Michele Schiariti

Pretreatment with the adenosine triphosphate-sensitive potassium channel opener nicorandil and improved myocardial protection during high-potassium ca rdioplegic hypoxia

We hypothesized that pretreatment with the potassium channel opener nicorandil might enhance myocardial protection achieved by cold (20 degrees C) high-potassium (16 mmol/L) cardioplegia (5 ml/min) during long-duration (120 minutes) myocardial hypoxia (average oxygen content 5.4 ml/dl). We tested a 15-minute infusion of nicorandil (1 mmol/L) given only before (group A, n = 8) or before and during cardioplegia (group B, n = 8) in guinea pig papillary muscle preparations contracting isometrically while stimulated (4 mA, 2 msec) at 1600 msec cycle length. Nicorandil was significantly negative inotropic before cardioplegia and shortened significantly action potential duration. During cardioplegia, time to arrest of contraction was shortened from 145 +/- 28 seconds (mean +/- standard error) in the vehicle group (dimethyl sulfoxide 1:100; n = 8) to 56 +/- 10 seconds (p < 0.02) and 68 +/- 5 seconds (p < 0.05) in groups A and B, respectively. Recovery of developed tension at 60 minutes of normothermic reoxygenation (expressed as percent of prehypoxia basal value) was ameliorated from 54% +/- 6% (vehicle group) to 92% +/- 4% (group A, p < 0.01) and to 119% +/- 19% (group B, p < 0.01). The specific potassium channel blocker glibenclamide (glib: 1 mumol/L, n = 8) prolonged action potential duration and was without effect on time to arrest. On reoxygenation, the glib group had prolonged time to half relaxation (versus group A, p < 0.02) and the worst percent developed tension at 60 minutes (40% +/- 4%). In the overall study, time to arrest and percent developed tension at 60 minutes were inversely correlated (r = -0.45, p < 0.01). Arrhythmias were never observed. Multivariate analysis showed that pretreatment with nicorandil (with or without drug adjunct to cardioplegic solution) was a significant factor (r2 = 0.65, p = 0.0001) to influence reoxygenation-mediated recovery of mechanical function. Neither the negative inotropic effect of nicorandil before cardioplegia nor its abbreviating action on time to arrest during cardioplegia was contributory to explain recovery of function on reoxygenation. In subgroup analysis, negative inotropism and the shortening of action potential duration were contributory factors. These data suggest that nicorandil pretreatment activates potassium channels and enhances the myocardial protection provided by cold cardioplegia an effect, which is evident after a long hypoxic period, late on reoxygenation.

The risk of myocardial stunning is decreased concentration-dependently by KATP channel activation with nicorandil before high K+ cardioplegia

BACKGROUND Drug-induced opening of the adenosine triphosphate-sensitive potassium channel (KATP) during hypoxia and/or ischemia, achieved significant myocardial protection in several in vitro and in vivo models. Pretreatment with KATP openers simulated preconditioning and thus enhanced recovery from ischemia. We have demonstrated that the risk of hypoxia-induced myocardial stunning is reversed by KATP activation with 1 mmol/l nicorandil before cold cardioplegic arrest. Whether lower concentrations were effective is not known. METHODS In guinea pig papillary muscle preparations contracting isometrically (driven at 1600 ms cycle), nicorandil was superfused (15 min) either 1 mumol/l (n = 4), 30 mumol/l (n = 4), 100 mumol/l (n = 4), or 1 mmol/l (n = 8) in Tyrodes solution (oxygen content 16 ml/l, 37 degrees C, 5 ml/min). Controls were superfused with saline (Tyrodes solution: n = 8). A group containing vehicle (DMSO 1%, n = 8) was also studied. In four preparations the KATP channel blocker glibenclamide 1 mumol/l was given before nicorandil 1 mmol/l. Then, long-lasting (120 min) but moderately hypoxic (oxygen content 5 ml/l: 31% of Tyrodes solution) superfusion with hypothermic (20 degrees C) high K+ (16 mmol/l) cardioplegic solution (5 ml/min) was performed. Recovery of contractility was evaluated after further 60 min of reoxygenation with Tyrodes solution based on DT/TPT (developed tension divided by time to peak tension) as percent of prehypoxia basal values (%DT/TPT60). DT/TPT was also studied following 15 min of inotropic stimulation with dobutamine 10 mumol/l (%DT/TPT75). To assess the risk of stunning, we used a multivariate linear model by all possible subsets analysis (BMDP-9R) aimed at predicting both %DT/TPT60 and %DT/TPT75 (as continuous dependent variables). RESULTS During cardioplegia induction, time to arrest (TTA) was (mean +/- S.D.) 103 +/- 48s in control preparations which had poor recovery of contractility (stunning) after reoxygenation (%DT/TPT60: 71 +/- 20%; %DT/TPT75: 443 +/- 272%). Nicorandil (1 mumol/l-1 mmol/l) abbreviated TTA concentration-dependently (163 +/- 74, 149 +/- 103, 82 +/- 20, and 56 +/- 27s) and improved both %DT/TPT60 (63 +/- 9, 78 +/- 17, 87 +/- 13, and 98 +/- 11%) and %DT/TPT75 (587 +/- 333, 619 +/- 107, 971 +/- 301, and 666 +/- 400%). Glibenclamide reversed the effects of nicorandil 1 mmol/l (TTA: 165 +/- 30 s, P < 0.01; %DT/TPT60: 43 +/- 12, P < 0.01; %DT/TPT75: 272 +/- 147, P < 0.05). Multivariate prediction of myocardial stunning at both 60 and 75 min reoxygenation showed that nicorandil (30 mumol/l-1 mmol/l) was a significant (P < 0.001) protectant whereas glibenclamide was a significant risk factor (P = 0.009). It is unclear whether negative inotropic effects of nicorandil (%DT/TPT at the end of pretreatment) was mechanistically related to reduced risk of stunning since contribution was seen only to predict %DT/TPT75 (t = 3.24, P = 0.003) whereas a positive association was observed with %DT/TPT60 (t = 1.89, P = 0.068). CONCLUSION Pretreatment with nicorandil concentration-dependently enhanced the cardioprotective effect of hypothermic high K+ cardioplegia. The risk of myocardial stunning was decreased by KATP opening with nicorandil and increased by KATP block with glibenclamide. Inotropic stimulation with dobutamine might unravel the role of negative inotropic effect of KATP opening as a contributory factor to explain the efficacy of nicorandil in our model.

Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone

Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more mineralocorticoid receptor-specific. From a marginal role as a potassium-sparing diuretic, spironolactone has been shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure. Also, spironolactone is safe and protective in arterial hypertension, particularly in patients with so-called resistant hypertension. Eplerenone is the second oral aldosterone antagonist available for the treatment of arterial hypertension and heart failure. Treatment with eplerenone has been associated with decreased blood pressure and improved survival for patients with heart failure and reduced left ventricular ejection fraction. Due to the selectivity of eplerenone for the aldosterone receptor, severe adverse effects such as gynecomastia and vaginal bleeding seem to be less likely in patients who take eplerenone than in those who take spironolactone. The most common and potentially dangerous side effect of spironolactone--hyperkalemia--is also observed with eplerenone but the findings from clinical trials do not indicate more hyperkalemia induced drug withdrawals. Treatment with eplerenone should be initiated at a dosage of 25mg once daily and titrated to a target dosage of 50mg once daily preferably within 4 weeks. Serum potassium levels and renal function should be assessed prior to initiating eplerenone therapy, and periodic monitoring is recommended, especially in patients at high risk of developing hyperkalemia.

4D-Analysis of Left Ventricular Heart Cycle Using Procrustes Motion Analysis

The aim of this study is to investigate human left ventricular heart morphological changes in time among 17 healthy subjects. Preliminarily, 2 patients with volumetric overload due to aortic insufficiency were added to our analyses. We propose a special strategy to compare the shape, orientation and size of cardiac cycle’s morphological trajectories in time. We used 3D data obtained by Speckle Tracking Echocardiography in order to detect semi-automated and homologous landmarks clouds as proxies of left ventricular heart morphology. An extended Geometric Morphometrics toolkit in order to distinguish between intra- and inter-individual shape variations was used. Shape of trajectories with inter-individual variation were compared under the assumption that trajectories attributes, estimated at electrophysiologically homologous times are expressions of left ventricular heart function. We found that shape analysis as commonly applied in Geometric Morphometrics studies fails in identifying a proper morpho-space to compare the shape of morphological trajectories in time. To overcome this problem, we performed a special type of Riemannian Parallel Transport, called “linear shift”. Whereas the two patients with aortic insufficiency were not differentiated in the static shape analysis from the healthy subjects, they set apart significantly in the analyses of motion trajectory’s shape and orientation. We found that in healthy subjects, the variations due to inter-individual morphological differences were not related to shape and orientation of morphological trajectories. Principal Component Analysis showed that volumetric contraction, torsion and twist are differently distributed on different axes. Moreover, global shape change appeared to be more correlated with endocardial shape change than with the epicardial one. Finally, the total shape variation occurring among different subjects was significantly larger than that observable across properly defined morphological trajectories.

An automated algorithm for online detection of fragmented QRS and identification of its various morphologies

Fragmented QRS (f-QRS) has been proven to be an efficient biomarker for several diseases, including remote and acute myocardial infarction, cardiac sarcoidosis, non-ischaemic cardiomyopathy, etc. It has also been shown to have higher sensitivity and/or specificity values than the conventional markers (e.g. Q-wave, ST-elevation, etc.) which may even regress or disappear with time. Patients with such diseases have to undergo expensive and sometimes invasive tests for diagnosis. Automated detection of f-QRS followed by identification of its various morphologies in addition to the conventional ECG feature (e.g. P, QRS, T amplitude and duration, etc.) extraction will lead to a more reliable diagnosis, therapy and disease prognosis than the state-of-the-art approaches and thereby will be of significant clinical importance for both hospital-based and emerging remote health monitoring environments as well as for implanted ICD devices. An automated algorithm for detection of f-QRS from the ECG and identification of its various morphologies is proposed in this work which, to the best of our knowledge, is the first work of its kind. Using our recently proposed time–domain morphology and gradient-based ECG feature extraction algorithm, the QRS complex is extracted and discrete wavelet transform (DWT) with one level of decomposition, using the ‘Haar’ wavelet, is applied on it to detect the presence of fragmentation. Detailed DWT coefficients were observed to hypothesize the postulates of detection of all types of morphologies as reported in the literature. To model and verify the algorithm, PhysioNets PTB database was used. Forty patients were randomly selected from the database and their ECG were examined by two experienced cardiologists and the results were compared with those obtained from the algorithm. Out of 40 patients, 31 were considered appropriate for comparison by two cardiologists, and it is shown that 334 out of 372 (89.8%) leads from the chosen 31 patients complied favourably with our proposed algorithm. The sensitivity and specificity values obtained for the detection of f-QRS were 0.897 and 0.899, respectively. Automation will speed up the detection of fragmentation, reducing the human error involved and will allow it to be implemented for hospital-based remote monitoring and ICD devices.

The pharmacological use of ellagic acid-rich pomegranate fruit.

Abstract In recent years, the therapeutic use of non-drug substances such as herbal and medicinal foods is increasing progressively. Of these substances, Punica granatum L., which is an ancient and highly distinctive fruit, has been proposed for treatment of several different illnesses. Ellagic acid (EA) is one of those biological molecules found in pomegranate and may have therapeutic potential in many diseases. EA has been detected not only in pomegranate but also in a wide variety of fruits and nuts such as raspberries, strawberries, walnuts, grapes and black currants, and is becoming an increasingly popular dietary supplement over recent years. Similar to other ellagitannins (ETs), EA is quite stable under physiological conditions in the stomach. EA and ETs as active agents induce vasorelaxation, oxygen free radical scavenging, hypolipidemic, anti-inflammatory and anti-carcinogenic activities in various animal preparations call an attention to the need for designing adequate tests in humans to assess these potentially useful properties in diseased states.

Multivariate prediction of spontaneous repetitive responses in ventricular myocardium exposed in vitro to simulated ischemic conditions

Guinea-pig ventricular myocardium was partly exposed to normal Tyrodes superfusion and partly to altered conditions (using modified Tyrodes solution) set to simulate acute myocardial ischemia (PO2 80 +/- 10 mmHg; no glucose; pH 7.00 +/- 0.05; K+ 12 mM). Using a double-chamber tissue bath and standard microelectrode technique, the occurrence of spontaneous repetitive responses was investigated during simulated ischemia (occlusion) and after reperfusing the previously ischemic superfused tissue with normal Tyrodes solution (reperfusion). In 62 experiments (42 animals) the effects of: (1) duration of simulated ischemia (1321 +/- 435 s), (2) stimulation rate (1002 +/- 549 ms) and (3) number of successive simulated ischemic periods (occlusions) (1.58 +/- 0.92) on: (1) resting membrane potential, (2) action potential amplitude, (3) duration of 50 and 90% action potentials and (4) maximal upstroke velocity of action potential were studied. All variables were considered as gradients (delta) between normal and ischemic tissue. Both during occlusion and upon reperfusion, spontaneous repetitive responses were coded as single, couplets, salvos (three to nine and > 10) or total spontaneous repetitive responses (coded present when at least one of the above-mentioned types was seen). The incidence of total spontaneous repetitive responses was 31% (19/62) on occlusion and 85% (53/62) upon reperfusion. Coxs models (forced and stepwise) were used to predict multivariately the occurrence of arrhythmic events considered as both total spontaneous repetitive responses and as separate entities. These models were applicable since continuous monitoring of the experiments enabled exact timing of spontaneous repetitive response onset during both occlusion and reperfusion. In predicting reperfusion spontaneous repetitive responses, total spontaneous repetitive responses and blocks observed during the occlusion period were also considered. Total occlusion spontaneous repetitive responses were predicted by: (1) longer delta 50% action potential duration (t = 2.68), (2) shorter delta 90% action potential duration (t = -2.17) and (3) fewer occlusive periods (t = -2.46). Total reperfusion spontaneous repetitive responses were predicted by a longer delta action potential amplitude (t = 2.18). Due to few events during occlusion, prediction of individual arrhythmic entities was not possible. Upon reperfusion single spontaneous repetitive responses were predicted by longer delta maximal upstroke velocity of action potential (t = 2.59) and shorter delta 90% action potential duration (t = -2.55); couplets were predicted by longer delta 50% action potential duration (t = 3.26); longer delta action potential amplitude predicted salvos (> 10) (t = 3.26).(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term efficacy of high-dose tirofiban versus double-bolus eptifibatide in patients undergoing percutaneous coronary intervention.

Background There is no head-to-head comparison between tirofiban versus eptifibatide in patients undergoing percutaneous coronary intervention (PCI) when added to standard antiaggregating drugs (AAD) to prevent ischemic events within 1 year. Methods We compared real-world patients undergoing PCI who were on oral single AAD and were block randomized to receive, immediately preintervention, high-dose tirofiban (n = 519) or double-bolus eptifibatide (n = 147) and a second oral antiplatelet agent. The incidence of composite ischemic events within 1 year, including death, acute myocardial infarction, angina, stent thrombosis or repeat PCI or coronary bypass surgery (primary end-point) was modelled by forced Coxs regression. Results There were overall 65 composite ischemic events: 47 (9.1%) in the tirofiban group and 18 (12.2%) in the eptifibatide group (univariate log-rank test: P = 0.22). On the basis of 21 potential covariates fitted simultaneously, multivariable adjusted hazard ratios showed that age [hazard ratio 1.03, 95% confidence interval (CI) 1.01–1.07, P = 0.01], chronic renal failure (hazard ratio 3.21, 95% CI 1.02–10.10, P = 0.05), pre-PCI values of creatine kinase-myocardial band (CK-MB) (hazard ratio 1.002, 95% CI 1.0002–1.0054, P = 0.04), intra-aortic balloon pump (hazard ratio 5.88, 95% CI 12.33–14.85, P = 0.0002) and the presence of eptifibatide (hazard ratio 1.85, 95% CI 1.04–3.29, P = 0.04) were significant risk factors whereas thrombolysis by tenecteplase (hazard ratio 0.19, 95% CI 0.05–0.69, P = 0.01) was a significant protector. Interestingly, eptifibatide versus tirofiban efficacy was explained based on pre-PCI values of CK-MB. Conclusion Head-to-head comparison between eptifibatide and tirofiban in patients undergoing PCI while on double AAD showed that eptifibatide had a lower efficacy on the incidence of composite ischemic events within 1 year, which might be explained by a reduced action on CK-MB pre-PCI.

Gender and Cardiovascular Mortality in Northern and Southern European Populations

BACKGROUND There are no ready explanations for differences in ischemic heart disease incidence between women and men under an epidemiological perspective. However, when myocardial infarction occurs, there are more likely individuals who happen to die. METHODS This review from a more recent literature was performed for a two-fold purpose, to describe gender wise: a) the role of classical and novel factors defined to evaluate coronary artery disease (CAD) risk and mortality, aimed at assessing applicability and relevance for primary and secondary prevention; b) the differences in northern versus southern European Countries in risk factors and CAD mortality. RESULTS Age-related risk patterns differ in men and women. It is uncertain whether standard factors may index CAD risk, including mortality, in different ways and/or whether specific factors might be targeted gender-wise. A list might be compiled: HDL-cholesterol levels, higher in pre-menopausal women than in men, are more strictly related to CAD; high triglycerides and Lp(a) have a similar relationship; HDL-cholesterol levels have an inverse relation with CAD incidence and mortality. The role of statins is not completely defined in primary prevention for women. However, in secondary prevention statins are equally effective in both genders. Weight and glycemic control are effective to reduce cardiovascular disease (CVD) mortality in women from middle to older age. Similarly, CVD mortality in women, from middle to older age, might be reduced by controlling blood pressure, particularly among diabetic or over weighted women. Renal dysfunction, either defined by UAE or eGFR or both may usefully predict primary CVD incidence and risk in both genders. In secondary prediction, kidney dysfunction predicts sudden death in women when left ventricular ejection fraction is also evaluated. Serum uric acid that normally increases with age, differentiates gender-related CVD incidences with a peculiar importance in women as compared to men. There has been much interest to investigate loss of ovarian function in explaining age-related differences between genders. More recently, some emphasis has been laid on the loss of ovarian function-related iron stores. There are subgroups of women as those with mitral valve prolapse and increased circulating levels of catecholamines in whom QT interval, physiologically longer in women than men, may be an arrhythmogenic risk index. However, no large population-based studies were ever conducted to assess this. Therefore, in the future, it will be important to implement risk score instruments (charts and softwares) in women using novel parameters, and among these inflammatory markers and reproductive hormones and serum uric acid. The important results of the WHO MONICA Project confirmed the northern versus southern European gradient in both men and women, for death rates and the proportion of all deaths from cardiovascular causes (including CAD, stroke and other CVD causes). The coronary event rate was initially as high as 1, 000 per 100, 000 inhabitants in Finland and less than 1 fifth of that in Spain with the corresponding figures in women of 200 and 30, respectively. CONCLUSION No doubt might still exist that all efforts need be undertaken for both men and women, for health and prolongation of life to effectively treat common risk factors such as cigarette consumption, high blood pressure, cholesterol levels and physical inactivity by also paying attention to optimal diet.

A New 4D Trajectory-Based Approach Unveils Abnormal LV Revolution Dynamics in Hypertrophic Cardiomyopathy

The assessment of left ventricular shape changes during cardiac revolution may be a new step in clinical cardiology to ease early diagnosis and treatment. To quantify these changes, only point registration was adopted and neither Generalized Procrustes Analysis nor Principal Component Analysis were applied as we did previously to study a group of healthy subjects. Here, we extend to patients affected by hypertrophic cardiomyopathy the original approach and preliminarily include genotype positive/phenotype negative individuals to explore the potential that incumbent pathology might also be detected. Using 3D Speckle Tracking Echocardiography, we recorded left ventricular shape of 48 healthy subjects, 24 patients affected by hypertrophic cardiomyopathy and 3 genotype positive/phenotype negative individuals. We then applied Generalized Procrustes Analysis and Principal Component Analysis and inter-individual differences were cleaned by Parallel Transport performed on the tangent space, along the horizontal geodesic, between the per-subject consensuses and the grand mean. Endocardial and epicardial layers were evaluated separately, different from many ecocardiographic applications. Under a common Principal Component Analysis, we then evaluated left ventricle morphological changes (at both layers) explained by first Principal Component scores. Trajectories’ shape and orientation were investigated and contrasted. Logistic regression and Receiver Operating Characteristic curves were used to compare these morphometric indicators with traditional 3D Speckle Tracking Echocardiography global parameters. Geometric morphometrics indicators performed better than 3D Speckle Tracking Echocardiography global parameters in recognizing pathology both in systole and diastole. Genotype positive/phenotype negative individuals clustered with patients affected by hypertrophic cardiomyopathy during diastole, suggesting that incumbent pathology may indeed be foreseen by these methods. Left ventricle deformation in patients affected by hypertrophic cardiomyopathy compared to healthy subjects may be assessed by modern shape analysis better than by traditional 3D Speckle Tracking Echocardiography global parameters. Hypertrophic cardiomyopathy pathophysiology was unveiled in a new manner whereby also diastolic phase abnormalities are evident which is more difficult to investigate by traditional ecocardiographic techniques.