In calcific aortic valve disease, the early sclerotic valve lesion is similar to the atherosclerotic arterial plaque, but at the later stage calcification prevails. Our aim was to assess the association of several new potential risk factors, eg. systemic inflammation, neurohormonal activation and altered calcium metabolism with aortic stenosis (AS) in patients with significant coronary artery disease..

In calcific aortic valve disease, the early sclerotic valve lesion is similar to the atherosclerotic arterial plaque, but at the later stage calcification prevails. Our aim was to assess the association of several new potential risk factors, eg. systemic inflammation, neurohormonal activation and altered calcium metabolism with aortic stenosis (AS) in patients with significant coronary artery disease..

Thesis (doctoral)--Universitetet i Lund.

No description available.

Diss. Linköping : Linköpings universitet, 2008.

No description available.

OBJECTIVE: This study aims to corroborate recent research demonstrating that patients with low body mass indexes tend to have worse postoperative survival outcomes compared to normal BMI patients. It also intends to compare survival outcomes and postoperative complications in transcatheter and surgical aortic valve replacement patients to determine which procedure, TAVR or SAVR respectively, is better for this challenging low BMI patient population. METHODS: This is a retrospective, single-center study comparing patient data collected from 2000-2013 at New York Presbyterian Hospital/Columbia University Medical Center. Patients were dividing into three groups on the basis of BMI and aortic valve procedure: low BMI SAVR (BMI < 22 kg/m2; n = 148; 20.36%), normal BMI SAVR (22-25 kg/m2; n = 458; 63.00%), and low BMI TAVR (< 22 kg/m2; n = 121; 16.64%). There is a total of 606 SAVR patients and 121 TAVR patients. To corroborate recent research that low BMI patients tend to fare worse than normal BMI patients, an unadjusted comparison were used to compare baseline demographics and postoperative outcomes of 148 low BMI patients who underwent SAVR with 458 normal BMI patients who underwent isolated SAVR. These cohorts were then compared via a Kaplan-Meier survival analysis and the log-rank test for 30 days, 6 months, 1 year and 3 years survival outcomes. The 148 low BMI SAVR patients were then compared to 121 low BMI patients who underwent TAVR on baseline demographics and preoperative risk factors. The two cohorts were compared using the Kaplan-Meier analysis and postoperative complications were compared utilizing a multivariable logistic regression after adjustment for age, gender, BMI and STS Scores. RESULTS: The unadjusted analysis of the low BMI and normal BMI SAVR cohorts displayed similar patient demographics and preoperative risk factors. The normal BMI group demonstrated higher EF (55% vs. 51.5%; p = 0.002) and incidence of HLD (47.68% vs. 37.76%; p = 0.038). Conversely, the low BMI cohort had more females (61.49% vs.42.79%; p < 0.001) and individuals with a history of Afib (27.78% vs.16.96%; p = 0.004). As shown in the Kaplan Meier curve, the normal BMI SAVR patients exhibited superior 6 months, 1 year and 3 years survival rates and low BMI was shown to be a significant independent predictor of mortality (HR 2.56; 95% CI: 1.47 – 4.47; p = 0.0009 at 1 year). The two groups had similar postoperative outcomes, however, the low BMI cohort had longer overall hospital stays (8 vs. 6.5 days; p = 0.0003). The low BMI SAVR and TAVR patient cohorts varied significantly on most patient demographics and preoperative risk factors. The low BMI TAVR patients tend to be older (95.04% vs. 55.41% of patients > 75 years old) and had higher STS Scores (10.41 vs. 3.88; p < 0.0001). They also demonstrated significant increases in all the preoperative risk factors excluding DM and prior CVA. The SAVR patients had significantly longer overall hospital stays (8 vs. 6 days; p < 0.0001), more re-exploration for bleeding (5.41% vs. 0.85%; p = 0.0411) and more patients discharged to home (68.24% vs. 50.85%; p = 0.0039) while the TAVR patients demonstrated higher rates of GI bleed (3.39% vs. 0.00%; p = 0.0240) and new PPM (10.17% vs. 0.68%; p = 0.0004). The low BMI SAVR cohort demonstrated better survival rates at 1 year and 3 years and low BMI TAVR was determined to be a significant independent predictor of mortality (HR 0.51; 95% CI: 0.30 – 0.88; p = 0.0146 at 1 year). After controlling for specific covariates in the multivariate logistic regression analysis, the low BMI SAVR had 1.73 times longer ICU stays, 1.90 times longer hospital stays and the odds of being discharged home was 17% less than the TAVR group (p = 0.0005, <0.0001, 0.5665). CONCLUSION: Although the rates of postoperative complications are fairly similar, patients with low BMIs demonstrated worse survival outcomes when compared to the normal BMI SAVR patients. With the current analysis, low BMI TAVR patients had a significantly worse preoperative profile compared to the corresponding SAVR cohort which explains the worse survival and postoperative outcomes. Despite this, the multivariable analysis showed that the low BMI SAVR patients had longer ICU and hospital stays as well as fewer discharges to home. As this is an ongoing study, steps should be made to balance the preoperative profile such that the low BMI SAVR and TAVR groups are comparable prior to survival and postoperative assessment. However, at the current status, TAVR has proven itself to be the preferred treatment for low BMI patients. / 2018-07-13T00:00:00Z

La sténose valvulaire aortique (SVA) est une valvulopathie résultant en l'ouverture incomplète de la valve aortique. La calcification des feuillets associée au vieillissement est la cause la plus importante de la SVA. Sa pathogénèse implique des dépôts de lipoprotéines, de l'inflammation et de la calcification des feuillets. Notre étude vise à identifier les gènes associés à une prédisposition à la SVA afin de mieux comprendre les mécanismes sous-jacents à cette maladie et potentiellement identifier de nouvelles cibles thérapeutiques. Pour ce faire, nous avons recruté 190 patients avec SVA dégénérative et 192 témoins, appariés pour l'âge et le sexe, puis effectué une étude d’association par gènes candidats en utilisant des marqueurs génétiques polymorphiques (SNP). Les gènes candidats choisis incluent (1) ceux dont les polymorphismes ont été présumés associés à la SVA dans des études antérieures (APOB, APOE, ESR1, PTH et VDR) (2) des gènes dont les polymorphismes ont été significativement associés et validés pour quelques maladies inflammatoires (IL-10, TNFAIP3) ou pour le métabolisme lipidique (PCSK9, LDLR) dans des études d’association pangénomiques, et (3) des gènes impliqués dans la pathogénie de la SVA à partir d’études faites sur des modèles animaux en lien avec la calcification (BMP2, CCR5, CTGF, LRP5, MSX2, WNT3), le remodelage tissulaire (CTSS, MMP9) ou le métabolisme lipidique (SMPD1). Pour les gènes des groupes (1) et (2), nous avons utilisé les SNPs rapportés dans la littérature comme étant significativement associés. Pour le groupe (3), nous avons effectué une approche par «tagSNP» qui consiste à sélectionner un groupe de SNP capturant la variabilité génétique dans la région ciblée. Au total, 81 SNPs dans 18 gènes ont été testés. Nous avons trouvé une association nominale avec les gènes BMP2 (OR = 1.55, IC95%: 1.14-2.10, p = 0.004) et LRP5 (OR = 1.47, IC95%: 1.06-2.03, p = 0.023) après ajustement pour la maladie coronarienne. Les gènes BMP2 et LRP5, impliqués dans la calcification selon certains modèles expérimentaux, sont donc associés à la SVA. Ce travail devrait être validé dans une cohorte indépendante plus large dans un avenir rapproché et il pourrait être étendu à d’autres gènes. / Aortic valve stenosis (AVS) is a valvular heart disease caused by calcification leading to incomplete opening of the aortic valve. Calcification of valve leaflets associated with aging is the most common cause of AVS. AVS pathogenesis involves lipoprotein deposits, chronic inflammation and calcification of the aortic valve leaflets. Our study aims to identify genes associated with AVS in order to better understand its mechanisms and potentially identify new therapeutic targets. We recruited 190 cases with AVS of different severity and 192 controls matched for age and sex. Then we conducted a candidate gene association study using single nucleotide polymorphisms (SNPs). The candidate genes selected include: (1) those with polymorphisms putatively implicated in previous genetic association studies of AVS (APOB, APOE, ESR1, PTH and VDR); (2) those with validated associations to inflammatory diseases (IL-10, TNFAIP3) or lipid metabolism (LDLR ,PCSK9) in genome-wide association studies and, (3) genes impliated in AVS pathogenesis from studies with animal models and thought to be involved in calcification (BMP2, CCR5, CTGF, LRP5, MXS2, WNT3); tissue remodeling (CTSS, MMP9) or lipid metabolism (SMPD1). For the first two categories of genes, we tested the SNPs reported to be associated in the literature and, in the third category we used a tag-SNP approach which consists of selecting a subset of SNPs to capture variability in the target region. Finally, 81 SNPs in 18 genes were tested. We found a nominal association of BMP2 (OR=1.55, CI: 1.14 – 2.10, p=0.004) and LRP5 (OR=1.47, CI: 1.06 – 2.03, p=0.023) with presence of AVS after adjustment for coronary heart disease. The genes BMP2 and LRP5, which are known to be involved in calcification based on animal models, are associated with AVS. The result of the current study should be validated in a larger independent cohort in the near future and then, it could also be extended to the study of other genes.

La sténose valvulaire aortique (SVA) est une valvulopathie résultant en l'ouverture incomplète de la valve aortique. La calcification des feuillets associée au vieillissement est la cause la plus importante de la SVA. Sa pathogénèse implique des dépôts de lipoprotéines, de l'inflammation et de la calcification des feuillets. Notre étude vise à identifier les gènes associés à une prédisposition à la SVA afin de mieux comprendre les mécanismes sous-jacents à cette maladie et potentiellement identifier de nouvelles cibles thérapeutiques. Pour ce faire, nous avons recruté 190 patients avec SVA dégénérative et 192 témoins, appariés pour l'âge et le sexe, puis effectué une étude d’association par gènes candidats en utilisant des marqueurs génétiques polymorphiques (SNP). Les gènes candidats choisis incluent (1) ceux dont les polymorphismes ont été présumés associés à la SVA dans des études antérieures (APOB, APOE, ESR1, PTH et VDR) (2) des gènes dont les polymorphismes ont été significativement associés et validés pour quelques maladies inflammatoires (IL-10, TNFAIP3) ou pour le métabolisme lipidique (PCSK9, LDLR) dans des études d’association pangénomiques, et (3) des gènes impliqués dans la pathogénie de la SVA à partir d’études faites sur des modèles animaux en lien avec la calcification (BMP2, CCR5, CTGF, LRP5, MSX2, WNT3), le remodelage tissulaire (CTSS, MMP9) ou le métabolisme lipidique (SMPD1). Pour les gènes des groupes (1) et (2), nous avons utilisé les SNPs rapportés dans la littérature comme étant significativement associés. Pour le groupe (3), nous avons effectué une approche par «tagSNP» qui consiste à sélectionner un groupe de SNP capturant la variabilité génétique dans la région ciblée. Au total, 81 SNPs dans 18 gènes ont été testés. Nous avons trouvé une association nominale avec les gènes BMP2 (OR = 1.55, IC95%: 1.14-2.10, p = 0.004) et LRP5 (OR = 1.47, IC95%: 1.06-2.03, p = 0.023) après ajustement pour la maladie coronarienne. Les gènes BMP2 et LRP5, impliqués dans la calcification selon certains modèles expérimentaux, sont donc associés à la SVA. Ce travail devrait être validé dans une cohorte indépendante plus large dans un avenir rapproché et il pourrait être étendu à d’autres gènes. / Aortic valve stenosis (AVS) is a valvular heart disease caused by calcification leading to incomplete opening of the aortic valve. Calcification of valve leaflets associated with aging is the most common cause of AVS. AVS pathogenesis involves lipoprotein deposits, chronic inflammation and calcification of the aortic valve leaflets. Our study aims to identify genes associated with AVS in order to better understand its mechanisms and potentially identify new therapeutic targets. We recruited 190 cases with AVS of different severity and 192 controls matched for age and sex. Then we conducted a candidate gene association study using single nucleotide polymorphisms (SNPs). The candidate genes selected include: (1) those with polymorphisms putatively implicated in previous genetic association studies of AVS (APOB, APOE, ESR1, PTH and VDR); (2) those with validated associations to inflammatory diseases (IL-10, TNFAIP3) or lipid metabolism (LDLR ,PCSK9) in genome-wide association studies and, (3) genes impliated in AVS pathogenesis from studies with animal models and thought to be involved in calcification (BMP2, CCR5, CTGF, LRP5, MXS2, WNT3); tissue remodeling (CTSS, MMP9) or lipid metabolism (SMPD1). For the first two categories of genes, we tested the SNPs reported to be associated in the literature and, in the third category we used a tag-SNP approach which consists of selecting a subset of SNPs to capture variability in the target region. Finally, 81 SNPs in 18 genes were tested. We found a nominal association of BMP2 (OR=1.55, CI: 1.14 – 2.10, p=0.004) and LRP5 (OR=1.47, CI: 1.06 – 2.03, p=0.023) with presence of AVS after adjustment for coronary heart disease. The genes BMP2 and LRP5, which are known to be involved in calcification based on animal models, are associated with AVS. The result of the current study should be validated in a larger independent cohort in the near future and then, it could also be extended to the study of other genes.

INTRODUÇÃO: A estenose aórtica, doença valvar de grande prevalência, tem na avaliação clínica e ecocardiográfica as principais ferramentas para avaliação dos pacientes. Ferramentas auxiliares de avaliação são desejáveis e neste contexto surgem os peptídeos natriuréticos. Os peptídeos natriuréticos BNP e NT-proBNP podem ser usados como marcadores diagnósticos e prognósticos em diversas situações clínicas. Postulamos que os peptídeos pudessem ter papel diagnóstico, mas principalmente valor prognóstico em pacientes com estenose aórtica grave. OBJETIVO: primariamente, definir o papel prognóstico de sobrevida dos peptídeos natriuréticos BNP e NT-proBNP no acompanhamento prospectivo de uma população de pacientes com estenose aórtica grave. Secundariamente, comparar os níveis séricos de BNP e NT-proBNP entre pacientes com EAo grave assintomáticos e sintomáticos. MÉTODOS: Foram incluídos de forma consecutiva 66 pacientes com estenose aórtica grave, definida pela presença de gradiente médio de pressão transvalvar aórtica maior que 40 mmHg. Os critérios de exclusão foram fibrilação atrial, outra valvopatia, cardiopatia associada, infecções ativas, neoplasias, doenças auto-imunes ou inflamatórias, insuficiência renal e obesidade. Dos 66 pacientes incluídos, 76% eram sintomáticos (50/66). Os sintomas foram definidos como dispnéia aos esforços, síncope ou angina. Na inclusão, todos os pacientes foram submetidos à avaliação clínica inicial, realização de ecocardiograma e dosagem de BNP e NT-proBNP. Os pacientes sintomáticos recebiam a indicação de tratamento cirúrgico e os pacientes assintomáticos eram conduzidos clinicamente. Os pacientes foram acompanhados prospectivamente. O desfecho clínico avaliado foi óbito cardiovascular, definido por morte súbita, morte por insuficiência cardíaca e óbito peri-operatório. RESULTADOS: Os pacientes foram acompanhados por 869 + 397 dias. Houve 11 óbitos durante o acompanhamento. Na inclusão, os níveis de BNP e NT-proBNP foram similares em assintomáticos e sintomáticos: BNP 72 (41-175) pg/mL versus 104 (46-270) pg/mL; p = 0,275 e NT-proBNP 676 (235-1356) pg/mL vs. 871 (310-2230) pg/mL; p = 0,226. Houve diferença entre os níveis de BNP e NT-proBNP e classe funcional (p < 0,001 e p < 0,001, respectivamente). Através da curva ROC foi determinado um valor de corte de BNP (105 pg/mL) e NT-proBNP (1500 pg/mL) capazes de predizer classe funcional III e IV (New York Heart Association), com área sob a curva de 0,806 e 0,786 respectivamente. BNP e NT-proBNP foram preditores de mortalidade (p=0,007 e p=0,001 respectivamente). BNP > 105 pg/mL aumentou o risco de óbito cardiovascular de forma independente [OR= 6,3 (IC95%: 1,36 - 29,25)]. NT-proBNP > 1500 pg/mL aumentou o risco de óbito cardiovascular de forma independente [OR = 6,5 (IC95%: 1,73 - 24,63)]. CONCLUSÃO: O BNP e o NTproBNP foram preditores independentes de mortalidade em pacientes com estenose aórtica grave em um acompanhamento de quatro anos. O BNP e o NT-proBNP foram preditores de classe funcional III e IV (New York Heart Association) em pacientes com estenose aórtica grave. O BNP e o NT-proBNP não permitiram diferenciar pacientes sintomáticos de assintomáticos / BACKGROUND: Aortic valve stenosis is a high prevalent cardiac valve disease, in which clinical and echocardiographic parameters are the most common approach of diagnosis and risk evaluation. Complementary methods are desirable and the natriuretic peptides BNP and NT-proBNP, both diagnostic and prognostic markers in multiple clinical situations, could improve patient assessment. We postulate that these peptides may have diagnostic purpose, but mainly a prognostic value in patients with severe aortic stenosis. OBJECTIVE: primarily, define the survival prognostic role of natriuretic peptides BNP and NT-proBNP in monitoring a population of patients with severe aortic stenosis prospectively. Secondarily, compare the serum levels of BNP and NT-proBNP among patients with symptomatic and asymptomatic severe aortic stenosis. METHODS: 66 consecutive patients with severe aortic stenosis, defined by the presence of gradient mean transvalvular aortic pressure greater than 40 mmHg were included. Exclusion criteria were concomitant atrial fibrillation, other valve disease, other myocardiopathies, active infections, autoimmunity diseases, inflammatory diseases, neoplasia, renal failure or obesity. 76% of patients were symptomatic (50/66), defined as dyspnea on exertion, syncope or angina. All patients underwent initial clinical evaluation, echocardiography and BNP and NT-proBNP measurement. Symptomatic patients were referred for surgical treatment and asymptomatic patients were clinically managed. (Patients were followed up prospectively). The clinical outcome was cardiovascular death, defined by sudden death, death from heart failure and peri-operative death. RESULTS: Patients were followed up for 869 + 397 days. There were 11 deaths during followup. On admission, levels of BNP and NT-proBNP were similar in asymptomatic and symptomatic individuals: BNP 72 (41-175) pg / mL vs. 104 (46-270) pg / mL, p = 0.275 and NT-proBNP 676 (235-1356) pg / mL vs. 871 (310-2230) pg / ml, p = 0.226. There were differences between the levels of BNP and NT-proBNP and functional class (p <0.001 p <0.001, respectively). ROC-curve analysis demonstrated a cut-off value of BNP (105 pg / mL) and NT-proBNP (1500 pg / mL) capable of predicting NYHA functional class III and IV, with an area under the curve of 0.806 and 0.786 respectively. BNP and NT-proBNP could predict mortality (p = 0.007 and p = 0.001 respectively). BNP > 105 pg/mL independently increased the risk of cardiovascular death [OR = 6.3 (95% CI: 1.36 to 29.25)]. NT-proBNP > 1500 pg/mL independently increased the risk of cardiovascular death [OR = 6.5 (95% CI: 1.73 to 24.63)]. CONCLUSION: BNP and NT-proBNP were independent predictors of mortality in patients with severe aortic stenosis after a follow up of 4 years. BNP and NT-proBNP were predictors of NYHA functional class III and IV in patients with severe aortic stenosis. BNP and NT-proBNP alone did not distinguish symptomatic from asymptomatic patients