Comparison of interleukin-6 and high-sensitivity C-reactive protein for cardiovascular risk assessment: Findings from the MESA study.

BACKGROUND AND AIMS: Inflammation is a risk factor for major adverse cardiovascular events (MACE). Elevated levels of both high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL6) have been associated with MACE. However, few studies have compared IL6 to hsCRP for cardiovascular risk assessment. Using the MESA (Multi-Ethnic Study of Atherosclerosis) study cohort, we aim to compare IL6 to hsCRP. METHODS: We divided IL6 and hsCRP by their median values and created 4 groups i.e., low-low, high-low, low-high and high-high. The median follow-up was 14 years. RESULTS: 6614 (97 %) participants had complete baseline IL6 and hsCRP data. The correlation between hsCRP and IL6 was modest (Rho = 0.53). IL6 ≥1.2 pg/mL (median) was present in 3309 participants, and hsCRP ≥1.9 mg/L (median) was present in 3339 participants. Compared to participants with low IL6 and low hsCRP, those with high IL6 and high hsCRP were older (64 vs. 60 years), more frequently women (63 % vs. 45 %), and with more cardiovascular co-morbidities. hsCRP outcome associations lost statistical significance when adjusting for IL6: MACE HR (95 %CI) 1.06 (0.93-1.20), p =0.39, whereas IL6 associations remained significant after adjusting for hsCRP: HR (95 %CI) 1.44 (1.25-1.64), p <0.001. The C-index of Framingham score for did not improve with hsCRP but improved with IL6. Compared to participants with low IL6 and low hsCRP, those with high IL6, regardless of hsCRP, experienced an increased risk of MACE, heart failure and mortality. CONCLUSIONS: In a diverse and asymptomatic population, IL6 showed a stronger association with atherosclerotic, heart failure and fatal outcomes than hsCRP.

Comparison of levosimendan, NO, and inhaled iloprost for pulmonary hypertension reversibility assessment in heart transplant candidates.

AIMS: Assessing reversibility of pulmonary vascular changes through vasoreactivity testing (VRT) optimizes end-stage heart failure patient selection for heart transplant. All efforts should be made to unload the left ventricle and reduce pulmonary vascular resistance to effectively exclude irreversible pulmonary hypertension. METHODS AND RESULTS: We reviewed our centre's cardiac transplant registry database (2009-2017) for VRT and compared haemodynamic responses with 40 ppm inhaled NO (n = 14), 14-17 µg inhaled iloprost (n = 7), and 24 h 0.1 µg/kg/min intravenous levosimendan (n = 14). Response to levosimendan was assessed by repeat right heart catheterization within 72 h. Baseline clinical and haemodynamic features were similar between groups. VRT was well tolerated in all patients. All drugs effectively reduced pulmonary artery pressures and transpulmonary gradient while increasing cardiac index, although levosimendan had a greater impact on cardiac index increase (P = 0.036). Levosimendan was the only drug that reduced pulmonary artery wedge pressure (P = 0.004) and central venous pressures (P < 0.001) and increased both left and right ventricular stroke work indexes (P = 0.020 and P = 0.042, respectively) and cardiac power index (P < 0.001) compared with NO and iloprost. Right ventricular end-diastolic pressures and central venous pressure were only decreased by levosimendan. The rate of positive responses (≥10 mmHg decrease or final mean pulmonary artery pressure ≤40 mmHg with increased/unaltered cardiac index) was lower with inhaled iloprost (14%) than with either levosimendan or NO (71% and 64%, respectively; P < 0.05). CONCLUSIONS: Levosimendan may be a safe and effective alternative for pulmonary hypertension reversibility assessment or a valuable pre-test medical optimization tool in end-stage heart failure patient assessment for heart transplantation offering extended haemodynamic benefits. Whether it increases the rate of positive responses or allows a better selection of candidates to heart transplantation remains to be established.

In Vitro Assessment of Cardiac Function Using Skinned Cardiomyocytes.

In this article, we describe the steps required to isolate a single permeabilized ("skinned") cardiomyocyte and attach it to a force-measuring apparatus and a motor to perform functional studies. These studies will allow measurement of cardiomyocyte stiffness (passive force) and its activation with different calcium (Ca2+)-containing solutions to determine, amongst others: maximum force development, myofilament Ca2+-sensitivity (pCa50), cooperativity (nHill) and the rate of force redevelopment (ktr). This method also enables determination of the effects of drugs acting directly on myofilaments and of the expression of exogenous recombinant proteins on both active and passive properties of cardiomyocytes. Clinically, skinned cardiomyocyte studies highlight the pathophysiology of many myocardial diseases and allow in vitro assessment of the impact of therapeutic interventions targeting the myofilaments. Altogether, this technique enables the clarification of cardiac pathophysiology by investigating correlations between in vitro and in vivo parameters in animal models and human tissue obtained during open heart or transplant surgery.

Noninvasive anatomical and functional assessment of coronary artery disease.

INTRODUCTION AND OBJECTIVE: In suspected coronary artery disease (CAD), invasive coronary angiography (ICA) is traditionally the diagnostic tool of choice. However, patients often have no significant disease. Moreover, assessment of fractional flow reserve (FFR) has been shown to have prognostic implications. Recently, coronary computed tomography angiography (CTA) and cardiac magnetic resonance (CMR) myocardial perfusion imaging (CMR-Perf) have gained increasing attention through their accurate anatomical and functional assessment, respectively. We studied the added value of integrating these tests (CT+CMRint) in the diagnosis of CAD, with FFR as the reference standard. METHODS: We included 101 patients consecutively referred for outpatient assessment of CAD who underwent CTA and CMR-Perf prior to ICA with FFR assessment. Lesions were considered positive by CT+CMRint only if positive in the two tests alone. The mean follow-up was 2.9±0.6 years. RESULTS: All patients completed the study protocol without adverse effects. Forty-four patients had CAD by FFR. CTA had excellent sensitivity and negative predictive value (100%) but, as expected, its specificity and positive predictive value were lower (61% and 67%, respectively). Diagnostic accuracy by FFR was 78% for CTA, 88% for CMR-Perf and 92% for CT+CMRint. Regarding diagnostic accuracy, CT+CMRint showed statistically significant superiority (AUC=0.917, 95% CI 0.845-0.963) compared with CTA (AUC=0.807, 95% CI 0.716-0.879, p=0.0057) or CMR-Perf (AUC=0.882, 95% CI 0.802-0.938, p=0.0398) alone. Regarding prediction of revascularization, the integrated protocol maintained its superior performance. CONCLUSIONS: CT+CMRint showed superior diagnostic accuracy and could thus lead to a considerable reduction in invasive procedures for CAD diagnosis, with less risk and greater patient comfort.

Rationale, design and methodology for Intraventricular Pressure Gradients Study: a novel approach for ventricular filling assessment in normal and falling hearts.

BACKGROUND: Intraventricular pressure gradients have been described between the base and the apex of the left ventricle during early diastolic ventricular filling, as well as, their increase after systolic and diastolic function improvement. Although, systolic gradients have also been observed, data are lacking on their magnitude and modulation during cardiac dysfunction. Furthermore, we know that segmental dysfunction interferes with the normal sequence of regional contraction and might be expected to alter the physiological intraventricular pressure gradients. The study hypothesis is that systolic and diastolic gradients, a marker of normal left ventricular function, may be related to physiological asynchrony between basal and apical myocardial segments and they can be attenuated, lost entirely, or even reversed when ventricular filling/emptying is impaired by regional acute ischemia or severe aortic stenosis. METHODS/DESIGN: Animal Studies: Six rabbits will be completely instrumented to measuring apex to outflow-tract pressure gradient and apical and basal myocardial segments lengthening changes at basal, afterloaded and ischemic conditions. Afterload increase will be performed by abruptly narrowing or occluding the ascending aorta during the diastole and myocardial ischemia will be induced by left coronary artery ligation, after the first diagonal branch.Patient Studies: Patients between 65-80 years old (n = 12), both genders, with severe aortic stenosis referred for aortic valve replacement will be selected as eligible subjects. A high-fidelity pressure-volume catheter will be positioned through the ascending aorta across the aortic valve to measure apical and outflow-tract pressure before and after aortic valve replacement with a bioprosthesis. Peak and average intraventricular pressure gradients will be recorded as apical minus outflow-tract pressure and calculated during all diastolic and systolic phases of cardiac cycle. DISCUSSION: We expect to validate the application of our method to obtain intraventricular pressure gradients in animals and patients and to promote a methodology to better understand the ventricular relaxation and filling and their correlation with systolic function.

[The role of leptin in the regulation of energy balance]. / O papel da leptina na regulação da homeostasia energética.

As a growing number of people suffer from obesity, understanding the mechanisms by which various hormones and neurotransmitters have influence on energy balance has been the subject of intensive research. Recent experimental studies have implicated leptin as a crucial controller of body weight. Leptin is a 167-aminoacid peptide hormone, which is mainly produced by adipocytes, and its levels in the circulation are increased in proportion to fat mass. Circulating leptin conveys information to the hypothalamus regarding the amount of energy stored in adipose tissue, suppressing appetite and affecting energy expenditure. Considerable evidence shows that this hormone is also involved in the regulation of several physiological processes such as reproduction, angiogenesis, immunity, hematopoiesis and bone remodelling. Leptin acts through leptin receptors that are ubiquitously distributed and hence explain the pleiotropic roles of leptin. In the present review, we will summarize the recent developments in the leptin field, with particular attention to aspects related with physiological and molecular mechanisms regulating energy homeostasis, as well as their implications in the pathophysiology of weight disorders.

Agreement between echocardiographic techniques in assessment of the left ventricular myocardial performance index in rabbits.

OBJECTIVE-To report reference values and examine the agreement in the myocardial performance (Tei) index of the left ventricle (LVTI) as measured by tissue Doppler imaging (TDI), pulsed-wave Doppler imaging (PWD), and M-mode echocardiography in clinically normal rabbits. ANIMALS-26 clinically normal male New Zealand White rabbits. PROCEDURES-Echocardiographic examinations that included TDI, PWD, and M-mode echocardiography were performed. Rabbits were sedated by SC administration of ketamine and midazolam. Intraclass correlation coefficients (ICCs) were used to measure absolute agreement among the 3 echocardiographic techniques. Intraclass correlation coefficients were computed for values a and b and for the equation (a - b)/b used to determine LVTI; value a equals the sum of isovolumic contraction time, ejection time, and isovolumic relaxation time, and value b equals the left ventricular ejection time. Values of ICC > 0.75 indicated good agreement between 2 echocardiographic techniques. RESULTS-For value a, Pearson correlation coefficients between pairs of techniques were all high (r r 0.7). However, only the septal TDI and the lateral wall TDI had good agreement (ICC, 0.86). For value b, correlations were generally low with the exception of the correlation between the septal and the lateral wall TDI. For value b, TDI was the only technique with good agreement (ICC, 0.77). For LVTI, only TDI techniques had a significantly positive correlation. All the other correlations were close to zero with a paradoxic moderate negative correlation between PWD-determined LVTI and lateral wall TDI-determined LVTI. CONCLUSIONS AND CLINICAL RELEVANCE-For LVTI, the absolute agreement was poor between all pairs of techniques.