Arie M. van Roon

The utility of low frequency heart rate variability as an index of sympathetic cardiac tone: A review with emphasis on a reanalysis of previous studies

This article evaluates the suitability of low frequency (LF) heart rate variability (HRV) as an index of sympathetic cardiac control and the LF/high frequency (HF) ratio as an index of autonomic balance. It includes a comprehensive literature review and a reanalysis of some previous studies on autonomic cardiovascular regulation. The following sources of evidence are addressed: effects of manipulations affecting sympathetic and vagal activity on HRV, predictions of group differences in cardiac autonomic regulation from HRV, relationships between HRV and other cardiac parameters, and the theoretical and mathematical bases of the concept of autonomic balance. Available data challenge the interpretation of the LF and LF/HF ratio as indices of sympathetic cardiac control and autonomic balance, respectively, and suggest that the HRV power spectrum, including its LF component, is mainly determined by the parasympathetic system.

Acute Chemotherapy-Induced Cardiovascular Changes in Patients With Testicular Cancer

PURPOSE After cisplatin- and bleomycin-containing chemotherapy for testicular cancer, part of the patient population will develop acute or long-term cardiovascular toxicity. It is largely unknown whether standard tests can be used to assess chemotherapy-induced cardiovascular changes. PATIENTS AND METHODS In 65 testicular cancer patients (median age, 27 years; range, 18 to 48 years), we measured the following cardiovascular parameters before and within 10 weeks after completion of cisplatin-based chemotherapy: platelet numbers, plasma levels of hemostatic and fibrinolytic factors, 24-hour ambulatory blood pressure, baroreflex sensitivity, intima-media thickness of the common carotid artery, and flow-mediated vasodilation of the brachial artery. RESULTS Compared with prechemotherapy values, the intima-media thickness of the carotid artery and plasma von Willebrand factor levels increased significantly after treatment. Platelet numbers and plasma levels of other hemostatic and fibrinolytic factors did not appear to change significantly. Blood pressure decreased significantly, but flow-mediated vasodilation and baroreflex sensitivity did not change. CONCLUSION In testicular cancer patients treated with cisplatin-based chemotherapy, we found an increase in plasma von Willebrand factor levels and in the intima-media thickness of the carotid artery. These changes may indicate chemotherapy-induced vascular damage and be of prognostic significance for the development of cardiovascular complications in the long term.

Influence of respiratory activity on the cardiac response pattern to mental effort

A group of 32 healthy adult volunteers completed three blocks of a reaction time task that varied in the degree of controlled processing load. A rest period preceded each of the task blocks. The task blocks were presented in the order of either increasing or decreasing cognitive load. For each of the six periods, mean values and spectral measures of heart rate and respiration variability were calculated. The spectral measures were obtained for three different frequency bands. Differences between the cardiac measures of the task and preceding rest periods were compared with respect to differences in task load and the order of task presentation. All comparisons were carried out while adjusting for respiratory variability in the corresponding frequency band. The frequency band in which task load-related changes in heart rate variability became manifest appeared to be dependent on the individuals breathing pattern.

The effects of dihydropyridine and phenylalkylamine calcium antagonist classes on autonomic function in hypertension: The VAMPHYRE Study*

The aim of the present study was to compare the effects of a long-acting dihydropyridine (amlodipine) and a nondihydropyridine (verapamil) on autonomic function in patients with mild to moderate hypertension. A total of 145 patients with a diastolic blood pressure (BP) between 95 and 110 mm Hg received 8 weeks of verapamil sustained release (240 mg) and amlodipine (5 mg) in a prospective randomized, double blind, cross-over study, both after 4 weeks of placebo. The 24-h autonomic balance was measured by analysis of 24-h heart rate variability and short-term autonomic control of BP by baroreflex sensitivity measurements. Plasma norepinephrine was sampled at rest. Blood pressure was equally reduced from 153/100 mm Hg to 139/91 mm Hg with verapamil and 138/91 mm Hg with amlodipine, P = .50/.59. The low- to high-frequency ratio (LF/HF), reflecting sympathovagal balance, was higher with amlodipine than with verapamil (4.66 v 4.10; P = .001). Baroreflex function was improved by both treatments; however, baroreflex sensitivity (BRS) was significantly higher with verapamil than with amlodipine (8.47 v 8.06 msec/mm Hg; P = .01). Plasma norepinephrine (NE) level was higher with amlodipine than with verapamil (1.59 v 1.32 nmol/L; P < .0001). Amlodipine induces a shift in sympathovagal balance, as measured by heart rate variability indices and plasma NE, toward sympathetic predominance compared with vagal predominance with verapamil. Short-term autonomic control of BP, as assessed by BRS, is more effectively improved by verapamil than by amlodipine. These contrasting effects on autonomic function suggest that the nondihydropyridine calcium antagonist verapamil may have additional beneficial effects beyond lowering BP compared with the dihydropyridine amlodipine.

Stressed out? Associations between perceived and physiological stress responses in adolescents : The TRAILS study

Studies regarding the interrelation of perceived and physiological stress indices have shown diverging results. Using a population sample of adolescents (N=715, 50.9% girls, mean age 16.11 years, SD=0.59), we tested three hypotheses: (1) perceived responses during social stress covary with concurrent physiological stress responses; (2) high pretest levels of perceived stress predict large physiological responses; and (3) large physiological responses to social stress predict low posttest perceived stress levels. Perceived arousal, unpleasantness, and dominance were related to heart rate, respiratory sinus arrhythmia, and cortisol responses to a laboratory social stress test. Although effect sizes were small, the results suggest covariation of perceived stress and concurrent physiological stress responses in both the ANS and the HPA axis, as well as inverse associations between heart rate responsiveness and the subsequent appraisal of stress.

Longitudinal study on premature atherosclerosis in patients with systemic lupus erythematosus

OBJECTIVES To determine risk factors of accelerated atherosclerosis and progression of intima-media thickness (IMT) in patients with systemic lupus erythematosus (SLE). METHODS 74 SLE patients, age ranging from 13 to 69 years, and 74 age- and sex-matched controls were included. IMT of the common carotid artery was determined by B-mode ultrasound imaging. Traditional risk factors for atherosclerosis and disease-related factors were recorded. Cardiovascular risk was estimated using systematic coronary risk evaluation (SCORE). Markers of inflammation (C-reactive protein, CRP) and endothelial activation (thrombomodulin, vascular cell adhesion molecule-1, and von Willebrand factor) were determined. Measurements were repeated in 52 patients after a follow-up of 32+/-7 months. RESULTS IMT was increased in SLE patients compared to controls. Prevalence of smoking and hypertension, use of lipid-lowering drugs and SCORE were higher in patients, as well as levels of CRP and markers of endothelial activation. The age-related increase in IMT was significantly higher in patients than in controls. In multivariate analysis, age and disease duration was independently related to IMT. Increase in IMT during follow-up was related to age only. CONCLUSION The age-related increase in IMT is higher in SLE, indicating that atherosclerosis is accelerated in SLE patients. This is mainly due to disease-related risk factors, as disease duration was independently associated with IMT.

Identifying Genetic Variants for Heart Rate Variability in the Acetylcholine Pathway

Heart rate variability is an important risk factor for cardiovascular disease and all-cause mortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3, SLC5A7, CHRNB4, CHRNA3, CHRNA, CHRM2 and ACHE) of the acetylcholine pathway were associated with variation in an established measure of heart rate variability reflecting parasympathetic control of the heart rhythm, the root mean square of successive differences (RMSSD) of normal RR intervals. The association was studied in a two stage design in individuals of European descent. First, analyses were performed in a discovery sample of four cohorts (n = 3429, discovery stage). Second, findings were replicated in three independent cohorts (n = 3311, replication stage), and finally the two stages were combined in a meta-analysis (n = 6740). RMSSD data were obtained under resting conditions. After correction for multiple testing, none of the SNPs showed an association with RMSSD. In conclusion, no common genetic variants for heart rate variability were identified in the largest and most comprehensive candidate gene study on the acetylcholine pathway to date. Future gene finding efforts for RMSSD may want to focus on hypothesis free approaches such as the genome-wide association study.

Urinary albumin excretion is related to cardiovascular risk indicators, not to flow-mediated vasodilation, in apparently healthy subjects.

Based on studies in diabetic and hypertensive populations it has been postulated that early endothelial dysfunction is the mechanism responsible for the increased cardiovascular risk in microalbuminuric subjects. We evaluated the relation between microalbuminuria and endothelial dysfunction, assessed as flow-mediated dilation of the brachial artery, in an apparently healthy population. Within the framework of the PREVEND Intervention Trial non-hypertensive and non-hypercholesterolemic subjects were recruited on the basis of reproducible microalbuminuria. Using high-resolution ultrasound, flow-mediated dilation and nitroglycerin-mediated dilation of the brachial artery was assessed to measure endothelium-dependent and endothelium-independent responses, respectively. For the current study subjects with diabetes mellitus, clinical atherosclerosis, and macroalbuminuria were excluded from the analyses. We studied 421 men and 233 women (mean age (SD) 50 (12)). Increasing levels of urinary albumin excretion were accompanied by a significant increase in age, percentage men, systolic and diastolic blood pressure, body mass index, and serum triglycerides, whereas there was no decrease of flow-mediated vasodilation or nitroglycerin-mediated vasodilation. Adjusted for age and sex, urinary albumin excretion was significantly related to systolic (r=0.19, P<0.001) and diastolic (r=0.16, P<0.001) blood pressure, body mass index (r=0.18, P<0.001), and triglycerides (r=0.13, P=0.001), but not to flow-mediated vasodilation (r=-0.01, P=0.8). In contrast to blood pressure, body mass index, and triglycerides, there was no relation between urinary albumin excretion and flow-mediated vasodilation in apparently healthy subjects. These data suggest that the presence of atherogenic risk factors precedes the development of endothelial dysfunction in microalbuminuric, but otherwise healthy subjects.

Validity of (Ultra-)Short Recordings for Heart Rate Variability Measurements

Objectives In order to investigate the applicability of routine 10s electrocardiogram (ECG) recordings for time-domain heart rate variability (HRV) calculation we explored to what extent these (ultra-)short recordings capture the “actual” HRV. Methods The standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences (RMSSD) were measured in 3,387 adults. SDNN and RMSSD were assessed from (ultra)short recordings of 10s(3x), 30s, and 120s and compared to 240s–300s (gold standard) measurements. Pearson’s correlation coefficients (r), Bland-Altman 95% limits of agreement and Cohen’s d statistics were used as agreement analysis techniques. Results Agreement between the separate 10s recordings and the 240s-300s recording was already substantial (r = 0.758–0.764/Bias = 0.398–0.416/d = 0.855–0.894 for SDNN; r = 0.853–0.862/Bias = 0.079–0.096/d = 0.150–0.171 for RMSSD), and improved further when three 10s periods were averaged (r = 0.863/Bias = 0.406/d = 0.874 for SDNN; r = 0.941/Bias = 0.088/d = 0.167 for RMSSD). Agreement increased with recording length and reached near perfect agreement at 120s (r = 0.956/Bias = 0.064/d = 0.137 for SDNN; r = 0.986/Bias = 0.014/d = 0.027 for RMSSD). For all recording lengths and agreement measures, RMSSD outperformed SDNN. Conclusions Our results confirm that it is unnecessary to use recordings longer than 120s to obtain accurate measures of RMSSD and SDNN in the time domain. Even a single 10s (standard ECG) recording yields a valid RMSSD measurement, although an average over multiple 10s ECGs is preferable. For SDNN we would recommend either 30s or multiple 10s ECGs. Future research projects using time-domain HRV parameters, e.g. genetic epidemiological studies, could calculate HRV from (ultra-)short ECGs enabling such projects to be performed at a large scale.

Effects of Fosinopril and Pravastatin on Carotid Intima-Media Thickness in Subjects With Increased Albuminuria

Background and Purpose— Elevated urinary albumin excretion (UAE) is associated with an increased carotid intima-media thickness (IMT). Because angiotensin-converting enzyme inhibitors as well as statins have been shown to lower UAE and the progression of IMT, we assessed the effects of fosinopril and pravastatin on carotid IMT in subjects with an increased UAE (15 to 300 mg/24 h). Methods— IMT was measured at the posterior wall of the left common carotid artery using radio-frequency signal analysis obtained by M-mode ultrasonography. 642 subjects were double-blind randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo and were available for intention-to-treat analysis. Results— Mean age was 51±11 years, 65% were male, the median UAE was 22.5 (15.5 to 40.8) mg/24 h, and the mean IMT at baseline was 0.77±0.18 mm. The overall progression rate of IMT in 4 years was 0.037±0.006 mm. No significant difference in IMT progression was found between fosinopril, pravastatin, or matching placebo. IMT after 4 years was predicted by IMT at baseline, age, gender, pulse pressure, and low-density lipoprotein cholesterol levels. Furthermore, a higher incidence of clinical events was observed in subjects with an IMT >1 mm after a mean follow-up of 46±7 months (hazard ratio, 3.13; 95% confidence interval, 1.59 to 6.16; P=0.001). Conclusions— In subjects with an increased UAE, treatment with fosinopril and pravastatin showed no significant effect on carotid IMT. Furthermore, an IMT <1 mm at baseline is an important indicator for event-free survival.