Test-Retest Reliability of Non-Invasive Cardiac Output Measurement during Exercise in Healthy Volunteers in Daily Clinical Routine / Confiabilidade Teste-Reteste de Medição Não-Invasiva de Débito Cardíaco durante Exercício em Voluntários Saudáveis sob Condições Clínicas de Rotina

Abstract Background: Thoracic bioreactance (TB), a noninvasive method for the measurement of cardiac output (CO), shows good test-retest reliability in healthy adults examined under research and resting conditions. Objective: In this study, we evaluate the test-retest reliability of CO and cardiac power (CPO) output assessment during exercise assessed by TB in healthy adults under routine clinical conditions. Methods: 25 test persons performed a symptom-limited graded cycling test in an outpatient office on two different days separated by one week. Cardiorespiratory (power output, VO2peak) and hemodynamic parameters (heart rate, stroke volume, CO, mean arterial pressure, CPO) were measured at rest and continuously under exercise using a spiroergometric system and bioreactance cardiograph (NICOM, Cheetah Medical). Results: After 8 participants were excluded due to measurement errors (outliers), there was no systematic bias in all parameters under all conditions (effect size: 0.2-0.6). We found that all noninvasively measured CO showed acceptable test-retest-reliability (intraclass correlation coefficient: 0.59-0.98; typical error: 0.3-1.8). Moreover, peak CPO showed better reliability (intraclass correlation coefficient: 0.80-0.85; effect size: 0.9-1.1) then the TB CO, thanks only to the superior reliability of MAP (intraclass correlation coefficient: 0.59-0.98; effect size: 0.3-1.8). Conclusion: Our findings preclude the clinical use of TB in healthy subject population when outliers are not identified.

Resumo Fundamento: A biorreatância torácica (BT), um método não invasivo destinado à medição do débito cardíaco (DC), mostra boa confiabilidade teste-reteste em adultos saudáveis examinados em condições de pesquisa e repouso. Objetivo: No presente estudo, avaliamos a confiabilidade teste-reteste da avaliação do DC e trabalho cardíaco (TC) durante exercício, avaliado por BT em adultos saudáveis sob condições clínicas de rotina. Métodos: 25 indivíduos realizaram teste ergométrico gradual sintoma-limitante em ambiente ambulatorial em dois dias diferentes, com intervalo de uma semana. Parâmetros cardiorrespiratórios (trabalho cardíaco, VO2máx) e hemodinâmicos (frequência cardíaca, volume sistólico, DC, pressão arterial média, TC) foram medidos em repouso e continuamente sob exercício utilizando sistema espiroergométrico e cardiógrafo de biorreatância (NICOM, Cheetah Medical). Resultados: Após 8 participantes terem sido excluídos devido a erros de medição (outliers), não houve viés sistemático em nenhum dos parâmetros em todas as condições (tamanho do efeito: 0,2-0,6). Observamos que todos os débitos cardíacos medidos de forma não invasiva apresentaram níveis aceitáveis de confiabilidade teste-reteste (coeficiente de correlação intraclasse: 0,59-0,98; erro típico: 0,3-1,8). Além disso, TC máximo apresentou melhor confiabilidade (coeficiente de correlação intraclasse: 0,80-0,85; tamanho do efeito: 0,9-1,1), seguido do DC pela BT, graças apenas à confiabilidade superior da PAM (coeficiente de correlação intraclasse: 0,59-0,98; tamanho do efeito: 0,3-1,8). Conclusão: Nossos achados impedem o uso clínico da BT em indivíduos saudáveis quando outliers não forem identificados.

New pulmonary hypertension model in conscious dogs to investigate pulmonary-selectivity of acute pharmacological interventions.

PURPOSE: Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. METHODS: Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO2) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP). RESULTS: The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 ± 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 ± 3.2 mmHg, p < 0.0001). Both, sildenafil (- 6.8 ± 4.4 mmHg) and ANP (- 6.4 ± 3.8 mmHg) significantly (p < 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified. CONCLUSIONS: By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.

Endostatin a Potential Biomarker for Heart Failure with Preserved Ejection Fraction / Endostatina é um Potencial Biomarcador para a Insuficiência Cardíaca com Fração de Ejeção Preservada

Abstract Background: Endostatin is a circulating endogenous angiogenesis inhibitor preventing neovascularization. Previous studies demonstrated the prognostic value of Endostatin among patients with heart failure with reduced ejection fraction (HFrEF). However, the role of Endostatin among patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. Objective: This study aimed to investigate the association between serum Endostatin levels, natriuretic peptide levels and the severity of left ventricular diastolic dysfunction and the diagnosis of HFpEF. Methods: Endostatin serum concentrations were measured in 301 patients comprising 77 HFpEF patients, 169 patients with asymptomatic left ventricular diastolic dysfunction (ALVDD), and 55 controls with normal cardiac function. Results: Endostatin serum levels were significantly elevated in patients with HFpEF (median/interquartile range 179.0 [159-220]) and ALVDD (163.8 [145.4-191.3]) compared to controls (149.1 [130.6-176.9]), p < 0.001 and p = 0.004, respectively) and significant correlated with N-terminal pro B-type natriuretic peptide (NT-proBNP). Conclusions: This hypothesis-generating pilot study gives first evidence that Endostatin correlates with the severity of diastolic dysfunction and may become a novel biomarker for HFpEF. We hypothesize a rise in Endostatin levels may reflect inhibition of adaptive angiogenesis and adverse cardiac remodeling.

Resumo Fundamentos: A Endostatina é um inibidor circulante endógeno da angiogênese que previne a neovascularização. Estudos anteriores demonstraram o valor prognóstico da Endostatina em pacientes com insuficiência cardíaca com fracção de ejeção reduzida (ICFEr). No entanto, o papel da Endostatina entre os pacientes com insuficiência cardíaca com fração de ejeção preservada (ICFEp) permanece incerto. Objetivo: Investigar a associação entre os níveis séricos de Endostatina, níveis de peptídeos natriuréticos e a gravidade de disfunção ventricular esquerda e diastólica e o diagnóstico de ICFEp. Métodos: Mediu-se a concentração sérica de Endostatina em 301 pacientes, compreendendo 77 pacientes com ICFEp, 169 pacientes com disfunção ventricular esquerda assintomática diastólica (DVEAD) e 55 controles com a função cardíaca normal. Resultados: Os níveis de Endostatina no soro foram significativamente elevados em pacientes com ICFEp (mediana / intervalo interquartil 179,0 [159-220]) e DVEAD (163,8 [145,4-191,3]) em comparação com os controles (149,1 [130,6-176,9]), p < 0,001 e p = 0,004, respectivamente) e correlação significativa com o terminal do pro-peptídeo natriurético tipo B (NT-proBNP). Conclusões: Este estudo piloto gerador de hipótese fornece a primeira evidência de que a Endostatina se correlaciona com a gravidade da disfunção diastólica e pode tornar-se um novo biomarcador para ICFEp. Nossa hipótese é de que um aumento nos níveis de Endostatina pode refletir inibição da angiogênese adaptativa e remodelação cardíaca adversa.

Endostatin a Potential Biomarker for Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Endostatin is a circulating endogenous angiogenesis inhibitor preventing neovascularization. Previous studies demonstrated the prognostic value of Endostatin among patients with heart failure with reduced ejection fraction (HFrEF). However, the role of Endostatin among patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. OBJECTIVE: This study aimed to investigate the association between serum Endostatin levels, natriuretic peptide levels and the severity of left ventricular diastolic dysfunction and the diagnosis of HFpEF. METHODS: Endostatin serum concentrations were measured in 301 patients comprising 77 HFpEF patients, 169 patients with asymptomatic left ventricular diastolic dysfunction (ALVDD), and 55 controls with normal cardiac function. RESULTS: Endostatin serum levels were significantly elevated in patients with HFpEF (median/interquartile range 179.0 [159-220]) and ALVDD (163.8 [145.4-191.3]) compared to controls (149.1 [130.6-176.9]), p < 0.001 and p = 0.004, respectively) and significant correlated with N-terminal pro B-type natriuretic peptide (NT-proBNP). CONCLUSIONS: This hypothesis-generating pilot study gives first evidence that Endostatin correlates with the severity of diastolic dysfunction and may become a novel biomarker for HFpEF. We hypothesize a rise in Endostatin levels may reflect inhibition of adaptive angiogenesis and adverse cardiac remodeling.

Safety and Tolerability of Neladenoson Bialanate, a Novel Oral Partial Adenosine A1 Receptor Agonist, in Patients With Chronic Heart Failure.

We studied safety and tolerability of neladenoson bialanate, a novel oral selective partial adenosine A1 receptor agonist that maintains the cardioprotective effects of adenosine without the undesired side effects of a full agonist, in 2 pilot studies in patients with heart failure with reduced ejection fraction (HFrEF). The ß-blocker interaction study was a single-blind, placebo-controlled study on the effects of a 30-mg single dose of neladenoson bialanate on atrioventricular (AV) conduction in 11 patients with HFrEF treated with ß-blockers. The PARSiFAL pilot study was a double-blind, placebo-controlled study on the effects of a 7-day treatment with 10 or 20 mg neladenoson bialanate or placebo in 31 patients with HFrEF on ß-blocker therapy. In the ß-blocker interaction study with 11 HFrEF patients, no second- or third-degree AV block was detected on 48-hour Holter monitoring. In the 31 HFrEF patients included in the PARSiFAL pilot study, no second- or third-degree AV blocks were observed during 24-hour Holter monitoring, and no effects were seen on heart rate and blood pressure. Median absolute changes in LVEF, measured by cardiac magnetic resonance, were 1.9% (interquartile range -1.1 to 4.3), 0.3% (-1.4 to 2.7), and 2.2% (0.4 to 4.5), in the placebo, 10-mg, and 20-mg groups, respectively. Treatment of HFrEF patients with the novel partial adenosine A1 agonist neladenoson bialanate appeared to be safe in 2 small pilot studies, and no atrioventricular conduction disorders or neurological side effects were observed. No significant early changes in cardiac function were detected.

Partial Adenosine A1 Agonist in Heart Failure.

Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.

Molecular and Digital Biomarker Supported Decision Making in Clinical Studies in Cardiovascular Indications.

Although a large number of pharmaceutical therapies are available to treat cardiovascular diseases like heart failure, in many medical conditions treatment is still not optimal and, therefore, the need for innovative, safe and efficacious drugs is still very high in this indication. Biomarkers are an important tool in the preclinical and clinical drug development process; they allow patient selection for clinical studies as well as therapy monitoring during studies. Biomarker concepts in cardiovascular indications differ very much from those in oncology and are very diverse. The present article gives an overview of the pathomechanisms of heart failure and describes the socioeconomic impact of the disease and the biomarker strategies being applied in the development of new heart failure drugs. The focus lies on protein biomarkers that can be measured in the blood and on functional biomarkers that can be derived from implanted and wearable medical devices.

Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure.

Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50%. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF.

Avaliação da área valvar aórtica combinando ecocardiografia e ressonância magnética / Assessment of aortic valve area combining echocardiography and magnetic resonance imaging / Evaluación del área valvular aórtica combinando ecocardiografía y resonancia magnética

FUNDAMENTO: A ecocardiografia transtorácica (ETT) é rotineiramente utilizada para calcular a área da valva aórtica (AVA) pela equação de continuidade (EC). No entanto, a medida exata das vias de saída do ventrículo esquerdo (VSVE) pode ser difícil e a aceleração do fluxo no VSVE pode levar a erro de cálculo da AVA. OBJETIVO: O objetivo do nosso estudo foi comparar as medições da AVA por ETT padrão, ressonância magnética cardíaca (RM) e uma abordagem híbrida que combina as duas técnicas. MÉTODOS: A AVA foi calculada em 38 pacientes (idade 73 ± 9 anos) com a ETT padrão, planimetria cine-RM e uma abordagem híbrida: Método híbrido 1: a medição da VSVE derivada pelo ETT no numerador CE foi substituída pela avaliação de ressonância magnética da VSVE e a AVA foi calculada: (VSVE RM/*VSVE-VTI ETT)/transaórtico-VTI ETT; Método 2: Substituímos o VS no numerador pelo VS derivado pela RM e calculamos a AVA = VS RM/transaórtico-VTI ETT. RESULTADOS: Amédia de AVAobtida pela ETTfoi 0,86 cm² ± 0,23 cm² e 0,83 cm² ± 0,3 cm² pela RM-planimetria, respectivamente. A diferença média absoluta da AVA foi de 0,03 cm² para a RM versus planimetria-ressonância magnética. A AVA calculada com o método 1 e o método 2 foi de 1,23 cm² ± 0,4 cm² e 0,92cm² ± 0,32 cm², respectivamente. A diferença média absoluta entre a ETT e os métodos 1 e 2 foi de 0,37 cm² e 0,06 cm², respectivamente (p < 0,001). CONCLUSÃO: A RM-planimetria da AVA e o método híbrido 2 são precisos e demonstraram boa consistência com as medições padrão obtidas pela ETT. Portanto, o método híbrido 2 é uma alternativa razoável na eventualidade de janelas acústicas ruins ou em caso de acelerações de fluxo VSVE que limitem a precisão da ETT, particularmente em pacientes com alto risco de um estudo hemodinâmico invasivo.

BACKGROUND: Transthoracic echocardiography (TTE) is routinely used to calculate aortic valve area (AVA) by continuity equation (CE). However, accurate measurement of the left ventricular outflow tract (LVOT) can be difficult and flow acceleration in the LVOT may lead to miscalculation of the AVA. OBJECTIVE: The aim of our study was to compare AVA measurements by standard TTE, cardiac magnetic resonance imaging (MRI) and a hybrid approach combining both techniques. METHODS: AVA was calculated in 38 patients (age 73±9 years) with standard TTE, cine-MRI planimetry and a hybrid approach: Hybrid Method 1: TTE-derived LVOT measurement in the CE numerator was replaced by the MRI assessment of the LVOT and AVA was calculated: (LVOT MRI/*LVOT-VTI TTE)/transaortic-VTI TTE. Method 2: We replaced the SV in the numerator by the MRI-derived SV and calculated AVA = SV MRI/ transaortic-VTI TTE. RESULTS: Mean AVA derived by TTE was 0.86 cm²±0.23 cm² and 0.83 cm²±0.3 cm² by MRI- planimetry, respectively. The mean absolute difference in AVA was 0.03cm² for TTE vs. MRI planimetry. AVA calculated with method 1 and method 2 was 1.23 cm²±0.4cm² and 0.92cm²±0.32cm², respectively. The mean absolute difference between TTE and method 1 and method 2 was 0.37cm² and 0.06cm², respectively (p<0.001). CONCLUSION: MRI-planimetry of AVA and hybrid method 2 are accurate and showed a good agreement with standard TTE measurements. Therefore, hybrid method 1 is a reasonable alternative if poor acoustic windows or LVOT flow accelerations limit the accuracy of TTE, particularly in patients at high risk for an invasive hemodynamic study.

FUNDAMENTO: La ecocardiografía transtorácica (ETT) es habitualmente utilizada para calcular el área de la válvula aórtica (AVA) por la ecuación de continuidad (EC). Mientras tanto, la medida exacta de las vías de salida del ventrículo izquierdo (VSVI) puede ser difícil y la aceleración del flujo en el VSVI puede llevar a error de cálculo del AVA. OBJETIVO: El objetivo del nuestro estudio fue comparar las mediciones del AVA por ETT estándar, resonancia magnética cardíaca (RM) y un abordaje híbrido que combina las dos técnicas. MÉTODOS: AEI AVA fue calculada en 38 pacientes (edad 73 ± 9 años) con la ETT estándar, planimetría cine-RM y un abordaje híbrido: Método híbrido 1: la medición de la VSVI derivada por el ETT en el numerador CE fue substituida por la evaluación de resonancia magnética de la VSVI y el AVA fue calculada: (VSVI RM/*VSVI-VTI ETT)/transaórtico-VTI ETT; Método 2: Substituimos el VS en el numerador por el VS derivado por la RM y calculamos el AVA = VS RM/transaórtico-VTI ETT. RESULTADOS: La media de AVA obtenida por la ETT fue 0,86 cm² ± 0,23 cm2 y 0,83 cm² ± 0,3 cm² por la RM-planimetría, respectivamente. La diferencia media absoluta del AVA fue de 0,03 cm² para la RM versus planimetría-resonancia magnética. El AVA calculada con el método 1 y el método 2 fue de 1,23 cm² ± 0,4 cm² y 0,92cm² ± 0,32 cm², respectivamente. La diferencia media absoluta entre la ETT y los métodos 1 y 2 fue de 0,37 cm² y 0,06 cm², respectivamente (p < 0,001). CONCLUSION: La RM-planimetría del AVA y el método híbrido 2 son precisos y demostraron buena consistencia con las mediciones estándar obtenidas por la ETT. Por lo tanto, el método híbrido 2 es una alternativa razonable en la eventualidad de ventanas acústicas malas o en caso de aceleraciones de flujo VSVI que limiten la precisión de la ETT, particularmente en pacientes con alto riesgo de un estudio hemodinámico invasivo.

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.