Efstathios K. Iliodromitis

Evaluation of left atrial longitudinal function in patients with hypertrophic cardiomyopathy: a tissue Doppler imaging and two-dimensional strain study

Objective: We sought to quantify left atrial longitudinal function by tissue Doppler (TDI) and two-dimensional (2D) strain in patients with hypertrophic cardiomyopathy (HCM). Design: Case-control study. Setting: Tertiary university hospital. Patients: 43 consecutive patients with familial HCM, aged 49 (SD 18) years, along with 21 patients with non-HCM left ventricular hypertrophy (LVH, aged 52 (12) years) and 27 healthy volunteers (aged 42 (13) years). Interventions: Subjects were studied by both TDI and 2D left atrial strain during all three atrial phases (reservoir, conduit, contractile), as well as by left ventricular systolic strain; total atrial deformation (TAD) was defined as the sum of maximum positive and maximum negative strain during a cardiac cycle. Main outcome measures: Left atrial longitudinal function. Results: Both TDI and 2D atrial strain and TAD were significantly reduced in HCM, compared to the other two groups in all atrial phases (p<0.001 in most cases); left ventricular systolic strain was also significantly reduced in HCM (p<0.001). Adding 2D contractile atrial strain to a model of conventional echo measurements (including left atrial diameter and volume index, interventricular septal thickness and E/A ratio and E/e′ ratios) increased its prognostic value in differentiating HCM from non-HCM LVH (p value of the change <0.001), while addition of TDI atrial strain or left ventricular strain did not. A cut-off for 2D contractile strain of −10.82% discriminated HCM from non-HCM LVH with a sensitivity of 82% and a specificity of 81%. Intra-observer and inter-observer variabilities for atrial strain in HCM were 16% and 17.5% for TDI and 8% and 9.5% for 2D, respectively. Processing time per case in HCM was 12.5 (2.6) minutes for TDI versus 3.8 (1.2) minutes for 2D strain (p<0.001). Conclusion: Left atrial longitudinal function is reduced in HCM compared to non-HCM LVH and healthy controls. In addition, 2D atrial strain has an additive value in differentiating HCM from non-HCM LVH and it is more reproducible and less time consuming than TDI strain.

Two-dimensional strain analysis in patients with hypertrophic cardiomyopathy and normal systolic function: A 12-month follow-up study

BACKGROUNDnAlthough left ventricular (LV) and left atrial (LA) echo indices may reliably reflect loading conditions in patients with hypertrophic cardiomyopathy (HCM), little is known about 2-dimensional strain imaging. We evaluated LV and LA 2-dimensional strain imaging in relation to long-term outcome in patients with HCM.nnnMETHODSnFifty consecutive patients (58% men, aged 51 +/- 18 years) with familial HCM and normal LV ejection fraction underwent 2-dimensional LV and LA strain imaging; total LA strain was defined as the sum of maximum positive and maximum negative atrial strain. Patients were followed up for 12 months for cardiovascular events, defined as death or hospitalization for cardiovascular causes.nnnRESULTSnTwenty patients (40%) experienced an event after a median time of 98 days: 2 (4%) died and 18 (36%) were hospitalized. In multivariate analysis, total LA strain was the strongest predictor of 12-month outcome (odds ratio 0.858, 95% CI 0.771-0.954, P = .005); a cutoff of 21% predicted events with 90% sensitivity and 86% specificity. Total LA strain was also an independent predictor of atrial fibrillation requiring hospitalization (odds ratio 0.853, 95% CI 0.748-0.972, P = .017).nnnCONCLUSIONSnIn patients with HCM and normal systolic function, total LA strain predicts 12-month outcome in terms of death and/or hospitalization.

Serum levels of retinol-binding protein-4 are associated with the presence and severity of coronary artery disease

BackgroundThe interplay between the novel adipokine retinol-binding protein-4 (RBP4) and coronary artery disease (CAD) is still obscure. We investigated the relationship between RBP4 levels and the presence and severity of angiographically proven CAD and determined its possible role in acute myocardial infarction (AMI).Methods305 individuals with angiographically proven CAD (CAD-patients), were classified into 2 subgroups: 1) acute myocardial infarction (AMI, nu2009=u2009141), and 2) stable angina (SA, nu2009=u2009164). Ninety-one age- and sex-matched individuals without CAD, but with at least 2 classical cardiovascular risk factors, served as controls (non-CAD group). RBP4 serum levels were measured at hospital admission and were analyzed in relation to the coronary severity stenosis, assessed by the Gensini-score and the number of coronary narrowed vessels. Other clinical parameters, including insulin levels, HOMA-IR, hsCRP, glycaemic and lipid profile, and left-ventricular ejection fraction were also assessed.ResultsSerum RBP4 levels were significantly elevated in patients with CAD compared to non-CAD patients (39.29u2009 ±u200911.72u2009mg/L vs. 24.83u2009 ±u200911.27u2009mg/L, pu2009<u20090.001). We did not observe a significant difference in RBP4 levels between AMI and SA subgroups (pu2009=u20090.734). Logistic regression analysis revealed an independent association of CAD presence with serum RBP4 (βu2009=u20090.163, pu2009=u20090.006), and hsCRP (βu2009=u20090.122, pu2009=u20090.022) levels, in the whole study group. Among variables, hsCRP (βu2009=u20090.220), HDL (βu2009=u2009β0.150), and RBP4 (βu2009=u20090.297), correlated in both univariate and multivariate analysis with CAD severity (R2u2009=u20090.422, pu2009<u20090.001). Similarly, RBP4 concentrations increased with the number of coronary narrowed vessels (pu2009<u20090.05).ConclusionPatients with CAD, both SA and AMI, showed elevated RBP4 serum levels. Notably, increased RBP4 concentration seemed to independently correlate with CAD severity, but no with AMI.Trial registrationThe ClinicalTrials.gov Identifier is: NCT00636766

Design and synthesis of novel antihypertensive drugs.

AT1 antagonists constitute a new generation of drugs for the treatment of hypertension and are designed and synthesized to mimic the C-terminal segment of Angiotensin II (Ang II) and to block its binding action on AT1 receptor. For this reason, the conformational analysis of Ang II and its derivatives as well as the AT1 antagonists belonging to SARTANs class of molecules were studied. Such studies offer the possibility to reveal the stereoelectronic factors responsible for bioactivity of AT1 antagonists and to design and synthesize new analogues with better pharmacological and financial profiles. An example of a novel synthetic non-peptide molecule is given which mimics the His(6)-Pro(7)-Phe(8) part of Ang II and is based on the (S)-pyroglutamic acid.

Design, synthesis and biological evaluation of cyclic angiotensin II analogues with 3,5 side-Chain bridges: Role of C-Terminal aromatic residue and ring cluster for activity and implications in the drug design of AT1 non-peptide antagonists

The novel amide linked angiotensin II (ANG II) cyclic analogues: gamma, epsilon -cyclo(3, 5)-[Sar(1)-Glu(3)-Lys(5)-Ile(8)] ANG II (I) and gamma, epsilon -cyclo(3, 5)-[Sar(1)-Glu(3)-Lys(5)-Phe(8)] ANG II (II) have been designed, synthesized and bioassayed in anesthetized rabbits in order to unravel structural ring cluster characteristics important for receptor activation. Analogue I with Ile at position 8 was an inhibitor of Angiotensin II while analogue II with Phe at position 8 was found to be an agonist. Similar results were reported for cyclic compounds that have reversed the linking between positions 3 and 5. The overall results show that positions 3 and 5 do not govern the biological activity of the synthetic analogues. It also appears that the aromatic ring cluster (Tyr-His-Phe) in agonist peptides is an essential stereo-electronic feature for Angiotensin II to exert its biological activity. A non-peptide mimetic of ANG II, 1-[2-[(N-benzyl)tetrazol-5-yl]biphenyl-4-yl]methyl]-2-hydroxymethylbenzimidazole (BZI8) has been designed and synthesized. This molecule is more rigid and much less active than AT(1) non-peptide mimetic losartan probably because it lacks to mimic the orientation of tetrazole and the pharmacophore segments of butyl chain and imidazole ring.

Epicardial Fat in Nonalcoholic Fatty Liver Disease: Properties and Relationships With Metabolic Factors, Cardiac Structure, and Cardiac Function.

Nonalcoholic fatty liver disease (NAFLD) is closely related to insulin resistance and the metabolic syndrome and might be an important cardiovascular (CV) risk factor. Epicardial adipose tissue (EAT) has been implicated in the pathogenesis of obesity-related CV disease. In an NAFLD population, we investigated EAT thickness and its possible relations to NAFLD and cardiac structure and function. This was an observational study of 57 patients with NAFLD and 48 age-matched controls. Patients with NAFLD had significantly higher body mass index (P < .0001), waist circumference (P < .0001), and high-sensitivity C-reactive protein (P = .005), whereas high-density lipoprotein cholesterol (P = .01) and adiponectin (P = .005) levels were significantly lower. The EAT was not thicker in NAFLD but was positively related to indices of impaired glucose tolerance and inflammation, with diabetes being an independent predictor of EAT thickness (b* = 0.29, P = .04). No relations were found between EAT and cardiac structure and function. In conclusion, this study confirms a pathologic phenotype of NAFLD. Epicardial fat was not significantly related to NAFLD per se, but diabetes, glucose metabolism, and inflammation were closely related to its thickness.

C-Reactive Protein, Interleukin 6, and N-Terminal Pro-Brain Natriuretic Peptide Following Cardioversion of Atrial Fibrillation: Is There a Role of Biomarkers in Arrhythmia Recurrence?

Aims: We investigated the role of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and N-terminal pro-brain natriuretic peptide (NTpro-BNP), in atrial fibrillation (AF) recurrence rate. Methods: A total of 80 patients with first AF episode were studied prospectively. Echocardiography (ECG), Holter ECG, and measurements of hsCRP, IL-6, and NTproBNP were performed immediately post conversion and at 1 month. Results: Recurrence was positively related to left atrial volume (P < .001), with no difference in NTpro-BNP, hsCRP, and IL-6. Decreased NTpro-BNP was observed in all at 1 month (P < .001, F = 63.4) and was positively related to left atrial volume (P < .01). In the lone AF subgroup, NTpro-BNP was lower and dropped significantly at 1 month (interaction F = 6.53, P < .01). Conclusions: Atrial volume was related to AF recurrence, whereas hsCRP, IL-6, and NTpro-BNP were not reliable for AF relapse. Relation of NTpro-BNP to left atrial volume could indicate a role in the atrial remodeling process.

Conformational and biological studies for a pair of novel synthetic AT1 antagonists: stereoelectronic requirements for antihypertensive efficacy

One of the major systems which interferes with the disease of hypertension, is the Renin Angiotensin Aldosterone System (RAS). The octapeptide hormone angiotensin II is the active product of RAS which causes vasoconstriction when binds to the AT(1) receptor. In the last years, there has been a development of drugs which block the Angiotensin II from binding the AT(1) receptor and are called AT(1) antagonists. In an effort to comprehend their stereoelectronic features, a study has been initiated to compare the conformational properties of drugs already marketed for the treatment of hypertension and others which are designed and synthesized in our laboratory possessing structural characteristics necessary for antihypertensive activity. In this study, two synthetic non-peptide AT(1) antagonists, are structurally elucidated and their conformational properties and bioactivity are compared to the prototype and first approved drug of this category in the market; losartan (trade name: COZAAR).

Staccato reperfusion improves myocardial microcirculatory function and long-term left ventricular remodelling: a randomised contrast echocardiography study

Objective To investigate the effects of staccato reperfusion (SR) during percutaneous coronary intervention (PCI) on myocardial microcirculatory function as assessed by myocardial contrast echocardiography. Setting Tertiary centre. Methods Thirty-nine patients were randomised to SR (n=20) or abrupt reperfusion (AR, n=19) within 48u2005h of an acute coronary syndrome. Contrast intensity replenishment curves were constructed to assess the blood volume (An), velocity (β) and flow (A×β) of the segments associated with the PCI-treated artery before, 48u2005h, 1 and 12u2005months after PCI. Left ventricular (LV) end-diastolic (EDVs) and systolic volumes (ESVs) were evaluated. Plasma malondialdehyde (MDA) was determined immediately before and 18u2005min after PCI to assess oxidative stress. Results SR was related to a greater improvement in An, β and A×β at 48u2005h, 1 and 12u2005months after intervention compared with AR (mean A×β: 0.91, 5.5, 7.14, 6.9 for SR vs 1.02, 3.34, 4.28, 3.71 for AR, p<0.01). After PCI, the mean MDA change was −27% in SR patients and +55% in the AR patients (p<0.05). The percentage change in MDA correlated with the percentage change in An at all time points (r=0.468, r=0.682, r=0.674, p<0.01). Compared with AR, SR was related to a greater percentage decrease in EDV (−11.61% vs −4.13%) and ESV (−34.68% vs −14.83%) at 12u2005months after PCI (p<0.05). The percentage change in ESV at 12u2005months correlated with the corresponding percentage changes in An, β and A×β (r=−0.410, r=−0.509, r=−0.577, respectively, p<0.05). Conclusions SR improves myocardial microcirculatory function after PCI, leading to a concomitant improvement in LV geometry, probably through reduction of oxidative stress.

Alternative pharmacological interventions that limit myocardial infarction.

Despite current optimal treatment, the morbidity and mortality of coronary heart disease remain significant worldwide and open the way for the development of novel cardioprotective therapies. In the last two decades, a remarkable scientific effort has focused on the limitation of infarct size. Important input from experimental studies has led the way in this direction. However, clinical and preclinical results using various cardioprotective strategies to attenuate reperfusion injury have generally not been applicable for every day clinical practice. Protection of the ischemic myocardium is known to occur as a result of ischemic preconditioning (PC), in which repetitive brief periods of ischemia protect the heart from a subsequent prolong ischemic insult. Although PC is a powerful form of protection, it is of limited clinical application for obvious ethical and practical reasons. Another endogenous form of cardioprotection, similar to PC but applicable at the time of reperfusion, termed postconditioning (PostC), has been recently described. Short series of repetitive cycles of brief reperfusion and re-occlusion of the coronary artery applied at the onset of reperfusion, reduce the infarct size and coronary artery endothelial dysfunction. At present, pharmacological PC and PostC are possible alternative methods that may substitute pharmaceutical treatments the short ischemic insults. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. We summarize the recent research efforts on novel therapeutic strategies and on the design of new compounds, based on the accumulated knowledge of the ligands, receptors and intracellular signaling pathways of PC and PostC.