D Aravot

Does synchronization reflect a true interaction in the cardiorespiratory system

Cardiorespiratory synchronization, studied within the framework of phase synchronization, has recently raised interest as one of the interactions in the cardiorespiratory system. In this work, we present a quantitative approach to the analysis of this nonlinear phenomenon. Our primary aim is to determine whether synchronization between HR and respiration rate is a real phenomenon or a random one. First, we developed an algorithm, which detects epochs of synchronization automatically and objectively. The algorithm was applied to recordings of respiration and HR obtained from 13 normal subjects and 13 heart transplant patients. Surrogate data sets were constructed from the original recordings, specifically lacking the coupling between HR and respiration. The statistical properties of synchronization in the two data sets and in their surrogates were compared. Synchronization was observed in all groups: in normal subjects, in the heart transplant patients and in the surrogates. Interestingly, synchronization was less abundant in normal subjects than in the transplant patients, indicating that the unique physiological condition of the latter promote cardiorespiratory synchronization. The duration of synchronization epochs was significantly shorter in the surrogate data of both data sets, suggesting that at least some of the synchronization epochs are real. In view of those results, cardiorespiratory synchronization, although not a major feature of cardiorespiratory interaction, seems to be a real phenomenon rather than an artifact.

Heme Oxygenase-1 Induction Improves Cardiac Function following Myocardial Ischemia by Reducing Oxidative Stress

Background Oxidative stress plays a key role in exacerbating diabetes and cardiovascular disease. Heme oxygenase-1 (HO-1), a stress response protein, is cytoprotective, but its role in post myocardial infarction (MI) and diabetes is not fully characterized. We aimed to investigate the protection and the mechanisms of HO-1 induction in cardiomyocytes subjected to hypoxia and in diabetic mice subjected to LAD ligation. Methods In vitro: cultured cardiomyocytes were treated with cobalt-protoporphyrin (CoPP) and tin protoporphyrin (SnPP) prior to hypoxic stress. In vivo: CoPP treated streptozotocin-induced diabetic mice were subjected to LAD ligation for 2/24 h. Cardiac function, histology, biochemical damage markers and signaling pathways were measured. Results HO-1 induction lowered release of lactate dehydrogenase (LDH) and creatine phospho kinase (CK), decreased propidium iodide staining, improved cell morphology and preserved mitochondrial membrane potential in cardiomyocytes. In diabetic mice, Fractional Shortening (FS) was lower than non-diabetic mice (35±1%vs.41±2, respectively p<0.05). CoPP-treated diabetic animals improved cardiac function (43±2% p<0.01), reduced CK, Troponin T levels and infarct size compared to non-treated diabetic mice (P<0.01, P<0.001, P<0.01 respectively). CoPP-enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, as indicated by the decrease in superoxide levels in cardiac tissues and plasma TNFα levels (p<0.05). The increased levels of HO-1 by CoPP treatment after LAD ligation led to a shift of the Bcl-2/bax ratio towards the antiapoptotic process (p<0.05). CoPP significantly increased the expression levels of pAKT and pGSK3β (p<0.05) in cardiomyocytes and in diabetic mice with MI. SnPP abolished CoPPs cardioprotective effects. Conclusions HO-1 induction plays a role in cardioprotection against hypoxic damage in cardiomyocytes and in reducing post ischemic cardiac damage in the diabetic heart as proved by the increased levels of pAKT with a concomitant inhibition of pGSK3β leading to preserved mitochondrial membrane potential.

An ultra-low dose of tetrahydrocannabinol provides cardioprotection.

UNLABELLEDnTetrahydrocannabinol (THC), the major psychoactive component of marijuana, is a cannabinoid agonist that exerts its effects by activating at least two specific receptors (CB1 and CB2) that belong to the seven transmembrane G-protein coupled receptor (GPCR) family. Both CB1 and CB2 mRNA and proteins are present in the heart. THC treatment was beneficial against hypoxia in neonatal cardiomyocytes in vitro. We also observed a neuroprotective effect of an ultra low dose of THC when applied to mice before brain insults. The present study was aimed to test and characterize the cardioprotective effects of a very low dose (0.002mg/kg) of THC which is 3-4 orders of magnitude lower than the conventional doses, administered before myocardial infarction in mice in vivo. Three regimens of THC administration were tested: single THC application 2h or 48h before the induction of infarct, or 3 weeks continuous treatment before MI. All protocols of THC administration were found to be beneficial. In the case of THC treatment 2h before MI, fractional shortening was elevated (37±4% vs. 42±1%, p<0.04), troponin T leakage to the blood was reduced (14±3ng/ml vs. 10±4ng/ml, p<0.008), infarct size decreased (29±4% vs. 23±4%, p<0.02), and the accumulation of neutrophils to the infarct area declined (36±10cells/field vs. 19±4cells/field, p<0.007) in THC- compared to vehicle-pretreated mice, 24h after MI. ERK1/2 phosphorylation following infarct was also inhibited by pre-treatment with THC (p<0.01).nnnCONCLUSIONnA single ultra low dose of THC before ischemia is a safe and effective treatment that reduces myocardial ischemic damage.

Late postoperative pleural effusion following lung transplantation: characteristics and clinical implications

OBJECTIVEnPleural effusions are extremely common in the early postoperative period after lung transplantation (LTX). It occurs in all transplant recipients, and like pleural fluid following other cardiothoracic surgery is bloody, exudative and neutrophil predominant. There was no information, however, on the characteristics of the late (14-45 days) postoperative pleural fluid after LTX. The purpose of this study was to describe the characteristics and the clinical implications of late postoperative pleural effusion after LTX.nnnMETHODSnThirty-five patients underwent TX between May 1997 and May 2001. Seven patients (20%) developed late postoperative pleural effusion. Thoracentesis were performed in these patients and the white blood cell counts, cell differential as well as biochemical parameters were determined.nnnRESULTSnThe median time for late pleural effusion appearance was 23 days (range, 14-34 days) after TX. The pleural effusions were medium in size (700 ml, range, 100-1300), exudative in all the patients and had lymphocyte predominance. No evidence of fluid recurrence or clinical deterioration was noted in these patients.nnnCONCLUSIONnLate-onset exudative lymphocytic pleural effusion after LTX is not uncommon. When there is no evidence of rejection or infection, it usually has a benign, favorable outcome.

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y2 and P2Y4 (UTP-activated), P2Y6, and P2Y14. Previously, we showed that uridine 5′-triphosphate (UTP) activating P2Y2R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y2R in vitro and in vivo following MI using uridine-5′-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y2R agonist. Cultured rat cardiomyocytes pretreated with MRS2768 displayed protection from hypoxia [as revealed by lactate dehydrogenase (LDH) release and propidium iodide (PI) binding], which was reduced by P2Y2R antagonist, AR-C118925 (5-((5-(2,8-dimethyl-5H-dibenzo[a,d][7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(1H-tetrazol-5-yl)furan-2-carboxamide). In vivo, echocardiography and infarct size staining of triphenyltetrazolium chloride (TTC) in 3 groups of mice 24xa0h post-MI: sham, MI, and MI+MRS2768 indicated protection. Fractional shortening (FS) was higher in MRS2768-treated mice than in MI alone (40.0u2009±u20093.1xa0% vs. 33.4u2009±u20092.7xa0%, pu2009<u20090.001). Troponin T and tumor necrosis factor-α (TNF-α) measurements demonstrated that MRS2768 pretreatment reduced myocardial damage (pu2009<u20090.05) and c-Jun phosphorylation increased. Thus, P2Y2R activation protects cardiomyocytes from hypoxia in vitro and reduces post-ischemic myocardial damage in vivo.

Very high frequency oscillations in the heart rate and blood pressure of heart transplant patients

The authors studied the recently reported very high frequency (VHF) peaks in the heart rate (HR) and blood pressure (BP) power spectra of heart transplant (HT) patients. These VHF peaks appear at frequencies much higher than the respiratory frequency, in addition to the typical low-frequency and high-frequency peaks. Twenty-five recordings obtained from 13 male HT patients (0.5–65 months following surgery) were compared with recordings from 14 normal male subjects. The ECG, continuous BP and respiration were recorded during 45 min of supine rest. Eight recordings from HT patients were excluded owing to arrhythmias. Spectral analysis was performed on all other recordings. VHF peaks were found in the spectra of both BP and HR in nine recordings obtained from six HT patients. In some cases, the power in the VHF peaks was markedly higher than that of the high-frequency peak. No VHF peaks were observed in eight recordings obtained from four HT patients or in recording from any of the normal subjects. No correlation was found between the incidence of VHF peaks and time after transplant. It was proved that the VHF peaks were not artifactual, and their significance within the framework of the theory of communication systems is discussed. The presence of those peaks was attributed to vagal denervation.

Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice

BACKGROUNDnSpontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. β-Adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation.nnnOBJECTIVEnTo optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2(Δ/Δ)) mouse model of CPVT2.nnnMETHODSnA heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy.nnnRESULTSnAdult CASQ2(Δ/Δ) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. β-Adrenergic blockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with α-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine-induced arrhythmia. In contrast, injection of α-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2(Δ/Δ) mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of calsequestrin-mutant mice expressed more α1-adrenergic receptor than did wild type control mice (P < .05).nnnCONCLUSIONnWe identified a contribution of the α-adrenergic pathway to the pathogenesis of catecholamine-induced arrhythmia. α-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to β-blockers.

Popeye domain-containing 1 is down-regulated in failing human hearts.

Congestive heart failure, a complex disease of heterogeneous etiology, involves alterations in the expression of multiple genes. The Popeye domain-containing (POPDC) family of three novel muscle-restricted genes (POPDC1-3) is evolutionarily conserved and developmentally regulated. In mice, POPDC1 has been shown to play an important role in skeletal and cardiac muscles subjected to injury or stress. However, it has never been explored in human hearts. In biopsies from non-failing and failing human hearts, we examined the cellular distribution of POPDC1 as well as the expression patterns of POPDC1-3 mRNAs. POPDC1 was visualized by immunohistochemistry and estimated by Western immunoblotting. The mRNA levels of POPDC1-3 and ß myosin heavy chain (MYHC7) were assessed using reverse transcription/quantitative polymerase chain reaction. POPDC1 was predominantly localized in the sarcolemma with an enhanced expression in the intercalated discs. In failing hearts, many cardiomyocytes appeared deformed and POPDC1 labeling was deranged. The three POPDC mRNAs were expressed in the four heart chambers with higher transcript levels in the ventricles compared to the atria. Heart failure concurred with reduced levels of POPDC1 mRNA and protein in the left ventricle. Correlation analyses of mRNA levels among the failing heart specimens indicated the coordinated regulation of POPDC1 with POPDC3 and of POPDC2 with MYHC7. It can be concluded that POPDC gene expression is modified in end-stage heart failure in humans in a manner suggesting regulatory and/or functional differences between the three family members and that POPDC1 is particularly susceptible to this condition.

Bicoherence analysis of new cardiovascular spectral components observed in heart-transplant patients: statistical approach for bicoherence thresholding

Following heart transplant (HT), the patients heart functions under complete cardiac denervation. As a result, the variability in physiologic signals is extremely reduced. We have previously reported that in addition to the typical spectral components (of very low amplitude), part of the HT patients (above 50%) demonstrated unexpected additional peaks in their heart rate and blood pressure spectra. These peaks may be a result of the development of compensatory mechanism induced by loss of parasympathetic control, or of increased importance of nonlinear control interactions. It is important to quantify these strange, unexpected very-high frequency (VHF) peaks, to understand their origin and their contribution to cardiac control in transplant patients. In this paper, we chose to examine these VHF peaks by applying the bicoherence approach. The reduced signal to noise ratio, occurring in these patients, results, however, in an extremely noisy bicoherence. We, therefore, developed several statistical tools in order to distinguish between true bicoherence peaks (reflecting true phase coupling) and spurious peaks. The outcome of these methods was an efficient and sensitive bicoherence thresholding procedure, able to identify most of the spurious peaks. Applying these tools to the bicoherence of cardiovascular signals which display VHF peaks, revealed several significant bicoherence peaks. Interestingly, these peaks consisted of two different types. The first type of VHF peaks simply reflects nonlinear cardiac-respiratory coupling, imposed by nonsinusoidal breathing. The second type, however, is clearly not induced by the respiratory system. We believe that these type-2 VHF peaks reflect the evolution of a new, yet unexplained, compensatory mechanism.

A bridge between hearts: mutual organ donation by Arabs and Jews in Israel.

Background. The availability of organ transplants depends largely on the will of the donor families. Given the current state of affairs in Israel, the authors evaluated the stance of Jews and Arabs toward mutual organ donations. Methods. Between October 1997 and December 1999, there were 4.8 million Jews and 1.09 million Arabs living in Israel. Data gathered from 22 general hospitals for this period yielded 373 potential organ donors and 171 families (45.8%) that consented to the procedure. Actual donation was obtained from 157 patients. The authors examined the characteristics of the potential organ donors and organ recipients and the reasons (religious and nonreligious) for familial consent or refusal. Donation made since onset of the Intifada (armed Palestinian resistance) was also reviewed to determine whether any changes took place. Results. Consent was obtained from 48.9% of the Jewish families approached, 30.7% of the Muslim Arabs, and 66.6% of the Christian Arabs. For the whole sample, altruism was the main reason for consenting. The percentages of Arabs and Jews (per population) on the waiting list for a heart (Jews, 90%; Arabs, 10%) or liver (Jews, 78.66%; Arabs, 21.34%) and who received a heart (Jews, 90%; Arabs, 10%) or liver (Jews, 78.36%; Arabs, 21.64%) were similar. There were relatively more Arab recipients of kidney transplants (waiting list, 11%; recipients, 18.6%) because of the higher percentage of children in the Arab group who were given priority. Since September 2000 (start of the Intifada), there has been a trend toward an increasing rate of refusal to donate among Arabs (consent obtained in 52.9% of Jewish families approached vs. 27.9% of the Muslim Arabs), mainly because of fear of rejection by the community for cooperating with Jews. Conclusions. The rate of organ donations among Arabs and Jews in Israel is proportional to their representation in the general population. The main reason for donating organs is altruism. Apparently, altruism cuts across the boundaries of religion and ethnic groups, even in a country where conflict prevails. We trust that progress in the international arena will bring the current cycle of violence to an end and allow humanitarian values to take preference over politics.