Andrej Gapelyuk

Dietary n-3 Polyunsaturated Fatty Acids and Direct Renin Inhibition Improve Electrical Remodeling in a Model of High Human Renin Hypertension

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180±3 mm Hg) compared with dTGRs (208±5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110±3 and 119±6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QTc intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) contribute to the regulation of cardiovascular function. CYP enzymes also accept EPA and DHA to yield more potent vasodilatory and potentially anti-arrhythmic metabolites, suggesting that the endogenous CYP-eicosanoid profile can be favorably shifted by dietary omega-3 fatty acids. To test this hypothesis, 20 healthy volunteers were treated with an EPA/DHA supplement and analyzed for concomitant changes in the circulatory and urinary levels of AA-, EPA-, and DHA-derived metabolites produced by the cyclooxygenase-, lipoxygenase (LOX)-, and CYP-dependent pathways. Raising the Omega-3 Index from about four to eight primarily resulted in a large increase of EPA-derived CYP-dependent epoxy-metabolites followed by increases of EPA- and DHA-derived LOX-dependent monohydroxy-metabolites including the precursors of the resolvin E and D families; resolvins themselves were not detected. The metabolite/precursor fatty acid ratios indicated that CYP epoxygenases metabolized EPA with an 8.6-fold higher efficiency and DHA with a 2.2-fold higher efficiency than AA. Effects on leukotriene, prostaglandin E, prostacyclin, and thromboxane formation remained rather weak. We propose that CYP-dependent epoxy-metabolites of EPA and DHA may function as mediators of the vasodilatory and cardioprotective effects of omega-3 fatty acids and could serve as biomarkers in clinical studies investigating the cardiovascular effects of EPA/DHA supplementation.

Aldosterone induces electrical remodeling independent of hypertension

BACKGROUND Treatment of heart failure patients with aldosterone antagonists has been shown to reduce the occurrence of sudden cardiac death. Therefore we aimed at determining the consequences of chronic exposure to aldosterone and the aldosterone antagonists eplerenone and spironolactone on the electrophysiological properties of the heart in a rat model. METHODS AND RESULTS Male Wistar rats were chronically treated (4weeks) with aldosterone (ALD) via an osmotic minipump. Spironolactone (SPI) or eplerenone (EPL) was administered with the rat chow. ALD treated animals developed left ventricular hypertrophy, prolonged QT-intervals, a higher rate of ventricular premature beats and non-sustained ventricular tachycardia despite normal blood pressure values. Spironolactone and eplerenone were both able to inhibit the alterations. Left-ventricular mRNA expressions of Kv4.2 and Kv4.3 (Ito), Kv1.5 (IKur), Kir2.1 and Kir2.3 (IK1) and of Cav1.2 (L-type Ca(2+) channel) were significantly down-regulated in ALD. Correspondingly, the protein expressions of subunits Kv1.5, Kir2.3 and Cav1.2 were significantly decreased. A diminished calcineurin activity and mRNA expression of the Aß subunit of calcineurin were found in ALD, which was insensitive to aldosterone antagonists. CONCLUSIONS Chronic aldosterone-overload induces blood pressure independent structural and electrical remodeling of the myocardium resulting in an increased risk for malignant ventricular arrhythmias.

Effect of CPAP therapy on daytime cardiovascular regulations in patients with obstructive sleep apnea

Obstructive sleep apnea (OSA) is a sleep disorder with a high prevalence that causes pathological changes in cardiovascular regulation during the night and also during daytime. We investigated whether the treatment of OSA at night by means of continuous positive airway pressure (CPAP) improves the daytime consequences. Twenty-eight patients with OSA, 18 with arterial hypertension, 10 with normal blood pressure, were investigated at baseline and with three months of CPAP treatment. Ten age and sex matched healthy control subjects were investigated for comparisons. We recorded a resting period with 20min quiet breathing and an exercise stress test during daytime with ECG and blood pressure (Portapres). The bicycle ergometry showed a significant reduction of the diastolic blood pressure at a work load of 50W and 100W (p<0.05 and p<0.01, respectively) and a decrease of the heart rate recovery time after the stress test (p<0.05). These results indicate a reduction of vascular resistance and sympathetic activity during daytime. The coupling analysis of the resting periods by means of symbolic coupling traces approach indicated an effect of the CPAP therapy on the baroreflex reaction in hypertensive patients where influences of the systolic blood pressure on the heart rate changed from pathological patterns to adaptive mechanisms of the normotensive patients (p<0.05).

Classification of cardiovascular time series based on different coupling structures using recurrence networks analysis

We analyse cardiovascular time series with the aim of performing early prediction of preeclampsia (PE), a pregnancy-specific disorder causing maternal and foetal morbidity and mortality. The analysis is made using a novel approach, namely the ϵ-recurrence networks applied to a phase space constructed by means of the time series of the variabilities of the heart rate and the blood pressure (systolic and diastolic). All the possible coupling structures among these variables are considered for the analysis. Network measures such as average path length, mean coreness, global clustering coefficient and scale-local transitivity dimension are computed and constitute the parameters for the subsequent quadratic discriminant analysis. This allows us to predict PE with a sensitivity of 91.7 per cent and a specificity of 68.1 per cent, thus validating the use of this method for classifying healthy and preeclamptic patients.

Investigation of an Automatic Sleep Stage Classification by Means of Multiscorer Hypnogram

OBJECTIVES Scoring sleep visually based on polysomnography is an important but time-consuming element of sleep medicine. Whereas computer software assists human experts in the assignment of sleep stages to polysomnogram epochs, their performance is usually insufficient. This study evaluates the possibility to fully automatize sleep staging considering the reliability of the sleep stages available from human expert sleep scorers. METHODS We obtain features from EEG, ECG and respiratory signals of polysomnograms from ten healthy subjects. Using the sleep stages provided by three human experts, we evaluate the performance of linear discriminant analysis on the entire polysomnogram and only on epochs where the three experts agree in their sleep stage scoring. RESULTS We show that in polysomnogram intervals, to which all three scorers assign the same sleep stage, our algorithm achieves 90% accuracy. This high rate of agreement with the human experts is accomplished with only a small set of three frequency features from the EEG. We increase the performance to 93% by including ECG and respiration features. In contrast, on intervals of ambiguous sleep stage, the sleep stage classification obtained from our algorithm, agrees with the human consensus scorer in approximately 61%. CONCLUSIONS These findings suggest that machine classification is highly consistent with human sleep staging and that error in the algorithms assignments is rather a problem of lack of well-defined criteria for human experts to judge certain polysomnogram epochs than an insufficiency of computational procedures.

Symbolic dynamics marker of heart rate variability combined with clinical variables enhance obstructive sleep apnea screening.

Many sleep centres try to perform a reduced portable test in order to decrease the number of overnight polysomnographies that are expensive, time-consuming, and disturbing. With some limitations, heart rate variability (HRV) has been useful in this task. The aim of this investigation was to evaluate if inclusion of symbolic dynamics variables to a logistic regression model integrating clinical and physical variables, can improve the detection of subjects for further polysomnographies. To our knowledge, this is the first contribution that innovates in that strategy. A group of 133 patients has been referred to the sleep center for suspected sleep apnea. Clinical assessment of the patients consisted of a sleep related questionnaire and a physical examination. The clinical variables related to apnea and selected in the statistical model were age (p < 10(-3)), neck circumference (p < 10(-3)), score on a questionnaire scale intended to quantify daytime sleepiness (p < 10(-3)), and intensity of snoring (p < 10(-3)). The validation of this model demonstrated an increase in classification performance when a variable based on non-linear dynamics of HRV (p < 0.01) was used additionally to the other variables. For diagnostic rule based only on clinical and physical variables, the corresponding area under the receiver operating characteristic (ROC) curve was 0.907 (95% confidence interval (CI) = 0.848, 0.967), (sensitivity 87.10% and specificity 80%). For the model including the average of a symbolic dynamic variable, the area under the ROC curve was increased to 0.941 (95% = 0.897, 0.985), (sensitivity 88.71% and specificity 82.86%). In conclusion, symbolic dynamics, coupled with significant clinical and physical variables can help to prioritize polysomnographies in patients with a high probability of apnea. In addition, the processing of the HRV is a well established low cost and robust technique.

Classifying healthy women and preeclamptic patients from cardiovascular data using recurrence and complex network methods

It is urgently aimed in prenatal medicine to identify pregnancies, which develop life-threatening preeclampsia prior to the manifestation of the disease. Here, we use recurrence-based methods to distinguish such pregnancies already in the second trimester, using the following cardiovascular time series: the variability of heart rate and systolic and diastolic blood pressures. We perform recurrence quantification analysis (RQA), in addition to a novel approach, ε-recurrence networks, applied to a phase space constructed by means of these time series. We examine all possible coupling structures in a phase space constructed with the above-mentioned biosignals. Several measures including recurrence rate, determinism, laminarity, trapping time, and longest diagonal and vertical lines for the recurrence quantification analysis and average path length, mean coreness, global clustering coefficient, assortativity, and scale local transitivity dimension for the network measures are considered as parameters for our analysis. With these quantities, we perform a quadratic discriminant analysis that allows us to classify healthy pregnancies and upcoming preeclamptic patients with a sensitivity of 91.7% and a specificity of 45.8% in the case of RQA and 91.7% and 68% when using ε-recurrence networks, respectively.

Cardiovascular regulation in different sleep stages in the obstructive sleep apnea syndrome.

Abstract Heart rate and blood pressure variability analysis as well as baroreflex sensitivity have been proven to be powerful tools for the assessment of autonomic control in clinical practice. Their ability to detect systematic changes caused by different states, diseases and treatments shall be shown for sleep disorders. Therefore, we consider 18 normotensive and 10 hypertensive patients suffering from obstructive sleep apnea syndrome (OSAS) before and after a three-month continuous positive airway pressure (CPAP) therapy. Additionally, an age and sex matched control group of 10 healthy subjects is examined. Linear and nonlinear parameters of heart rate and blood pressure fluctuation as well as the baroreflex sensitivity are used to answer the question whether there are differences in cardiovascular regulation between the different sleep stages and groups. Moreover, the therapeutic effect of CPAP therapy in OSAS patients shall be investigated. Kruskal-Wallis tests between the sleep stages for each group show significant differences in the very low spectral component of heart rate (VLF/P: 0.0033–0.04 Hz, p<0.01) which indicates differences in metabolic activity during the night. Furthermore, the decrease of Shannon entropy of word distribution as a parameter of systolic blood pressure during non-REM sleep reflects the local dominance of the vagal system (p<0.05). The increased sympathetic activation of the patients leads to clear differences of cardiovascular regulation in different sleep stages between controls and patients. We found a significant reduction of baroreflex sensitivity in slow wave sleep in the OSAS patients (Mann-Whitney test, p<0.05) compared to controls, which disappeared after three months of CPAP therapy. Hence, our results demonstrate the ability of cardiovascular analyzes to separate between healthy and pathological regulation as well as between different severities of OSAS in this retrospective study.

Cardiac Magnetic Resonance and Cardiac Magnetic Field Mapping in a Patient with Stress‐Induced Cardiomyopathy (Tako‐Tsubo)

We encountered a 65‐year‐old woman with typical electrocardiogram (ECG) changes and new‐onset left ventricular dysfunction with apical ballooning that exhibited typical changes of tako‐tsubo‐like cardiomyopathy. We used cardiac magnetic resonance (CMR) and cardiac magnetic field mapping (CMFM) to detect changes in structural, mechanical, and electrophysiological myocardial properties during follow‐up. CMR displayed an acute myocardial injury, but neither fibrosis nor necrosis. CMFM exhibited severely disturbed repolarization with an inhomogeneous magnetic field. These pathological findings persisted much longer than the abnormalities detected by CMR and the ECG.