Jan Simek

Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial — FAT)

OBJECTIVE It has been repeatedly proven that statins improve endothelial function in isolated hypercholesterolaemia but there is far less evidence in the case of combined hyperlipidaemia. Studies assessing the effects of fibrates on endothelium have been neglected. Therefore, we conducted a trial in which the effects of fenofibrate and atorvastatin monotherapy on both endothelium-dependent vascular reactivity and biochemical parameters were compared in patients with combined hyperlipidaemia. METHODS 29 otherwise healthy males (aged 47.4+/-7.8 years) with combined hyperlipidaemia (total cholesterol 7.55+/-1.20 mmol/l, triglycerides 5.41+/-4.54 mmol/l) were included into the randomised, single-blind, cross-over study to receive either 200 mg of micronised fenofibrate or 10 mg of atorvastatin daily--each of the drugs for a period of 10 weeks. Analysed biochemical parameters were as follows: serum total-, LDL- and HDL-cholesterol, apolipoproteins A-I and B, triglycerides, fibrinogen, uric acid, C-reactive protein (CRP), insulin, and homocysteine. Endothelial function was investigated by duplex Doppler ultrasonography at the brachial artery. Two indices of endothelial-dependent postischaemic changes were used - the recently introduced index of peak blood flow (PBF) representing the level of reactive hyperaemia and traditional flow-mediated dilatation (FMD). RESULTS We observed a small improvement in FMD after both fenofibrate and atorvastatin (from 2.26% to 2.98% and 2.87%, respectively; NS). PBF increased from 448 ml/min to 536 ml/min after fenofibrate (P=0.04) and to 570 ml/min after atorvastatin (P=0.03). The effects of both fenofibrate and atorvastatin on endothelial function did not differ significantly (P-values of 0.82 and 0.47 for FMD and PBF, respectively). Significant correlations (P<0.01) between the changes of vascular reactivity and biochemical indices were found between FMD and CRP (r=-0.60) and between both FMD and PBF, and insulinaemia (r=-0.48 and -0.56, respectively) only during treatment with fenofibrate. CONCLUSIONS Both fenofibrate and atorvastatin significantly improved endothelium-dependent vascular reactivity without mutual difference. The PBF was superior to FMD for the detection of this improvement. The beneficial effect of both drugs did not correlate with the change of lipid profile during therapy. The improvement of vascular reactivity during treatment with fenofibrate (opposed to atorvastatin) was related to the reduction of indirect marker of chronic vessel wall inflammation and of insulin resistance. The PBF was more reproducible than FMD because of considerably lower intra-subject variability.

Prevalent Low-Frequency Oscillation of Heart Rate Novel Predictor of Mortality After Myocardial Infarction

Background—This study evaluates a novel method for postinfarction risk stratification based on frequency-domain characteristics of heart rate variability (HRV) in 24-hour Holter recordings. Methods and Results—A new risk predictor, prevalent low-frequency oscillation (PLF), was determined in the placebo population of the European Myocardial Infarction Amiodarone Trial (EMIAT). Frequencies of peaks detected in 5-minute low-frequency HRV spectra were averaged to obtain the PLF index. PLF ≥0.1 Hz was the strongest univariate predictor of all-cause mortality associated with relative risk of 6.4 (95% CI, 3.9 to 10.6; P<10−12). In a multivariate Cox’s regression model including clinical risk factors, mean RR interval, HRV index, low- and high-frequency HRV spectral power, and heart rate turbulence, PLF was the most powerful mortality predictor, with a relative risk of 4.6 (95% CI, 2.2 to 9.3; P=0.00003). Predictive power of PLF was blindly validated in the population of the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) trial. PLF ≥0.1 Hz was associated with univariate relative risk of 6.1 (95% CI, 2.9 to 12.9; P<10−5) for cardiac mortality or resuscitated cardiac arrest. In multivariate Cox’s regression model including age, left ventricular ejection fraction, baroreflex sensitivity, mean RR interval, standard deviation of normal RR intervals, low- and high-frequency HRV spectral power, and heart rate turbulence, only left ventricular ejection fraction and PLF were significant predictors, with relative risks of 4.2 (95% CI, 1.5 to 11.7; P=0.007) and 3.6 (95% CI, 1.3 to 10.5; P=0.02), respectively. Conclusions—An innovative analysis of frequency-domain HRV, which characterizes the distribution of spectral power within the low-frequency band, is a potent and independent risk stratifier in postinfarction patients.

Comparison of the effects of atorvastatin or fenofibrate on nonlipid biochemical risk factors and the LDL particle size in subjects with combined hyperlipidemia

BACKGROUND Combined hyperlipidemia (CH) is an increasingly prevalent risk factor for premature heart disease, and its treatment is troublesome. The aim of this study was to compare the effects of atorvastatin and fenofibrate on nonlipid biochemical risk factors and the low-density lipoprotein (LDL) particle size in subjects with CH. METHODS Twenty-nine middle-aged men with CH were randomly assigned to open-label therapy with atorvastatin (10 mg daily) or micronized fenofibrate (200 mg daily); they were sequentially treated with both drugs, with crossover of medication after 10 weeks. RESULTS Atorvastatin was more efficient in the reduction of total cholesterol, whereas fenofibrate was more efficient in the reduction of triglycerides. Only atorvastatin led to a significant reduction of LDL cholesterol and apolipoprotein B. Only fenofibrate increased high-density lipoprotein cholesterol. Neither drug influenced lipoprotein(a). Mean LDL particle size increased both after fenofibrate (3.08%) and atorvastatin (1.77%). Fenofibrate increased serum homocysteine (HCY) by 36.5%. Atorvastatin had no effect on HCY. Only atorvastatin increased fibrinogen by 17.4%. Only fenofibrate reduced C-reactive protein by 51.7%. Neither drug influenced HOMA (homeostasis model assessment) index of insulin resistance. The plasma level of thiobarbituric acid reactive substances, an index of oxidative stress, decreased after both treatments. CONCLUSIONS Both atorvastatin and fenofibrate had similar beneficial effects on LDL particle size and on oxidative stress. The effects of both drugs on other parameters such as triglycerides, total and high-density lipoprotein cholesterol, fibrinogen, or HCY differed significantly. These differences, together with the risk profile of a patient, should be considered during selection of a particular lipid-lowering modality.

Effect of Atorvastatin and Fenofibrate on autonomic tone in subjects with combined hyperlipidemia

This randomized open-label trial investigated whether autonomic cardiovascular control is altered in middle-aged men with combined hyperlipidemia and whether such alterations are affected by short-term, lipid-lowering therapy with atorvastatin and/or fenofibrate. Compared with normolipidemic subjects, untreated subjects with combined hyperlipidemia had several abnormalities of autonomic tone, indicating increased sympathetic tone and decreased baroreflex sensitivity. The alterations in autonomic cardiovascular control were partially reversible by each of the lipid-lowering drugs.

Pulse wave analysis during supine rest may identify subjects with recurrent vasovagal syncope

In the present study, we studied whether analysis of the FAP (finger arterial pressure) waveform during supine rest discriminates subjects with recurrent VVS (vasovagal syncope) from healthy controls. Signal-averaged FAP waveforms (Finapres) were obtained in 32 head-up tilt-test-positive subjects with recurrent VVS (35 +/- 13 years) and in 32 sex- and age-matched healthy controls. The DT (time delay) between the systolic and diastolic peaks of the FAP waveform was measured and large artery SI (stiffness index) was calculated as a ratio of body height and DT. VVS patients had significantly shorter DT compared with controls (303 +/- 31 compared with 329 +/- 18 ms; P < 0.001) and higher SI (5.79 +/- 0.70 compared with 5.20 +/- 0.36 m/s; P < 0.001). The differences were independent of heart rate and blood pressure. SI > 5.45 m/s identified subjects with syncope with a sensitivity of 72% and a specificity of 84%. Age-corrected DT (cDT = DT + age-350) identified subjects with syncope with a sensitivity of 75% and a specificity of 84%. Combined use of cDT <0 ms and SI > 5.45 m/s increased sensitivity and specificity to 81% and 96% respectively. The discriminative power of FAP descriptors improved further when younger subjects were excluded. In subjects aged >30 years (median age), the combination of cDT and SI identified subjects with syncope with a sensitivity of 93% and a specificity of 100%. These results suggest that FAP descriptors during supine rest might be useful in the diagnosis of VVS in middle-aged subjects.

Predictive characteristics of holter-based postinfarction risk stratifiers appear superior to electrophysiological testing.

Prevalent low‐frequency (PLF) oscillation of heart rate and turbulence slope (TS) are both powerful postmyocardial infarction (MI) risk factors. Abnormal composite risk stratifier (CRS) was defined as abnormal PLF or abnormal TS when PLF was not analyzable. We compared the predictive power of CRS with the previously published predictive value of conventional electrophysiological (EP) testing based on the presence of nonsustained ventricular tachycardia (NSVT) and inducibility of sustained ventricular tachycardia/fibrillation (VT/VF) during programmed ventricular stimulation (PVS). PLF and TS were calculated from baseline Holter recordings in the placebo population of European Amiodarone Infarction Myocardial Infarction Trial (EMIAT trial) (n = 633; LVEF ≤ 40%; 87 deaths; 22‐month follow‐up). Previously established cut‐off values of PLF ≥ 0.1 Hz and TS ≤ 2.5 ms/RR were used. The clinical characteristics of the EMIAT population were similar to those of the Multicenter Unsustained Tachycardia Trial (MUSTT trial). Therefore, we compared the predictive power of CRS and conventional PVS using the values of 35% VT/VF inducibility during PVS in NSVT patients, and a 33% and 50% increase in all‐cause and arrhythmic mortality, respectively, associated with VT/VF inducibility in MUSTT. Projecting the predictive power of PVS in MUSTT into the EMIAT population yielded a sensitivity of 13.8% and 14.0% and positive predictive value (PPV) of 27.9% and 14.0% for all‐cause and arrhythmic mortality, respectively, whereas an abnormal CRS was associated with sensitivities of 46.0% and 46.5% and PPV of 37.4% and 18.7%. Compared with the noninvasive Holter‐based CRS, invasive PVS appears inferior in the identification of high‐risk post‐MI patients with left ventricular dysfunction.

Cross-spectral analysis of heart rate and blood pressure modulations.

The cross‐spectral analysis of heart rate (HR) and blood pressure (BP) variabilities provides “amplitude” and “phase” related measures. Compared to the amplitude measure, that is the baroreflex gain, the phase related measure characterizing the time lag between HR and BP oscillations has been studied to a much lesser extent. A population of 103 patients (73 men, 30 women, aged 53 ±12, range 20–82 years) referred for the management of coronary artery disease and/or hypertension were studied. In each subject, electrocardiogram and BP recordings were obtained in the supine and sitting positions of 5 minutes of rest (spontaneous respiration), 3 minutes of controlled respiration at 0.1 Hz (slow‐controlled respiration), and 3 minutes of controlled respiration at 0.33 Hz (fast‐controlled respiration). The frequency of maximum coherence (above the arbitrary threshold of 0.5) of BP and RR interval variabilities was searched between 0.033–0.133 Hz and 0.200–0.400 Hz to obtain baroreflex gain and phase shift in low and high frequency bands, respectively. Mean phase shifts of ‐79.1 and ‐67.0 degrees (‐2.4 and ‐2.1 s) were found during slow‐controlled respiration in the supine and sitting body positions, respectively. The mean phase shift between systolic BP and RR interval in the low frequency band was found between 83 and ‐109 degrees for body positions and respiration regimes. The actual baroreflex related time lag between systolic BP and RR variations was found between 3.5 and 5.1 seconds. The study concludes that the appropriate, and not always easy, selection of the frequency of maximum coherence between BP and HR oscillation is crucial for an accurate cross‐spectral assessment of baroreflex sensitivity.

Nitroglycerin induced syncope occurs in subjects with delayed phase shift of baroreflex action.

MELENOVSKY, V., et al.: Nitroglycerin Induced Syncope Occurs in Subjects with Delayed Phase Shift of Baroreflex Action. Nitroglycerin (NTG) administration occasionally leads to syncope due to severe hypotension and bradycardia. This reaction resembles neurocardiogenic syncope but it may occur when the patient is in the supine position. To address the possible role of prevailing autonomic tone and baroreflex control in precipitation of NTG induced syncope, continuous noninvasive blood pressure and an ECG were taken shortly before NTG application in the supine position. Frequency‐domain measures of heart rate variability (HRV) and noninvasive indices of baroreflex were compared between subjects who did (n = 6) and did not (n = 41) develop syncope after NTG. Both groups differed only in the phase shift (PCR) between oscillations of blood pressure and heart rate during controlled respiration (0.1 Hz). PCR was significantly delayed in subjects who developed syncope than in controls (−99.3 ± 14.1 vs −65.5 ± 27.0 degrees, P = 0.002). Thus, subjects with prolonged PCR are prone to NTG induced syncope because of increased lagging and, consequently, less stable baroreflex control.

Von Willebrand factor and assessment of endothelial function

We thank Prof. Lip et al. for their comments, which focused on the reproducibility of methods used for the assessment of endothelial function. It has been shown in our paper that flow mediated dilatation (FMD) has considerably worse reproducibility than peak blood flow (PBF). This observation is in contradiction to the widespread opinion that FMD is generally a reproducible technique, suitable even for an individual risk assessment [1]. Poor reproducibility of FMD observed in our study was not due to high intra- and interobserver variability—only one observer saw the video-records and the intra-observer bias expressed as the coefficient of variation of the diameter calculation was low (0.87%). Thus we concluded that FMD has high spontaneous intra-individual variability. This fact should be taken into account if similar studies are designed in future. This conclusion is further supported by the fact that normal values of FMD …