Revisiting the obesity paradox in heart failure: Per cent body fat as predictor of biomarkers and outcome.

AIMS: Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2)). METHODS: In an individual patient dataset, BMI was calculated as weight (kg)/height (m) 2 , and PBF through the Jackson-Pollock and Gallagher equations. RESULTS: Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5-2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4-33.0%) with the Jackson-Pollock equation, and 28.0% (23.8-33.5%) with the Gallagher equation, with an extremely strong correlation (r = 0.996, p < 0.001). Patients in the first PBF tertile had the worst prognosis, while patients in the second and third tertile had similar survival. The risks of all-cause and cardiovascular death decreased by up to 36% and 27%, respectively, per each doubling of PBF. Furthermore, prognosis was better in the second or third PBF tertiles than in the first tertile regardless of model variables. Both BMI and PBF were inverse predictors of NT-proBNP, but not hs-TnT. In obese patients (BMI ≥ 30 kg/m2, third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome. CONCLUSION: In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients.

sST2 Predicts Outcome in Chronic Heart Failure Beyond NT-proBNP and High-Sensitivity Troponin T.

BACKGROUND: Soluble suppression of tumorigenesis-2 (sST2) is a biomarker related to inflammation and fibrosis. OBJECTIVES: This study assessed the independent prognostic value of sST2 in chronic heart failure (HF). METHODS: Individual patient data from studies that assessed sST2 for risk prediction in chronic HF, together with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT), were retrieved. RESULTS: A total of 4,268 patients were evaluated (median age 68 years, 75% males, 65% with ischemic HF, 87% with left ventricular ejection fraction [LVEF] <40%). NT-proBNP, hs-TnT, and sST2 were 1,360 ng/l (interquartile interval: 513 to 3,222 ng/l), 18 ng/l (interquartile interval: 9 to 33 ng/l), and 27 ng/l (interquartile interval: 20 to 39 ng/l), respectively. During a 2.4-year median follow-up, 1,319 patients (31%) experienced all-cause death (n = 932 [22%] for cardiovascular causes). Among the 4,118 patients (96%) with available data, 1,029 (24%) were hospitalized at least once for worsening HF over 2.2 years. The best sST2 cutoff for the prediction of all-cause and cardiovascular death and HF hospitalization was 28 ng/ml, with good performance at Kaplan-Meier analysis (log-rank: 117.6, 61.0, and 88.6, respectively; all p < 0.001). In a model that included age, sex, body mass index, ischemic etiology, LVEF, New York Heart Association functional class, glomerular filtration rate, HF medical therapy, NT-proBNP, and hs-TnT, the risk of all-cause death, cardiovascular death, and HF hospitalization increased by 26%, 25%, and 30%, respectively, per each doubling of sST2. sST2 retained its independent prognostic value across most population subgroups. CONCLUSIONS: sST2 yielded strong, independent predictive value for all-cause and cardiovascular mortality, and HF hospitalization in chronic HF, and deserves consideration to be part of a multimarker panel together with NT-proBNP and hs-TnT.

Troponinas de alta sensibilidad T vs I en Sindrome Coronario Agudo: Predicción de lesiones coronarias significativas y pronóstico a largo plazo / High-Sensitivity Troponin T vs I in Acute Coronary Syndrome: Prediction of Significant Coronary Lesions and Long-term Prognosis

Antecedentes: Los ensayos de troponinas cardíacas de alta sensibilidad (hs-cTn) tanto T e I son una herramienta crucial y bien establecida para el diagnóstico de infarto agudo de miocardio (IAM), ya que se ha demostrado ampliamente su superioridad respecto a las antiguas determinaciones de troponina. Sin embargo, eventuales diferencias entre ambos ensayos en la predicción de lesiones coronarias significativas y el pronóstico a largo plazo en pacientes con síndrome coronario agudo (SCA) no han sido aclarados completamente. Métodos: Se evaluaron las concentraciones séricas de hs-cTnT (Roche), hs-cTnI (Abbott) y porción amino-terminal del pro-péptido natriurético tipo B (NT-proBNP) (Roche) en 390 pacientes con SCA sin elevación del segmento ST, y se relacionaron con lesiones coronarias significativas detectadas por angiografía coronaria (definidas como estenosis >50% del diámetro luminal, con necesidad de revascularización) y con la precisión pronóstica de mortalidad cardiovascular, mortalidad por cualquier causa, así como también con el punto final compuesto por mortalidad cardiovascular y hospitalizaciones por IAM o insuficiencia cardiaca. Resultados: La media (+DE) del seguimiento fue de 2921+168 días. Las concentraciones absolutas de hs-cTnI fueron significativamente mayores que las concentraciones de hs-cTnT. La relación entre los biomarcadores analizados y lesiones coronarias significativas en angiografía coronaria, cuantificada por el área bajo la curva ROC (AUC), no reveló diferencias entre hs-cTnT [AUC, 0,81; IC del 95%, 0,77- 0,86] y hs-cTnI (AUC, 0,81; IC del 95%, 0,76-0,86; P=NS). Sin embargo, NT-proBNP fue superior a ambos ensayos de hs-cTn en relación con la precisión pronóstica tanto para mortalidad cardiovascular y por cualquier causa, como para el punto final compuesto durante el seguimiento, aún también en análisis multivariados. Conclusiones: Los determinaciones de hs-cTnT y hs-cTnI mostraron una capacidad similar para predecir lesiones coronarias significativas en pacientes con SCA sin elevación del segmento ST. NT-proBNP fue superior a ambos ensayos de uscTn, como marcador de pronóstico a largo plazo en este grupo de pacientes.

Background: High-sensitivity cardiac troponin (hs-cTn) T and I assays are established as crucial tools for the diagnosis of acute myocardial infarction (AMI), as they have been found superior to old troponin assays. However, eventual differences between the assays in prediction of significant coronary lesions and long-term prognosis in patients with acute coronary syndrome (ACS) have not been fully unraveled. Methods: Serum concentrations of hs-cTnT (Roche), hs-cTnI (Abbott), and amino-terminal pro-B-type natriuretic peptide (NT-proBNP; Roche) in 390 non-ST-elevation (NSTE) ACS patients were evaluated in relation to significant coronary lesions on coronary angiography (defined as a stenosis >50% of the luminal diameter, with need for revascularization) and prognostic accuracy for cardiovascular mortality, all-cause mortality, as well as the composite end point of cardiovascular mortality and hospitalizations for AMI or heart failure. Results: The mean+SD follow-up was 2921+168 days. Absolute hs-cTnI concentrations were significantly higher than the hs-cTnT concentrations. The relationship between analyzed biomarkers and significant coronary lesions on coronary angiography, as quantified by the area under the ROC curve (AUC), revealed no difference between hs-cTnT [AUC, 0.81; 95% CI, 0.77-0.86] and hs-cTnI (AUC, 0.81; 95% CI, 0.76-0.86; P=NS). NT-proBNP was superior to both hs-cTn assays regarding prognostic accuracy for both cardiovascular and all-cause mortality and for the composite end point during follow-up, also in multivariate analyses. Conclusions: The hs-cTnT and hs-cTnI assays displayed a similar ability to predict significant coronary lesions in NSTE-ACS patients. NT-proBNP was superior to both hs-cTn assays as a marker of long-term prognosis in this patient group.

Connective tissue growth factor and bone morphogenetic protein 2 are induced following myocardial ischemia in mice and humans.

We aimed to study the cardiac expression of bone morphogenetic protein 2, its receptor 1 b, and connective tissue growth factor, factors implicated in cardiac embryogenesis, following ischemia/hypoxia, heart failure, and in remodeling hearts from humans and mice. Biopsies from the left ventricle of patients with end-stage heart failure due to dilated cardiomyopathy or coronary artery disease were compared with donor hearts and biopsies from patients with normal heart function undergoing coronary artery bypass grafting. Mouse model of post-infarction remodeling was made by permanent ligation of the left coronary artery. Hearts were analyzed by real-time polymerase chain reaction and Western blotting after 24 hours and after 2 and 4 weeks. Patients with dilated cardiomyopathy and mice post-infarction had increased cardiac expression of connective tissue growth factor. Bone morphogenetic protein 2 was increased in human hearts failing due to coronary artery disease and in mice post-infarction. Gene expression of bone morphogenetic protein receptor 1 beta was reduced in hearts of patients with failure, but increased two weeks following permanent ligation of the left coronary artery in mice. In conclusion, connective tissue growth factor is upregulated in hearts of humans with dilated cardiomyopathy, bone morphogenetic protein 2 is upregulated in remodeling due to myocardial infarction while its receptor 1 b in human failing hearts is downregulated. A potential explanation might be an attempt to engage regenerative processes, which should be addressed by further, mechanistic studies.

Limited Added Value of Circulating Inflammatory Biomarkers in Chronic Heart Failure.

OBJECTIVES: This study sought to evaluate whether a panel of biomarkers improved prognostication in patients with heart failure (HF) and reduced ejection fraction of ischemic origin using a systematized approach according to suggested requirements for validation of new biomarkers. BACKGROUND: Modeling combinations of multiple circulating markers could potentially identify patients with HF at particularly high risk and aid in the selection of individualized therapy. METHODS: From a panel of 20 inflammatory and extracellular matrix biomarkers, 2 different biomarker panels were created and added to the Seattle HF score and the prognostic model from the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study (n = 1,497), which included conventional clinical characteristics and C-reactive protein and N-terminal pro-B-type natriuretic peptide. Interactions with statin treatment were also assessed. RESULTS: The two models-model 1 (endostatin, interleukin 8, soluble ST2, troponin T, galectin 3, and chemokine [C-C motif] ligand 21) and model 2 (troponin T, soluble ST2, galectin 3, pentraxin 3, and soluble tumor necrosis factor receptor 2)-significantly improved the CORONA and Seattle HF models but added only modestly to their Harrell's C statistic and net reclassification index. In addition, rosuvastatin had no effect on the levels of a wide range of inflammatory and extracellular matrix markers, but there was a tendency for patients with a lower level of biomarkers in the 2 panels to have a positive effect from statin treatment. CONCLUSIONS: In the specific HF patient population studied, a multimarker approach using the particular panel of biomarkers measured was of limited clinical value for identifying future risk of adverse outcomes.

Soluble glycoprotein 130 predicts fatal outcomes in chronic heart failure: analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

BACKGROUND: Glycoprotein 130 (gp130) is the common signal-transducing receptor subunit of the interleukin-6 (IL-6) family, which may be involved in the progression of heart failure (HF). We hypothesized that soluble gp130 would provide prognostic information beyond that of IL-6 in a population with HF from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). METHODS AND RESULTS: The associations of soluble gp130 and IL-6 with morbidity, mortality, and mode of death were assessed by immunoassays in a subset of 1452 patients enrolled in the CORONA trial, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. In multivariable analyses, including C-reactive protein, IL-6, troponin T, and N-terminal pro-B-type natriuretic peptide, elevated soluble gp130 (fifth quintile versus all lower quintiles) was associated with all-cause mortality (hazard ratio, 1.47 [1.11-1.93]; P=0.006), cardiovascular mortality (hazard ratio, 1.38 [1.01-1.87]; P=0.042), and death from worsening HF (hazard ratio, 1.85 [1.09-3.14]; P=0.002), but not with the primary end point (composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke; hazard ratio, 1.12 [0.84-1.50]; P=0.44). Plasma IL-6 was not associated with outcomes in multivariable analyses. CONCLUSIONS: Marked elevations in soluble gp130 are associated with total and cardiovascular mortality, as well as deaths from worsening HF, in elderly patients with HF of ischemic cause CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Myocardial connective tissue growth factor (CCN2/CTGF) attenuates left ventricular remodeling after myocardial infarction.

AIMS: Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI. METHODS AND RESULTS: Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15. CONCLUSION: Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis.

Gene therapy with hypoxia-inducible factor 1 alpha in skeletal muscle is cardioprotective in vivo.

AIMS: Gene therapy of a peripheral organ to protect the heart is clinically attractive. The transcription factor hypoxia-inducible factor 1 alpha (HIF-1α) transactivates cardioprotective genes. We investigated if remote delivery of DNA encoding for HIF-1α is protective against myocardial ischemia-reperfusion injury in vivo. MAIN METHODS: DNA encoding for human HIF-1α was delivered to quadriceps muscles of mice. One week later myocardial infarction was induced and four weeks later its size was measured. Echocardiography and in vivo pressure-volume analysis was performed. Coronary vascularization was evaluated through plastic casting. HL-1 cells, transfected with either HIF-1α or HMOX-1 or administered bilirubin or the carbon monoxide (CO) donor CORM-2, were subjected to lipopolysacharide (LPS)-induced cell death to compare the efficacy of treatments. KEY FINDINGS: After four weeks of reperfusion post infarction, animals pretreated with HIF-1α showed reduced infarct size and left ventricular remodeling (p<0.05, respectively). Fractional shortening was preserved in mice pretreated with HIF-1α (p<0.05). Invasive hemodynamic parameters indicated preserved left ventricular function after HIF-1α (p<0.05), which also induced coronary vascularization (p<0.05). HIF-1α downstream target heme oxygenase 1 (HMOX-1) was upregulated in skeletal muscle, while serum bilirubin was increased. Transfection of HL-1 cells with HIF-1α or HMOX-1 and administration of bilirubin or CORM-2 comparably salvaged cells from lipopolysacharide (LPS)-induced cell death (all p<0.05). SIGNIFICANCE: HIF-1α gene delivery to skeletal muscle preceding myocardial ischemia reduced infarct size and postischemic remodeling accompanied by an improved cardiac function and vascularization. Similar to HIF-1α, HMOX-1, bilirubin and CO were protective against LPS-induced injury. This observation may have clinical potential.

Mechanisms of novel cardioprotective functions of CCN2/CTGF in myocardial ischemia-reperfusion injury.

CCN2/connective tissue growth factor (CTGF), a CCN family matricellular protein repressed in healthy hearts after birth, is induced in heart failure of various etiologies. Multiple cellular and biological functions have been assigned to CCN2/CTGF depending on cellular context. However, the functions and mechanisms of action of CCN2/CTGF in the heart as well as its roles in cardiac physiology and pathophysiology remain unknown. Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) were generated and compared with nontransgenic littermate control (NLC) mice. Tg-CTGF mice displayed slightly lower cardiac mass and inconspicuous increase of myocardial collagen compared with NLC mice but no evidence of contractile dysfunction. Analysis of the myocardial transcriptome by DNA microarray revealed activation of several distinct gene programs in Tg-CTGF hearts involved in cardioprotection and growth inhibition. Indeed, Tg-CTGF mice subjected to ischemia-reperfusion injury by in situ transient occlusion of the left anterior descending coronary artery in vivo displayed reduced vulnerability with markedly diminished infarct size. These findings were recapitulated in isolated hearts perfused with recombinant human (h)CTGF before the ischemia-reperfusion procedure. Consistently, Tg-CTGF hearts, as well as isolated adult cardiac myocytes exposed to recombinant hCTGF, displayed enhanced phosphorylation and activity of the Akt/p70S6 kinase/GSK-3ß salvage kinase pathway and induction of several genes with reported cardioprotective functions. Inhibition of Akt activities also prevented the cardioprotective phenotype of hearts from Tg-CTGF mice. This report provides novel evidence that CTGF confers cardioprotection by salvage phosphokinase signaling leading to inhibition of GSK-3ß activities, activation of phospho-SMAD2, and reprogramming of gene expression.

Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors.

BACKGROUND: Carcinoid heart disease, a known complication of neuroendocrine tumors, is characterized by right heart fibrotic lesions. Carcinoid heart disease has traditionally been defined by the degree of valvular involvement. Right ventricular (RV) dysfunction due to mural involvement may also be a manifestation. Connective tissue growth factor (CCN2) is elevated in many fibrotic disorders. Its role in carcinoid heart disease is unknown. We sought to investigate the relationship between plasma CCN2 and valvular and mural involvement in carcinoid heart disease. METHODS: Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation. RESULTS: Mean strain was -21% +/- 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% +/- 3). Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR). Thirty-six patients had normal or mildly reduced RV function (strain < or = -20%, mean -25% +/- 3). There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p < 0.001). Patients with reduced RV function had higher plasma CCN2 levels than those with normal or mildly reduced RV function (p < 0.001). Plasma CCN2 > or = 77 microg/L was an independent predictor of reduced RV function (odds ratio 15.36 [95% CI 4.15;56.86]) and had 88% sensitivity and 69% specificity for its detection (p < 0.001). Plasma CCN2 was elevated in patients with mild or greater TR/PR compared to those with no or minimal TR/PR (p = 0.008), with the highest levels seen in moderate to severe TR/PR (p = 0.03). CONCLUSIONS: Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.

[Unexpected sudden death after percutaneous coronary intervention]. / Plutselig uventet dødsfall etter perkutan koronar intervensjon.

BACKGROUND: Myocarditis is one of several important differential diagnoses in patients presenting with chest pain or symptoms of heart failure. The prevalence of myocarditis is probably underestimated. In young patients with sudden cardiac death, myocarditis is a common finding at autopsy. MATERIAL AND METHODS: A previously healthy 54-year-old man presented with a first episode of chest pain. Smoking was the only risk factor for coronary artery disease. RESULTS: Plasma levels of both Troponin-I and CK-MB mass were negative at admission, but were elevated in a second sample. A subtotal stenosis in the left anterior descending artery was treated with PCI. The patient was discharged after four days. He was found dead at home six days after PCI. Autopsy revealed a massive myocarditis, no signs of myocardial necrosis and only minor coronary artery disease. INTERPRETATION: This case illustrates the importance of keeping less frequent differential diagnoses in mind when patients present with chest pain. Also, this case underscores the importance of keeping a high autopsy rate; for feedback to clinicians, for correct cause-of-death statistics and for research.