Fator de diferenciação de crescimento 15: um novo biomarcador em pacientes com disfunção diastólica? / Growth-differentiation factor-15: a novel biomarker in patients with diastolic dysfunction? / Factor de diferenciación de crecimiento 15: ¿un nuevo biomarcador en pacientes con disfunción diastólica?

FUNDAMENTO: O fator de diferenciação de crescimento-15 ou GDF-15, uma citocina de resposta ao estresse relacionada ao fator transformador de crescimento beta (TGF-ß), está elevado e independentemente relacionado à prognóstico adverso na insuficiência cardíaca sistólica. OBJETIVO: O objetivo do presente estudo é investigar os níveis plasmáticos de GDF-15 em pacientes com disfunção diastólica pré-clínica ou insuficiência cardíaca com fração de ejeção normal (ICFEN). MÉTODOS: Avaliamos 119 pacientes com fração de ejeção (FE) normal, encaminhados à angiografia coronariana eletiva, dos quais 75 (63 por cento) tinham doença arterial coronariana (DAC). Os indivíduos foram classificados como tendo disfunção diastólica ventricular esquerda leve (DDVE grau I, n = 61), ICFEN (DDVE grau II ou III, n = 38) ou função diastólica normal (controles, n = 20). Em um subgrupo de 20 indivíduos, alterações no débito cardíaco (DC) foram medidas através de reinalação de gás inerte (Innocor®) em resposta a um teste hemodinâmico ortostático. RESULTADOS: Os níveis de GDF-15 na ICFEN [mediana 1,08, variação interquartil (0,88-1,30) ng/ml] eram significantemente mais altos do que nos controles [0,60 (0,50-0,71) ng/ml, p = 0,003] e em pacientes com DDVE grau I [0,78 (0,62-1,04) ng/ml, p < 0.001]. Além disso, os níveis de GDF-15 estavam significantemente elevados em pacientes com DDVE grau I, em comparação aos controles (p = 0,003). Adicionalmente, GDF-15 estava correlacionado com os marcadores ecocardiográficos de disfunção diastólica e estava correlacionado com a magnitude da resposta do CO à alteração na posição do corpo de ereta para supina (r = -0,67, p = 0,005). CONCLUSÃO: Os níveis de GDF-15 estão elevados em indivíduos com ICFEN e podem diferenciar função diastólica normal de DDVE. Além disso, os níveis de GDF-15 estão associados com uma redução na resposta do DC no teste hemodinâmico ortostático.

BACKGROUND: Growth differentiation factor-15 (GDF-15), a stress-responsive transforming growth factor-ß-related cytokine, is elevated and independently related to an adverse prognosis in systolic heart failure. OBJECTIVE: This study aimed to investigate plasma levels of GDF-15 in patients with preclinical diastolic dysfunction or heart failure with normal ejection fraction (HFnEF). METHODS: We evaluated 119 patients with normal ejection fraction referred for an elective coronary angiography, 75 (63 percent) of whom had coronary artery disease. Subjects were classified as having either mild left ventricular diastolic dysfunction (LVDD grade I, n = 61), HFnEF (LVDD grade II or III, n = 38) or normal diastolic function (controls, n = 20). In a subgroup of 20 subjects, changes in cardiac output (CO) were measured by inert gas rebreathing (InnocorTM) in response to an orthostatic hemodynamic test. RESULTS: Growth differentiation factor-15 levels in HFnEF [median 1.08, interquartile range (0.88-1.30) ng/ml] were significantly higher than in controls [0.60 (0.50-0.71) ng/ml, p = 0.003] and in patients with LVDD grade I [0.78 (0.62-1.04) ng/ml, p < 0.001]. In addition, GDF-15 was significantly elevated in patients with LVDD grade I compared to controls (p = 0.003). Furthermore, GDF-15 was correlated with echocardiographic markers of diastolic dysfunction and was correlated with the magnitude of CO response to the change in body position from standing to supine (r = -0.67, p = 0.005). CONCLUSION: Growth differentiation factor-15 levels are elevated in subjects with HFnEF and can differentiate normal diastolic function from asymptomatic LVDD. In addition, GDF-15 is associated with a reduced cardiac output response in the orthostatic hemodynamic test.

FUNDAMENTO: El factor de diferenciación de crecimiento-15 o GDF-15, una citocina de respuesta al estrés relacionada con el factor transformador de crecimiento beta (TGF-ß), es elevado y está independientemente relacionado con el pronóstico adverso en la insuficiencia cardíaca sistólica. OBJETIVO: El objetivo del presente estudio es investigar los niveles plasmáticos de GDF-15 en pacientes con disfunción diastólica preclínica o insuficiencia cardíaca con fracción de eyección normal (ICFEN). MÉTODOS: Evaluamos a 119 pacientes con fracción de eyección (FE) normal, derivados a angiografía coronaria electiva, de los cuales 75 (63 por ciento), tenían enfermedad arterial coronaria (EAC). Los individuos fueron clasificados como teniendo una disfunción diastólica ventricular izquierda leve (DDVI grado I, n = 61), ICFEN (DDVI grado II o III, n = 38), o función diastólica normal (controles, n = 20). En un subgrupo de 20 individuos, las alteraciones en el débito cardíaco (DC), se midieron a través de una nueva inhalación de gas inerte (Innocor®) en respuesta a un test hemodinámico ortostático. RESULTADOS: Los niveles de GDF-15 en la ICFEN [mediana 1,08, variación intercuartil (0,88-1,30) ng/ml], eran significantemente más altos que en los controles [0,60 (0,50-0,71) ng/ml, p = 0,003] y en los pacientes con DDVI grado I [0,78 (0,62-1,04) ng/ml, p < 0,001]. Además, los niveles de GDF-15 estaban significantemente elevados en los pacientes con DDVI grado I, en comparación con los controles (p = 0,003). Por añadidura, el GDF-15 estaba correlacionado con los marcadores ecocardiográficos de disfunción diastólica y con la magnitud de la respuesta del DC a la alteración en la posición del cuerpo variando de la posición erecta a la posición supina (r = -0,67, p = 0,005). CONCLUSIÓN: Los niveles de GDF-15 están elevados en individuos con ICFEN y pueden diferenciar una función diastólica normal de DDVI. Además, los niveles de GDF-15 están asociados con una reducción en la respuesta del DC en el test hemodinámico ortostático.

Screening for overt diabetes by oral glucose tolerance test: stratification by fasting blood glucose and patients' age improve practicability of guidelines in cardiological routine.

BACKGROUND/OBJECTIVES: Guidelines recommend screening all patients with cardiovascular disease by oral glucose tolerance test (OGTT). Due to its time-consuming protocol, costs and overall inconvenience performance of OGTT is limited in cardiological routine. Thus, we aimed to identify easily available parameters that could help to reduce the numbers of OGTT needed. METHODS: OGTTs (n=1215) were performed in all patients without known type 2 diabetes mellitus (T2DM) that were submitted to the heart center Wuppertal with known or suspected coronary artery disease for an elective coronary angiography from January to October 2007. RESULTS: 31.4% had normal glucose tolerance; prediabetes was present in 50.7%, whereas 17.9% were newly diagnosed with T2DM. Thus, 998 OGTTs did not result in the new diagnosis of so far undiagnosed T2DM. Multiple logistic regression and receiver operated characteristic analyses demonstrated that fasting blood glucose (FBG)≥ 90 mg/dl and age ≥ 55 years were predictive for so far undiagnosed T2DM. Considering these two parameters 81.1% (=sensitivity) of so far undiagnosed T2DM patients would have been identified (specificity=63.4%) and the number of OGTTs could have been reduced from 1215 to 541. CONCLUSIONS: About 70% of patients were newly diagnosed with impaired glucose metabolism. FBG ≥ 90 mg/dl and age ≥ 55 years were predictive for so far undiagnosed T2DM and OGTTs could be reduced by 55.5%. This should alleviate the implementation of the current guidelines in daily cardiological practice.

Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders.

BACKGROUND: Diabetes mellitus (DM) has reached epidemic proportions and is an important risk factor for heart failure (HF). Left ventricular diastolic dysfunction (LVDD) is recognized as the earliest manifestation of DM-induced LV dysfunction, but its pathophysiology remains incompletely understood. We sought to evaluate the relationship between proinflammatory cytokine levels (TNF-alpha, IL-6) and tissue Doppler derived indices of LVDD in patients with stable coronary artery disease. METHODS: We enrolled 41 consecutive patients (mean age 65+/-10 years) submitted for coronary angiography. Echocardiographic assessment was performed in all patients. Pulsed tissue Doppler imaging was performed at the mitral annulus and was characterized by the diastolic early relaxation velocity Em. Conventional transmitral flow was measured with pw-doppler. Early (E) transmitral flow velocity was measured. LVDD was defined as E/Em ratio >or= 15, E/Em 8-14 was classified as borderline. Plasma levels of TNF-alpha and IL-6 were determined in all patients. A standardized oral glucose tolerance test was performed in subjects without diabetes. RESULTS: Patients with E/Em ratio >or= 15, classified as LVDD and those with E/Em ratio 8-14 (classified as borderline) had significantly higher IL-6 (P = 0,001), TNF-alpha (P < 0,001) and NT-pro- BNP (P = 0,001) plasma levels compared to those with normal diastolic function. TNF-alpha and IL-6 levels remains significantly elevated after adjustment for sex, age, left ventricular ejection function, body mass index, coronary heart disease, smoking, hypertension and diabetes mellitus with linear regression analysis. Furthermore, in subjects LVDD or borderline LV diastolic function, 75% had diabetes or IGT, respectively. When subjects without diabetes were excluded, both IL-6 (P = 0,006) and TNF-alpha (P = 0,002) remained significantly elevated in subjects with E/Em ratio >or= 15. CONCLUSION: This study reveals that increased plasma levels of IL-6 and TNF-alpha were associated with LVDD. These findings suggest a link between low-grade inflammation and the presence of LVDD. An active proinflammatory process may be of importance in the pathogenesis of diastolic dysfunction.

Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.

Congenital coronary artery fistulas in adults: concomitant pathologies and treatment.

BACKGROUND: Coronary artery fistula is a rare congenital malformation. Complications such as intracardiac shunts, endocarditis, myocardial infarction, aneurysm and sudden death can be observed. The purpose of this article is to present our experience with concomitant cardiac pathologies and discuss various therapeutic approaches including surgical and percutaneous intervention. MATERIALS AND METHODS: During 18,272 diagnostic cardiac catheterizations, coronary artery fistulas were identified incidentally in 10 patients (0.05%). There were 3 female and 7 male patients. The patients' ages ranged from 42 to 76 years. All patients with coronary artery fistula were preoperatively in New York Heart Association functional class and Canadian Cardiovascular Society class II or III. RESULTS: In addition to coronary artery fistula, coronary artery disease was detected in 4 patients (40%), a ventricular septal defect and an aneurysm of the sinuses of Valsalvae with aortic regurgitation in one patient (10%) and an anomalous origin of the LAD from the pulmonary trunk in one patient (10%) during cardiac catheterization. Four (40%) of the total of 10 patients had only coronary artery fistula. Surgical closure of the coronary artery fistula was performed in 7 patients (70%). An interventional fistula closure with a coil device was confirmed by cardiac catheterization in another 3 patients (30%). One patient of the latter group showed a small residual shunt from the LAD to the pulmonary trunk. No death or long-term morbidities could be observed. CONCLUSIONS: Coronary artery fistulas are incidentally diagnosed during coronary artery angiographies in adults and should be closed to prevent complications.

Genetic testing in patients with aortic aneurysms/dissections: a novel genotype/phenotype correlation?

OBJECTIVE: Mutations in the genes encoding fibrillin-1 (FBN1) and transforming growth factor beta receptor type II (TGFBR2) are known causes of Marfan syndrome (MFS) and related disorders. However, a sound correlation between the genotype and the cardiovascular phenotype has not yet been established. The objective of the present study was to identify novel mutations in FBN1 and TGFBR2 and to assess whether the type of mutation is linked to a particular clinical subtype of the cardiovascular condition. METHODS: The clinical records of 36 patients referred to us for molecular genetic diagnosis were reviewed to assess the course and severity of the vascular deterioration. A semiautomatic protocol was established enabling a rapid and cost-effective screening of the genes FBN1 and TGFBR2 by direct sequencing of all coding exons and flanking intronic regions. RESULTS: Novel mutations in FBN1 and TGFBR2 were detected in 12 and 2 patients, respectively. Four individuals carried a recurrent mutation in FBN1. Throughout the study cohort, the incidence of aortic dissections per se did not depend on the type of mutation. However, we found that mutations affecting the calcium-binding epidermal growth factor-like domain were more frequently associated with a dissection of distal parts of the aorta than mutations that lead to a premature termination codon (chi(1)(2): p=0.013), suggesting that the spatio-temporal pattern of vascular deterioration may vary with the type of mutation. CONCLUSIONS: Detecting a mutation in the genes FBN1 and TGFBR2 proves the genetic origin of vascular findings and allows the identification of family members at risk who should undergo preventive checkups. Routine genetic testing of patients with suspected MFS or thoracic aortic aneurysms/dissections could provide further insight into genotype/phenotype correlations related to aortic dissection.

Systemic stress hormone response in patients undergoing open heart surgery with or without cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass often causes a stress hormonal response with subsequent changes in hemodynamics and organ perfusion. Leptin, an adipocyte-derived factor, has been proposed to play a role in systemic inflammation. We examined perioperative release of leptin and cortisol in patients undergoing open heart surgery with or without cardiopulmonary bypass. METHODS: Forty-nine patients were enrolled in this prospective study. Conventional coronary artery bypass grafting was performed in 19 patients (ONCABG; group I), and heart valve surgery in 15 patients (group II). Fifteen patients (group III) received off-pump coronary artery bypass grafting (OPCABG). Blood samples were collected preoperatively and for as long as 72 hours postoperatively. Plasma levels of leptin and cortisol were measured by enzyme-linked immunosorbent assay. RESULTS: Leptin serum levels decreased during the operation, reaching 73.2% of the baseline in group I, 85.3% in group II, and 38.9% in group III (p < 0.05), 2 hours postoperatively. Thereafter, leptin levels increased gradually to 218.6% of the baseline in group I and 313.7% in group II 24 hours after the operation (p < 0.01). However, patients in the OPCABG group showed only a moderate increase in serum leptin levels. Plasma cortisol levels rose to a maximum of 532.9% of baseline in group I, 526.4% in group II, and 280% in group III 12 hours postoperatively (p < 0.01). CONCLUSIONS: Open heart surgery is associated with acute perioperative changes in plasma levels of neurohormonal stress factors leptin and cortisol. A different pattern of leptin and cortisol release was observed in patients operated on without cardiopulmonary bypass.

Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy.

BACKGROUND: Muscle LIM protein (MLP) is an essential nuclear regulator of myogenic differentiation. Additionally, it may act as an integrator of protein assembly of the actin-based cytoskeleton. MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM). MLP is therefore a candidate gene for heritable forms of hypertrophic cardiomyopathy (HCM) and DCM in humans. METHODS AND RESULTS: We analyzed 1100 unrelated individuals (400 patients with DCM, 200 patients with HCM, and 500 controls) for mutations in the human CRP3 gene that encodes MLP. We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls. All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain, which is responsible for interaction with alpha-actinin and with certain muscle-specific transcription factors. Protein-binding studies indicate that mutations in the CRP3 gene lead to a decreased binding activity of MLP to alpha-actinin. All 3 index patients were characterized by typical asymmetrical septal hypertrophy. Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP. CONCLUSION: Here, we present evidence that mutations in the CRP3/MLP gene can cause HCM.