional methodology and that there is a strong correlation between left ventricular twist and the clinical severity index, E/E\' ratio, left ventricle end diastolic volume index and the pulmonary systolic arterial pressure.

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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.

Les maladies cardiovasculaires sont la première cause de mortalité dans le monde. Les coronaropathies ischémiques dont l’infarctus du myocarde (IDM) sont responsables de la moitié de ces décès. Après un IDM, le cœur met en place un processus de cicatrisation afin de pallier la mort des cardiomyocytes et la perte de contractilité. S’il est dérégulé, ce processus peut conduire à un remodelage ventriculaire gauche (RVG) délétère qui altère la fonction ventriculaire (FV) et prédispose à l’insuffisance cardiaque. La découverte de nouveaux biomarqueurs capables de prédire le risque du RVG pourrait permettre d’améliorer la prise en charge des patients à risque et ainsi de réduire l’incidence de l’insuffisance cardiaque. De nombreuses différences ont été mises en évidence entre les hommes et les femmes avec IDM, et ce au niveau de la pathophysiologie, des symptômes, des biomarqueurs et même du processus du RVG. Ces différences impliquent le besoin de découvrir des biomarqueurs spécifiques à chaque sexe ou d’utiliser les biomarqueurs actuels différemment chez les femmes et les hommes. L’objectif de ce travail de thèse a été de mettre en évidence de nouveaux biomarqueurs de la FV après un IDM. Nous nous sommes particulièrement intéressés aux différences homme-femme dans les capacités prédictives de ces biomarqueurs. La première étude a eu pour objectif de valider l’association de cinq gènes avec la FV après un IDM établie lors d’études préliminaires. Une combinaison de trois gènes (LTBP4, TGFBR1 et TNXB) a été identifiée comme étant capable d’améliorer la prédiction de la dysfonction ventriculaire par les marqueurs actuels. Dans un second temps, nous avons montré dans une cohorte nationale d’IDM que le peptide natriurétique NT-proBNP n’était pas capable de prédire la FV chez les femmes alors que la troponine cardiaque était associée avec la dysfonction ventriculaire dans ce groupe. Dans une troisième étude, nous avons mis en évidence l’association entre le gène CDKN1C et la dysfonction ventriculaire spécifiquement chez les femmes. En conclusion, nos études contribuent à la découverte de nouveaux biomarqueurs du RVG post-IDM et attirent l’attention sur les différences hommes-femmes pour l’utilisation de ces biomarqueurs vers une médecine personnalisée / Cardiovascular disease is the first cause of mortality worldwide. Ischemic heart diseases among which myocardial infarction (MI), are responsible for half of these deaths. In order to cope with the loss of cardiomyocytes after MI and to attenuate the alteration of contractility, a repair process is implemented in the heart. If this repair process is dysregulated, it could lead to a maladaptive left ventricular remodeling (LVR) altering LV function and leading to heart failure. The discovery of novel biomarkers able to predict accurately the risk of LVR could lead to a better management of the patients at risk and reduce the incidence of heart failure. Many differences have been highlighted between men and women with MI, regarding the pathophysiology, the symptoms, levels of cardiac biomarkers and the process of LVR. These differences imply the discovery of novel sex-specific biomarkers for LVR prediction or the use of the known biomarkers in a sex-specific manner. The aim of this work was to discover novel biomarkers of left ventricular function (LVF) after an AMI, focusing on sex-differences. First, we aimed to validate the association between five genes previously found to be associated with LVF in small-scale studies. A panel of three genes (LTBP4, TGFBR1 and TNXB) was able to improve the ability of a clinical model to predict LVF. Second, we observed that the cardiac biomarker NT-proBNP was not predictor of LVF in women, whereas cardiac troponin was associated with LVF in this sex-group. A third study showed the association of the gene CDKN1C with LVF post-MI in a female-specific manner. In conclusion, our studies contribute to the discovery of novel biomarkers of LVF and draw the attention to sex differences in the clinical use of biomarkers towards the implementation of personalized medicine