Does ageing originate in utero?

Ageing still remains a conundrum on the cellular and molecular level, while environmental factors and interactions further increase the complexity of the ageing process. On the other hand is cancer, for which 20 years ago, it was proposed by Trichopoulos that it might have intrauterine origin. We herein discuss the idea that parameters such as the influence of insulin-like growth factor (IGF) signalling, of hormones and of the number of stem cells, as well as the effect of foetal and early life nutrition on ageing may also commence in utero and we provide epidemiological and biological data to advocate for this hypothesis. Finally, we analyse the public health implication of this hypothesis based on the World Health Organization (WHO) report that the burden of diseases, including ageing, may be due to impaired foetal development.     

Inflammatory mediators in the elderly

Ageing is accompanied by 2-4-fold increases in plasma/serum levels of inflammatory mediators such as cytokines and acute phase proteins. A wide range of factors seems to contribute to this low-grade inflammation, including an increased amount of fat tissue, decreased production of sex steroids, smoking, subclinical infections (e.g. asymptomatic bacteriuria), and chronic disorders such as cardiovascular diseases and Alzheimer's disease. Furthermore, there is some evidence that ageing is associated with a dysregulated cytokine response following stimulation. Several inflammatory mediators such as tumour necrosis factor-alpha and interleukin-6 have the potential to induce/aggravate risk factors in age-associated pathology, providing a positive feedback mechanism. Thus, it is possible that inflammatory mediators constitute a link between life style factors, infections and physiological changes in the process of ageing on the one hand and risk factors for age-associated diseases on the other. Consistent with this, inflammatory mediators are strong predictors of mortality independently of other known risk factors and co-morbidity in elderly cohorts. A direct pathogenetic role of inflammatory mediators would be highly likely if longevity was shown to be associated with cytokine polymorphisms regulating cytokine production. Several studies support indeed this hypothesis but, unfortunately, findings in this area are conflicting, which probably reflects the complexity of the effect of cytokine polymorphisms and their interaction with the lifestyle and sex.     

Time-Domain Evaluation of Cyclosporine Interaction with Hemodynamic Variability in Rats

Summary This study investigated the effects of chronic exposure of Wistar rats to the immunosuppressant drug cyclosporine on blood pressure, heart rate, and their variability and the role of sympathovagal balance in this interaction. The blood pressure variability was determined as the standard deviation of the mean arterial pressure (SDMAP). Two time-domain heart rate variability indices were employed, the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive beat-to-beat differences in R-R interval durations (rMSSD). Subcutaneous cyclosporine administration (20 mg/kg/day) for 12 days had no effect on blood pressure or its variability index (SDMAP). In contrast, the average level of heart rate and its variability indices (SDRR and rMSSD) showed significant increases and decreases, respectively, in cyclosporine- compared with vehicle-treated rats. Vagal (atropine) or -adrenergic (propranolol) blockade had no effect on blood pressure but elicited increases and decreases, respectively, in heart rate. Compared with control rats, cyclosporine-treated rats exhibited lesser tachycardic responses to atropine and greater bradycardic responses to propranolol, suggesting alterations of cardiac vagal (attenuation) and sympathetic (enhancement) activity by cyclosporine. Further, atropine reduced indices of heart rate variability (rMSSD and SDRR) in control rats, effects that were blunted by cyclosporine treatment. On the other hand, propranolol had no effect on heart rate variability in either cyclosporine-treated or control rats. These findings implicate vagally-mediated alterations in the cardiac sympathovagal balance in the cyclosporine-induced impairment of heart rate oscillations.     

Decreased heart rate variability and its association with increased mortality after acute myocardial infarction

A high degree of heart rate (HR) variability is found in compensated hearts with good function, whereas HR variability can be decreased with severe coronary artery disease, congestive heart failure, aging and diabetic neuropathy. To test the hypothesis that HR variability is a predictor of long-term survival after acute myocardial infarction (AMI), the Holter tapes of 808 patients who survived AMI were analyzed. Heart rate variability was defined as the standard deviation of all normal RR intervals in a 24-hour continuous electrocardiogram recording made 11 +/- 3 days after AMI. In all patients demographic, clinical and laboratory variables were measured at baseline. Mean follow-up time was 31 months. Of all Holter variables measured, HR variability had the strongest univariate correlation with mortality. The relative risk of mortality was 5.3 times higher in the group with HR variability of less than 50 ms than the group with HR variability of more than 100 ms. HR variability remained a significant predictor of mortality after adjusting for clinical, demographic, other Holter features and ejection fraction. A hypothesis to explain this finding is that decreased HR variability correlates with increased sympathetic or decreased vagal tone, which may predispose to ventricular fibrillation.     

Autonomic imbalance during the day in patients with inflammatory bowel disease in remission. Evidence from spectral analysis of heart rate variability over 24 hours

BACKGROUND: Autonomic function in inflammatory bowel disease has not yet been studied by means of analysis of 24-hour heart rate variability. AIM: To measure heart rate variability in inflammatory bowel disease patients in remission. PATIENTS AND METHODS: Study population comprised 27 patients with inflammatory bowel disease in remission and 28 healthy, sex- and age-matched controls. Two frequency ranges were analysed: low frequency (0.06-0.15 Hz) and high frequency (0.15-0.40 Hz). RESULTS: Mean values of low frequency and low frequency/high frequency ratio were lower in patients than in controls (p < 0.001). High frequency in patients tended to be higher than in controls (p = 0.09). The only factor that had a marginal effect on heart rate variability indexes was age. In high frequency, there was a significant time effect (p = 0.001) for both groups. There was also a significant time effect in low frequency/high frequency ratio in both groups (p < 0.001). During daytime, the mean values in low frequency/high frequency ratio were lower in patients than in controls (p < 0.001). CONCLUSIONS: There is a shift in the autonomic balance in patients with inflammatory bowel disease in remission towards a condition of relative parasympathetic predominance, which, in the first place, reflects a sympathetic pullback. This imbalance has a circadian rhythm and it is more pronounced during the day.     

Epidemiology of heart failure

The heart failure syndrome has first been described as an emerging epidemic about 25 years ago. Today, because of a growing and ageing population, the total number of heart failure patients still continues to rise. However, the case mix of heart failure seems to be evolving. Incidence has stabilized and may even be decreasing in some populations, but alarming opposite trends have been observed in the relatively young, possibly related to an increase in obesity. In addition, a clear transition towards heart failure with a preserved ejection fraction has occurred. Although this transition is partially artificial, due to improved recognition of heart failure as a disorder affecting the entire left ventricular ejection fraction spectrum, links can be made with the growing burden of obesity‐related diseases and with the ageing of the population. Similarly, evidence suggests that the number of patients with heart failure may be on the rise in low‐income countries struggling under the double burden of communicable diseases and conditions associated with a Western‐type lifestyle. These findings, together with the observation that the mortality rate of heart failure is declining less rapidly than previously, indicate we have not reached the end of the epidemic yet. In this review, the evolving epidemiology of heart failure is put into perspective, to discern major trends and project future directions.     

Relation of mean heart rate and heart rate variability in patients with left ventricular dysfunction.

The new finding was that mean heart rate and heart rate variability were more closely coupled in patients with more advanced LV dysfunction. Mean heart rate explained a larger portion of variance in heart rate variability in patients in the lowest LVEF quartile than in those in the highest one. These results support our hypothesis that sympathetic activation in patients with more severe LV dysfunction results in closer correlation between heart rate and heart rate variability. Generally, the correlation between mean heart rate and heart rate variability is weak because heart rate and heart rate variability represent different modalities of cardiovascular regulation. Mean heart rate is normally determined by the interactions of both the sympathetic and parasympathetic nervous systems, whereas modulation of these activities, with different gains, determines the magnitude of heart rate variability. This results in great complexity in control of the heart by the autonomic nervous system. However, heart rate is likely to be more dominantly regulated by the sympathetic nervous system because of vagal withdrawal in patients with more severe LV dysfunction. The effect of sympathetic cardiac modulation has been shown to be more sluggish than that of the parasympathetic nervous system in beat-to-beat regulation of heart rate. This may result in more blunted heart rate variability concomitantly with elevated mean heart rate. Thus, variation in heart rate variability in any given mean heart rate is likely to be lower than in patients with more preserved LV function, and hence with more complex cardiac autonomic regulation with involvement of the parasympathetic nervous system. Indeed, even the slopes of regression lines between mean heart rate and heart rate variability were similar in the first and fourth LVEF quartile; the intercept of the regression line was significantly higher in the fourth quartile than in the first one. This further supports our hypothesis.     

Cardiac-directed expression of adenylyl cyclase and heart rate regulation

Abstract. Mice with cardiac-directed overexpression of AC_VI show increased cardiac responsiveness to -adrenergic receptor stimulation but regulation of heart rate is unknown. Telemetry was used to test the hypothesis that mice overexpressing cardiac adenylyl cyclase type VI (AC_VI) would have normal heart rate regulation. Mice overexpressing cardiac AC_VI were generated using the MHC promoter and studied 10 days after implantation of telemetry devices. Cardiac transgene AC_VI presence and expression was verified using PCR, RT-PCR and immunoblotting. Ambulatory heart rates were assessed using time and frequency domain analysis over two 24 hour light-dark cycles. Heart rates then were assessed following pharmacological blockade. Time domain analyses showed ambulatory heart rates were unchanged (AC_VI: 597 ± 15 (SEM) bpm, Control: 595 ± 12 bpm; p = 0.92). Circadian heart rate variability was preserved and not different from control mice (ANOVA, p = 0.52). Frequency domain analysis of heart rate variability also was unchanged. No difference in heart rate response to pharmacological autonomic blockade was found (intrinsic heart rate: AC_VI 622 ± 17 bpm, control 616 ± 16 bpm, p = 0.79). In conclusion, mice overexpressing cardiac AC_VI have normal conscious ambulatory heart rates and normal heart rate variability. Overexpression of cardiac AC_VI does not result in altered heart rate regulation in contrast to cardiac overexpression of other elements of the -adrenergic signaling pathway.This work was supported by Merit Awards (DMR) and (HKH) from the Department of Veterans Affairs, NIH 2P50 HL53773-06 (HKH), and NIH 1P01 HL66941-01A1 (HKH, DMR).     

Hemodynamics and exercise capacity during pacemaker stimulation

This review summarizes the present knowledge concerning the hemodynamic and myocardial effects of various pacing modalities with special reference to the importance of heart rate variability and atrioventricular synchronization. An adequate increase in heart rate, irrespective of atrioventricular synchronization, seems to be the most important denominator for cardiac output and exercise tolerance. Atrioventricular synchronization will add some hemodynamic benefit, which is most pronounced at rest. The importance of a rate-adaptive atrioventricular delay and a normalized ventricular activation sequence remains, however, to be fully established. Myocardial oxygen consumption does not differ during fixed rate ventricular pacing, atrial synchronous or non-synchronous rate-adaptive ventricular pacing, neither at rest nor during exercise, despite a higher cardiac output during the rate-adaptive modes. This indicates a more "economic" cardiac work with rate-adaptive pacing. Fixed rate ventricular pacing, on the other hand, may have negative long-term effects on myocardial function due to an increased cardiac sympathetic activity compared with rate-adaptive ventricular pacing, in particular during exercise. It is concluded that the majority of pacemaker-dependent patients will benefit from restored rate variability, with the atrial electrogram still being the most appropriate trigger for rate-adaptive ventricular pacing. When the atrial signal cannot be used or when it is unreliable, however, other rate-triggering signals can be used with comparable results regarding hemodynamics and exercise tolerance.     

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

A large variability in occurrence, complications, and age/gender manifestations characterizes individual susceptibility of sporadic thoracic aortic aneurysms (TAA), even in subjects with the same risk factor profiles. The reasons are poorly understood. On the other hand, TAA pathophysiology mechanisms remain unclear than those involved in abdominal aorta aneurysms. However, recent evidence is suggesting a crucial role of biological ageing in inter-individual risk variation of cardiovascular diseases, including sporadic TAA. Biological age rather than chronological age is a better predictor of vascular risk. Relevant assumptions support this concept. In confirming this evidence and our preliminary data, the mean of blood leukocyte telomere length, through use of terminal restriction fragment assay and in blood samples from sporadic TAA patients and controls, was examined. Telomerase activity was also analyzed in two groups. In addition, we verified the weight of genetic inflammatory variants and the major TAA risk factors in telomere/telomerase impairment. Aorta histopathological abnormalities and systemic inflammatory mediators were ultimately correlated with telomere/telomerase impairment. Data obtained demonstrated shorter telomeres and a reduced telomerase activity in TAA patients significantly associated with a genetic inflammatory risk profile, age, gender, smoking, hypertension, a histopathological phenotype, and higher levels of systemic inflammatory mediators than controls. In conclusion, telomere and telomerase activity’s detection might be used as predictor biomarkers of sporadic TAA. Their impairment also suggests a strong role of vascular ageing in sporadic TAA, evocated by both environmental and genetic inflammatory factors.     

Autonomic response to standardized stress predicts subsequent disease activity in ulcerative colitis

OBJECTIVES: Prospective studies of the role of psychological stress in ulcerative colitis are inconsistent or show a modest relationship. We tested the hypothesis that individual differences in autonomic function are associated with differences in the disease course of ulcerative colitis. METHODS: The spectral power of heart rate variability, an indirect marker of autonomic function, was measured during a standardized stress protocol in 93 ulcerative colitis patients. Patients were categorized as typical or atypical by an increase or decrease, respectively, in the high frequency band of heart rate variability from a period of acute stress to recovery 5 min later. Disease activity was measured at baseline (time 1) and a second time point (time 2) 7-37 months later. RESULTS: An atypical pattern of heart rate variability at time 1, present in 29% of patients, was associated with lower mean disease activity at time 2 (atypical, 0.56+/-0.93; typical, 2.27+/-2.56, P=0.001). The contribution of heart rate variability pattern to explaining time 2 disease activity was independent of the contributions of other factors that differed between groups, including time 1 disease activity and lifetime corticosteroid use. DISCUSSION: An atypical pattern of autonomic reactivity may be a marker of individual differences in stress regulation that has prognostic significance in ulcerative colitis.     

Effect of Graded Increases in Parasympathetic Tone on Heart Rate Variability

Parasympathetic Effects on Heart Rate Variability. Introduction : Time- and frequency-domain measurements of heart rate variability have been used as indices of parasympathetic tone. However, studies of the effect of parasympathetic stimulation on these indices in humans have yielded conflicting results.
Methods and Results : This study evaluated the effects of parasympathetic stimulation on heart rate variability. Twelve normal subjects (7 males, 5 females; age 24.8 ± 3.4 years) were evaluated in the Clinical Research Center. Five-minute ECG recordings were obtained at baseline and during graded phenylephrine infusions (0.3 and 0.6 μg/kg per min). Recordings were made during spontaneous respiration and when breathing was timed with a metronome at 15 cycles/min. Heart rate variability analysis was performed using standard time- and frequency-domain parameters. Graded phenylephrine infusion resulted in a progressive increase in blood pressure and RR interval but no consistent changes in heart rate variability for the group. The results during normal versus metronome breathing were similar. Stepwise linear regression analysis revealed that the phenylephrine-induced changes in heart rate variability were inversely correlated with the baseline heart rate variability and not related to the baseline KR interval or the phenylephrine-induced change in RR interval.
Conclusion : These findings suggest that the respiratory variation in "parasympathetic effect" typically observed at the sinus node can be either increased or decreased by parasympathetic stimulation, depending on the initial level of parasympathetic tone and the intensity of stimulation. This resolves the previously conflicting data. Thus, evaluation of parasympathetic tone using heart rate variability techniques should be cautiously undertaken.     

Are the leukocyte telomere length attrition and telomerase activity alteration potential predictor biomarkers for sporadic TAA in aged individuals?

A large variability in occurrence, complications, and age/gender manifestations characterizes individual susceptibility of sporadic thoracic aortic aneurysms (TAA), even in subjects with the same risk factor profiles. The reasons are poorly understood. On the other hand, TAA pathophysiology mechanisms remain unclear than those involved in abdominal aorta aneurysms. However, recent evidence is suggesting a crucial role of biological ageing in inter-individual risk variation of cardiovascular diseases, including sporadic TAA. Biological age rather than chronological age is a better predictor of vascular risk. Relevant assumptions support this concept. In confirming this evidence and our preliminary data, the mean of blood leukocyte telomere length, through use of terminal restriction fragment assay and in blood samples from sporadic TAA patients and controls, was examined. Telomerase activity was also analyzed in two groups. In addition, we verified the weight of genetic inflammatory variants and the major TAA risk factors in telomere/telomerase impairment. Aorta histopathological abnormalities and systemic inflammatory mediators were ultimately correlated with telomere/telomerase impairment. Data obtained demonstrated shorter telomeres and a reduced telomerase activity in TAA patients significantly associated with a genetic inflammatory risk profile, age, gender, smoking, hypertension, a histopathological phenotype, and higher levels of systemic inflammatory mediators than controls. In conclusion, telomere and telomerase activity’s detection might be used as predictor biomarkers of sporadic TAA. Their impairment also suggests a strong role of vascular ageing in sporadic TAA, evocated by both environmental and genetic inflammatory factors.     

Vagus block in the therapy of bradycardial arrhythmias--the role of autonomic balance

A medicamentous therapy of bradycardiac disturbances of heart rhythm can be performed on the one hand by stimulation of the sympathetic nerve, on the other hand by blockade of the parasympathetic system. An ester of the tropic acid, Ipratropiumbromide (IP), shall be used for answering the question to what extent the heart rate may be increased in such arrhythmias. In 10 patients (4 females and 6 males, m 60 +/- 9 years old) with asymptomatic bradycardiac arrhythmias (heart rate less than 60 per min in the routine ECG; 3 patients AV-block III, 1 patient AV-block II II, 6 patients sinus bradycardia) at first a 24-hour long-term ECG was recorded under ambulatory conditions, after this 1 mg IP was administered intravenously under continuous long-term ECG. After 4 days 10 mg IP orally thrice a day, in 3 patients also after 15 mg IP t.i.d. a repeated long-term ECG was performed. These were evaluated using the computer-assisted "multipass scanning" system. Results: 1 hour after 1 mg IP intravenously the m heart rate significantly increased about 17-87% (m 55%) in all patients (p less than 0.001). Proportionally to the increase of the heart rate it lasted 7-14 hrs. till the initial heart rate was reached again. 1-4 hours after intravenous injection in 2 patients sinus tachycardias developed as an expression of an increased sympathicotonia. 10 mg IP led to an increase of the heart rate of m 8% of the patients, during the day m 9%, during the night 4%.(ABSTRACT TRUNCATED AT 250 WORDS)     

The normal range and determinants of the intrinsic heart rate in man

Jose and Collison published a study on the normal range and the determinants of intrinsic heart rate in man in Cardiovascular Research in 1970 [Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970; 4: 160-167)]. The intrinsic heart rate is the heart rate under complete pharmacological blockade. They showed that (i) the resting heart rate is lower than the intrinsic heart rate and that (ii) the intrinsic heart rate declines with age. They also established that the variability in intrinsic heart rate between individuals of the same age is of the same order as the effect of ageing at the population level. This update discusses the relevance of these data with emphasis on sinus node function and autonomic balance. The paper of Jose and Collison was cited more than 200 times. The frequency of citation started to increase more than 10 years after publication.     

Dual-Source Computed Tomographic Coronary Angiography: Image Quality and Stenosis Diagnosis in Patients with High Heart Rates

We sought to evaluate prospectively the effects of heart rate and heart-rate variability on dual-source computed tomographic coronary image quality in patients whose heart rates were high, and to determine retrospectively the accuracy of dual-source computed tomographic diagnosis of coronary artery stenosis in the same patients.We compared image quality and diagnostic accuracy in 40 patients whose heart rates exceeded 70 beats/min with the same data in 40 patients whose heart rates were 70 beats/min or slower. In both groups, we analyzed 1,133 coronary arterial segments. Five hundred forty-five segments (97.7%) in low-heart-rate patients and 539 segments (93.7%) in high-heart-rate patients were of diagnostic image quality. We considered P < 0.05 to be statistically significant. No statistically significant differences between the groups were found in diagnostic-image quality scores of total segments or of any coronary artery, nor were any significant differences found between the groups in the accurate diagnosis of angiographically significant stenosis.Calcification was the chief factor that affected diagnostic accuracy. In high-heart-rate patients, heart-rate variability was significantly related to the diagnostic image quality of all segments (P = 0.001) and of the left circumflex coronary artery (P = 0.016). Heart-rate variability of more than 5 beats/min most strongly contributed to an inability to evaluate segments in both groups. When heart rates rose, the optimal reconstruction window shifted from diastole to systole.The image quality of dual-source computed tomographic coronary angiography at high heart rates enables sufficient diagnosis of stenosis, although variability of heart rates significantly deteriorates image quality.Key words: Artifacts, coronary angiography/methods, coronary stenosis/diagnosis/radiography, diastole/physiology, heart rate/physiology, image processing, computer-assisted, prospective studies, radiographic image interpretation, computer-assisted, sensitivity and specificity, systole/physiology, technology assessment, biomedical, tomography, spiral computed/instrumentation/methods/standardsDuring the past few years, noninvasive coronary angiography upon multidetector-row computed tomography (MDCT) has rapidly progressed and has shown promise with regard to the detection and quantification of coronary artery stenosis.^1–4 However, despite the increase in temporal resolution from 16- to 64-detector-row computed tomography (CT), coronary CT angiography remains sensitive to motion artifacts, which occur especially at higher heart rates.^2,5–7 Results of a study³ of 64-detector-row CT coronary angiography showed a nonsignificant tendency toward lower image quality at higher mean heart rates, and a significant negative relation between image quality and heart-rate variability. In order to reduce motion artifacts, it has been proposed that patients be administered oral β-blocker medication for heart-rate control, even when 64-detector-row CT is to be used.^8–11 In most studies that have involved 16- or 64-detector-row CT, the target for scanning has been maintained at heart rates slower than 70 or even 60 beats/min, so that good-quality images of coronary arteries could be obtained. The requirement to premedicate patients with β-blocker drugs in order to achieve a sufficiently low heart rate for scanning has been considered a major limitation surrounding the clinical use of MDCT coronary angiography.Dual-source CT (DSCT) coronary angiography incorporates 2 X-ray tubes and 2 detectors that are mounted onto a rotating gantry, with an angular offset of 90°.¹² The DSCT system affords a high temporal resolution of 83 ms in monosegment reconstruction mode. In contrast with single-source CT systems that rely on multisegment reconstruction techniques, temporal resolution upon DSCT is independent of heart rate. Initial studies have shown that DSCT enables the study of coronary arteries with excellent diagnostic quality in all patients, independent of heart rate—thus obviating the need to premedicate patients with β-blockers.^12–15 We believed that the effects of heart rate and heart-rate variability on image quality, diagnostic accuracy, and optimal reconstruction windows merited further evaluation in patients whose heart rates exceeded 70 beats/min.The aim of this study was to evaluate prospectively the effect of heart rate and heart-rate variability on DSCT image quality in patients who had high heart rates, and to determine retrospectively the accuracy of DSCT in the diagnosis of coronary artery stenosis, using invasive coronary angiography as the reference standard.     

Decreased beating rate variability of spontaneously contracting cardiomyocytes after co-incubation with endotoxin

Decreased heart rate variability (HRV) in critically ill patients indicates a poor prognosis. In heart failure patients, there is an elevated sympathetic tone, reflected by a dominance of sympathetic parameters in HRV, whereas in critically ill patients sympathetic and parasympathetic modulation of heart rate is attenuated despite increased catecholamine blood levels. Thus, autonomic dysfunction in the critically ill cannot be causally related to an impairment at the level of neural transmission, but may be due to a derangement of signal transduction at the effector cell level. On the basis of our working hypothesis that endotoxin may be involved in this blunting of effector cell response to nerval input, we studied the spontaneous beating of cardiomyocytes under the influence of endotoxin. Applying the clinically established indices of HRV to the analysis of beating rate variability (BRV) of neonatal rat cardiomyocytes in serum-free medium, a narrowing of their BRV by endotoxin is demonstrated. We propose that the narrowing of HRV in critically ill patients does not only reflect the altered input from the central or peripheral neurons, but rather a remodeling of the cardiac pacemaker cells by endotoxin and inflammatory mediators.     

Effect of mibefradil on heart rate variability in patients with chronic heart failure

BACKGROUND: Mibefradil was recently withdrawn from the market because of an unfavorable clinical profile in patients with chronic heart failure. Although drug interactions appear to play a role, other mechanisms such as proarrhythmia and autonomic deterioration could also be relevant. Chronic heart failure is accompanied by autonomic impairment and analysis of heart rate variability can be used to examine autonomic modulation of heart rate. METHODS: We studied 18 heart failure patients (age 63.2+/-10.1 years (mean+/-S.D. ), ejection fraction 0.21+/-0.07) treated with mibefradil or placebo, who participated in the MACH-I (Mortality Assessment in Chronic Heart failure) trial in our center, and compared them with 18 healthy matched controls. Heart rate variability analysis was performed at baseline and after 7 months of treatment. RESULTS: At baseline, heart rate variability parameters were impaired in patients with heart failure compared to healthy controls (P<0.05). After 7 months of treatment a reduction in (24-h) heart rate was observed (P=0.02, versus placebo). Apart from the effect on mean NN, no significant differences were observed for the remaining heart rate variability parameters. CONCLUSIONS: Mibefradil does not impair autonomic balance and in fact reduces heart rate in patients with heart failure. These findings suggest that autonomic activation did not contribute to the adverse effects of mibefradil.     

Poor reproducibility of parameters of heart rate variations]

The analysis of heart rate variability is supposed to be a marker of autonomic cardiac activity and is used for risk stratification of post-infarction patients. Analysis of heart rate variability in the frequency domain may permit a differentiation of vagal and sympathetic control; for such analyses only short time intervals characterized by a steady-state autonomic balance can be used. Yet, it is unclear whether single determinations of heart rate variability indices derived from short time intervals yield reproducible results. Therefore, the reproducibility of heart rate variability indices was studied with weekly measurements in 10 healthy volunteers under the following defined conditions: 13 min supine rest, 10 min standing, 13 min sitting, and 15 min cycle ergometry followed by a 14 min recovery period. Heart rate variability was determined in the frequency domain (fast Fourier transformation) and in the time domain. The reproducibility was estimated by the coefficient of variation (CV). Additionally, the reproducibility of heart rate, blood pressure, and the expiratory-inspiratory ratio of heart rate was determined. The reproducibility of the frequency domain indices (36.6-74.9% CV) and of the time domain indices (19.6-32.8% CV) was considerably worse than that of heart rate (5.2-8.2% CV), blood pressure (5.1-8.2% CV) and the expiratory-inspiratory ratio of heart rate (4.6% CV). The reproducibility of heart rate variability indices was not improved by orthostatic or ergometric challenge. This poor reproducibility does not permit a reliable interpretation of heart rate variability on the basis of single measurements in healthy volunteers. Given the wide range and scatter of the measured parameters, the diagnostic and prognostic value of heart rate variability indices derived from short recording periods appears questionable.     

Effect of Flecainide on Heart Rate Variability in Subjects Without Coronary Artery Disease or Congestive Heart Failure

Heart rate variability is a noninvasive indicator of autonomic nervous system activity. The role of the autonomic nervous system in the genesis of atrial or ventricular arrhythmias is now well established. Little is known about the effects of flecainide on heart rate variability in patients with normal heart structure, the main population receiving flecainide. This study was designed to evaluate the effects of flecainide on heart rate variability in patients without coronary artery disease or congestive heart failure. Time and frequency domain analysis of heart rate variability on 24-hour electrocardiogram recording were assessed in 40 patients with normal echocardiography and without evidence of coronary artery disease before and after 2 months of oral treatment with flecainide (321 ± 57 mg/day) prescribed for Wolff Parkinson White syndrome with circus movement tachycardia. Flecainide significantly decreased all parameters of heart rate variability in the time domain (median % –10% to –25%) and in the frequency domain (median % –27% to –38%), including the markers of vagal activity. There was no correlation between plasma concentrations of flecainide and reduction in heart rate variability. It was concluded that in subjects without coronary artery disease or congestive heart failure, flecainide decreases all the measurements of heart rate variability and this decrease is not related to plasma concentrations of flecainide.