Resting heart rate and incident heart failure and cardiovascular mortality in older adults: role of inflammation and endothelial dysfunction: the PROSPER study

Resting heart rate is a promising modifiable cardiovascular risk marker in older adults, but the mechanisms linking heart rate to cardiovascular disease are not fully understood. We aimed to assess the association between resting heart rate and incident heart failure (HF) and cardiovascular mortality, and to examine whether these associations might be attributable to systemic inflammation and endothelial dysfunction.

QTc interval and resting heart rate as long-term predictors of mortality in type 1 and type 2 diabetes mellitus: a 23-year follow-up

We evaluated the association of QT interval corrected for heart rate (QT(c)) and resting heart rate (rHR) with mortality (all-causes, cardiovascular, cardiac, and ischaemic heart disease) in subjects with type 1 and type 2 diabetes.

[Is resting heart rate a cardiovascular risk factor?]

During recent years, resting heart rate was not considered as a cardiovascular risk factor. However, new evidences have showed that resting heart rate is an important prognostic factor for sudden cardiac death and heart failure in the general population, and especially among patients with known cardiac disease. Interestingly, resting heart rate not only predicts cardiac mortality but also all-cause mortality. The most common pathophysiological explanation is related to the fact that increased heart rate increases myocardial oxygen consumption and in parallel reduces coronary blood flow (reduction in the diastolic duration).

Heart rate is a prognostic risk factor for myocardial infarction: a post hoc analysis in the PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack) study population

BACKGROUND Elevated resting heart rate is known to be detrimental to morbidity and mortality in cardiovascular disease, though its effect in patients with ischemic stroke is unclear. We analyzed the effect of baseline resting heart rate on myocardial infarction (MI) in patients with a recent noncardioembolic cerebral ischemic event participating in PERFORM. METHODS We compared fatal or nonfatal MI using adjusted Cox proportional hazards models for PERFORM patients with baseline heart rate <70 bpm (n=8178) or ≥70 bpm (n=10,802). In addition, heart rate was analyzed as a continuous variable. Other cerebrovascular and cardiovascular outcomes were also explored. RESULTS Heart rate ≥70 bpm was associated with increased relative risk for fatal or nonfatal MI (HR 1.32, 95% CI 1.03-1.69, P=0.029). For every 5-bpm increase in heart rate, there was an increase in relative risk for fatal and nonfatal MI (11.3%, P=0.0002). Heart rate ≥70 bpm was also associated with increased relative risk for a composite of fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (excluding hemorrhagic death) (P<0001); vascular death (P<0001); all-cause mortality (P<0001); and fatal or nonfatal stroke (P=0.04). For every 5-bpm increase in heart rate, there were increases in relative risk for fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (4.7%, P<0.0001), vascular death (11.0%, P<0.0001), all-cause mortality (8.0%, P<0.0001), and fatal and nonfatal stroke (2.4%, P=0.057). CONCLUSION Elevated heart rate ≥70 bpm places patients with a noncardioembolic cerebral ischemic event at increased risk for MI.

Early autonomic dysfunction in patients with diabetes mellitus assessed by spectral analysis of heart rate and blood pressure variability

Patients with diabetes mellitus (DM) often have alterations of the autonomic nervous system (ANS), even early in their disease course. Previous research has not evaluated whether these changes may have consequences on adaptation mechanisms in DM, e.g. to mental stress. We therefore evaluated whether patients with DM who already had early alterations of the ANS reacted with an abnormal regulatory pattern to mental stress. We used the spectral analysis technique, known to be valuable and reliable in the investigation of disturbances of the ANS. We investigated 34 patients with DM without clinical evidence of ANS dysfunction (e.g. orthostatic hypotension) and 44 normal control subjects (NC group). No patients on medication known to alter ANS responses were accepted. The investigation consisted of a resting state evaluation and a mental stress task (BonnDet). In basal values, only the 21 patients with type 2 DM were different in respect to body mass index and systolic blood pressure. In the study parameters we found significantly lower values in resting and mental stress spectral power of mid-frequency band (known to represent predominantly sympathetic influences) and of high-frequency and respiration bands (known to represent parasympathetic influences) in patients with DM (types 1 and 2) compared with NC group (5.3 +/- 1.2 ms2 vs. 6.1 +/- 1.3 ms2, and 5.5 +/- 1.6 ms2 vs. 6.2 +/- 1.5 ms2, and 4.6 +/- 1.7 ms2 vs. 6.2 +/- 1.5 ms2, for resting values respectively; 4.7 +/- 1.4 ms2 vs. 5.9 +/- 1.2 ms2, and 4.6 +/- 1.9 ms2 vs. 5.6 +/- 1.7 ms2, and 3.7 +/- 2.1 ms2 vs. 5.6 +/- 1.7 ms2, for stress values respectively; M/F ratio 6/26 vs. 30/14). These differences remained significant even when controlled for age, sex, and body weight. However, patients with DM type 2 (and significantly higher body weight) showed only significant values in mental stress modulus values. There were no specific group effects in the patients with DM in adaptation mechanisms to mental stress compared with the NC group. These findings demonstrate that power spectral examinations at rest are sufficiently reliable to diagnose early alterations in ANS in patients with DM. The spectral analysis technique is sensitive and reliable in investigation of ANS in patients with DM without clinically symptomatic autonomic dysfunction.

Relationship between heart rate variability, interleukin-6, and soluble tissue factor in healthy subjects

Decreased heart rate variability (HRV) has been associated with an increased risk of atherosclerosis. We hypothesized that a decrease in frequency domains of resting HRV would be associated with elevated plasma levels of interleukin (IL)-6 and soluble tissue factor (sTF) both previously shown to prospectively predict atherothrombotic events in healthy subjects. Subjects were 102 healthy and unmedicated black and white middle-aged men and women. We determined IL-6 and sTF antigen in plasma and HRV measures from surface electrocardiogram data using spectral analysis. All statistical analyses controlled for age, gender, ethnicity, smoking status, blood pressure, and body mass index. Low amounts of low frequency (LF) power (beta=-0.31, p=0.007) and high frequency (HF) power (beta=-0.36, p=0.002) were associated with increased amounts of IL-6, explaining 7% and 9% of the variance, respectively. Interactions between LF power and IL-6 (p=0.002) and between HF power and IL-6 (p=0.012) explained 8% and 5%, respectively, of the variance in sTF. Post hoc analyses showed associations between IL-6 and sTF when LF power (beta=0.51, p<0.001) and HF power (beta=0.48, p<0.001) were low but not when LF power and high HF power were high. The findings suggest that systemic low-grade inflammatory activity is associated with a decrease in HRV. Furthermore, there was a positive relationship between plasma levels of IL-6 and sTF antigen when HRV was low. Inflammation and related hypercoagulability might particularly contribute to atherothrombotic events in a setting of decreased HRV.

Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.

AIMS The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. METHODS AND RESULTS We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10(-40)), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10(-40) and rs16899974; P = 1.5 × 10(-38)) and one in SLC25A45 (rs34400381; P = 2.5 × 10(-10)). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. CONCLUSIONS AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function.

Heart rate variability and biomarkers of systemic inflammation in patients with stable coronary heart disease: findings from the Heart and Soul Study

Chronic low-grade systemic inflammation is a key component in atherogenesis. Decreased heart rate variability (HRV), a strong predictor of cardiovascular events, has been associated with elevations in circulating levels of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen in apparently healthy individuals. We investigated whether decreased HRV is associated with inflammatory markers in patients with coronary heart disease (CHD).

Effects of non-ionic iodinated contrast media on patient heart rate and pressures during intra-cardiac or intra-arterial injection

PURPOSE: To compare the effects on heart rate (HR), on left ventricular (LV) or arterial pressures, and the general safety of a non-ionic low-osmolar contrast medium (CM) and a non-ionic iso-osmolar CM in patients undergoing cardiac angiography (CA) or peripheral intra-arterial digital subtraction angiography (IA-DSA). MATERIALS AND METHODS: Two double-blind, randomized studies were conducted in 216 patients who underwent CA (n=120) or peripheral IA-DSA (n=96). Patients referred for CA received a low-osmolar monomeric CM (iomeprol-350, n=60) or an iso-osmolar dimeric CM (iodixanol-320; n=60). HR and LV peak systolic and end-diastolic pressures were determined before and after the first injection during left and right coronary arteriography and left ventriculography. Monitoring for all types of adverse event (AE) was performed for 24 h following the procedure. t-tests were performed to compare CM for effects on HR. Patients referred for IA-DSA received iomeprol-300 (n=49) or iodixanol-320 (n=47). HR and arterial blood pressure (BP) were evaluated before and after the first 4 injections. Monitoring for AE was performed for 4 h following the procedure. Repeated-measures ANOVA was used to compare mean HR changes across the first 4 injections, whereas changes after the first injection were compared using t-tests. RESULTS: No significant differences were noted between iomeprol and iodixanol in terms of mean changes in HR during left coronary arteriography (p=0.8), right coronary arteriography (p=0.9), and left ventriculography (p=0.8). In patients undergoing IA-DSA, no differences between CM were noted for effects on mean HR after the first injection (p=0.6) or across the first 4 injections (p=0.2). No significant differences (p>0.05) were noted in terms of effects on arterial BP in either study or on LV pressures in patients undergoing CA. Non-serious AE considered possibly CM-related (primarily headache and events affecting the cardiovascular and digestive systems) were reported more frequently by patients undergoing CA and more frequently after iodixanol (14/60 [23.3%] and 2/47 [4.3%]; CA and IA-DSA, respectively) than iomeprol (10/60 [16.7%] and 1/49 [2%], respectively). CONCLUSIONS: Iomeprol and iodixanol are safe and have equally negligible effects on HR and LV pressures or arterial BP during and after selective intra-cardiac injection and peripheral IA-DSA. CLINICAL APPLICATION: Iomeprol and iodixanol are safe and equally well tolerated with regard to cardiac rhythm and clinical preference should be based on diagnostic image quality alone.

Heart rate variability does not discriminate between different levels of haemodynamic responsiveness during surgical anaesthesia

BACKGROUND: Hypnotic depth but not haemodynamic responsiveness is measured with EEG-based monitors. In this study we compared heart rate variability (HRV) in unstimulated patients and stimulation-induced HRV at different levels of anaesthesia. METHODS: A total of 95 ASA I or II patients were randomly assigned to five groups (Group 1: BIS 45(5), remifentanil 1 ng ml(-1); Group 2: BIS 45(5), remifentanil 2 ng ml(-1); Group 3: BIS 45(5), remifentanil 4 ng ml(-1); Group 4: BIS 30(5), remifentanil 2 ng ml(-1); Group 5: BIS 60(5), remifentanil 2 ng ml(-1)). A time- and frequency-domain analysis of the RR interval (RRI) from the electrocardiogram was performed. HRV before induction, before and after a 5 s tetanic stimulus of the ulnar nerve, and before and after tracheal intubation was compared between groups, between stimuli, and between responders to intubation [systolic arterial pressure (SAP) increase >20 mm Hg, a maximal heart rate (HR) after intubation >90 min(-1) or both] and non-responders (anova). RESULTS: Induction of anaesthesia significantly lowered HR and HRV. Mean RRI before stimulation was higher in G3 than in G1, G2, and G4 (P < 0.001), whereas the other HRV parameters were similar. Intubation induced a greater HRV response than tetanic stimulation. The mean RRI after intubation was lower in G3 compared with the other groups and the sd of the RRI after tetanic stimulation was lower in G3 compared with G5. Otherwise, unstimulated HRV and stimulation-induced HRV were similar in responders and non-responders. CONCLUSION: HRV parameters discriminate between awake and general anaesthesia, are different after tracheal intubation and a 5 s ulnar nerve stimulation, but do not discriminate between different levels of haemodynamic responsiveness during surgical anaesthesia.

Day-to-night time differences in the relationship between cardiorespiratory coordination and heart rate variability

Heart rate variability (HRV) and cardiorespiratory coordination, i.e. the temporal interplay between oscillations of heartbeat and respiration, reflect information related to the cardiovascular and autonomic nervous system. The purpose of this study was to investigate the relationship between spectral measures of HRV and measures of cardiorespiratory coordination. In 127 subjects from a normal population a 24 h Holter ECG was recorded. Average heart rate (HR) and the following HRV parameters were calculated: very low (VLF), low (LF) and high frequency (HF) oscillations and LF/HF. Cardiorespiratory coordination was quantified using average respiratory rate (RespR), the ratio of heart rate and respiratory rate (HRR), the phase coordination ratio (PCR) and the extent of cardiorespiratory coordination (PP). Pearson's correlation coefficient r was used to quantify the relationship between each pair of the variables across all subjects. HR and HRR correlated strongest during daytime (r = 0.89). LF/HF and PP showed a negative correlation to a reasonable degree (r = -0.69). During nighttime sleep these correlations decreased whereas the correlation between HRR and RespR (r = -0.47) as well as between HRR and PCR (r = 0.73) increased substantially. In conclusion, HRR and PCR deliver considerably different information compared to HRV measures whereas PP is partially linked reciprocally to LF/HF.

Effects of verum acupuncture compared to placebo acupuncture on quantitative EEG and heart rate variability in healthy volunteers

OBJECTIVES: The aim of this single-blind randomized crossover study was to evaluate specific effects of manual acupuncture on central and vegetative nervous system activity measured by quantitative electroencephalography (qEEG) and heart rate variability (HRV). DESIGN: Twenty (20) healthy volunteers (mean: 25.2 +/- 3.6 years) were monitored simultaneously using a qEEG system and a 12-channel electrocardiogram recorder during verum acupuncture (VA) at acupuncture point Large Intestine 4 (Hegu) (LI4) or placebo acupuncture (PA) at a sham point. RESULTS: In the EEG conduction of the occipital area, needle stimulation in VA increased alpha1-frequency significantly, and the ratio alpha1/theta was shifted to the benefit of alpha1 over all electrodes. The HRV parameters showed a significant increase of the low frequency/high frequency (HF) ratio during the first minute of stimulation in VA, indicating an initial increase of sympathetic activation. However, an increase of HF power in the minute after stimulation followed by a decrease in heart rate suggests delayed vagal activation. De qi (a sensation that is typical of acupuncture needling) occurred in 16 subjects during VA and in 9 volunteers during PA (80% versus 45%). CONCLUSIONS: Manual stimulation on LI4 seems to lead to specific changes in alpha EEG-frequency and in HRV parameters. A linear relationship between the HRV parameters and the alpha EEG band might point to a specific modulation of cerebral function by vegetative effects during acupuncture.