Heart rate variability in young adults - Reference values and associations with cardiometabolic risk factors and vascular properties. The Cardiovascular Risk in Young Finns Study.

Background: The function of the autonomic nervous system (ANS) can be evaluated with heart rate variability (HRV). Decreased HRV is associated with aging, the male sex, increased heart rate, and overall increased cardiometabolic risk. It has been hypothesized that early atherosclerotic vascular changes and ANS function are related. Aims: The aims were to assess reference values on HRV in young adults, and examine associations with HRV and cardiometabolic risk factors and metabolic syndrome (MetS) and to study relations between HRV and ultrasonographically measured vascular properties. Participants and methods: The present thesis is part of the Cardiovascular Risk in Young Finns Study. The thesis is based on the follow-up study in 2001, when the study individuals were 24-39 years of age. HRV data were available on 1 956 individuals. Results: HRV was inversely associated with age and heart rate (for all p<0.001). Highfrequency HRV (HF) was higher, and low-frequency HRV (LF) lower in women than men (p<0.0001 for both). MetS was associated with 11% decreased HF and 12% increased LF/HF-ratio in women, and 8% decreased HF and 4% increased LF/HF-ratio in men. Carotid artery distensibility was independently associated with HF and total HRV (for both p<0.05). Conclusions: The reference values in young adults were generated. Decreased HRV was associated with age, the male sex and increased heart rate. Women had higher HF and lower LF variability than men. MetS was related to decrease in HRV. The observed associations between carotid elasticity and HRV, supports the hypothesis that reduction in carotid elasticity may lead to decrease in autonomic cardiac control.

Heart rate changes during the Valsalva maneuver in patients with isolated aortic insufficiency

To determine the possible relationship between left ventricular dilatation and heart rate changes provoked by the Valsalva maneuver (Valsalva ratio), we studied 9 patients with isolated chronic aortic insufficiency. Left ventricular systolic function was assessed by two-dimensional echocardiography and cardiac catheterization. All patients were asymptomatic (functional class I of the New York Heart Association). The left ventricular internal diameters and volumes were significantly increased in all patients. The asymptomatic patients had either normal or slightly depressed ejection fraction (EF>0.40). The Valsalva ratio of these asymptomatic patients showed no significant correlation with the left ventricular volumes or with the left ventricular ejection fraction. In other words, parasympathetic heart rate control, as expressed by the Valsalva ratio, was normal in the asymptomatic patients with left ventricular dilatation and preserved left ventricular ejection fraction. Therefore, left ventricular dilatation may not be the major mechanism responsible for the abnormal parasympathetic heart rate control of patients with acquired heart disease

Time course of changes in heart rate and blood pressure variability in streptozotocin-induced diabetic rats treated with insulin

Autonomic neuropathy is a frequent complication of diabetes associated with higher morbidity and mortality in symptomatic patients, possibly because it affects autonomic regulation of the sinus node, reducing heart rate (HR) variability which predisposes to fatal arrhythmias. We evaluated the time course of arterial pressure and HR and indirectly of autonomic function (by evaluation of mean arterial pressure (MAP) variability) in rats (164.5 ± 1.7 g) 7, 14, 30 and 120 days after streptozotocin (STZ) injection, treated with insulin, using measurements of arterial pressure, HR and MAP variability. HR variability was evaluated by the standard deviation of RR intervals (SDNN) and root mean square of successive difference of RR intervals (RMSSD). MAP variability was evaluated by the standard deviation of the mean of MAP and by 4 indices (P1, P2, P3 and MN) derived from the three-dimensional return map constructed by plotting MAPn x [(MAPn+1) - (MAPn)] x density. The indices represent the maximum concentration of points (P1), the longitudinal axis (P2), and the transversal axis (P3) and MN represents P1 x P2 x P3 x 10-3. STZ induced increased urinary glucose in diabetic (D) rats compared to controls (C). Seven days after STZ, diabetes reduced resting HR from 380.6 ± 12.9 to 319.2 ± 19.8 bpm, increased HR variability, as demonstrated by increased SDNN, from 11.77 ± 1.67 to 19.87 ± 2.60 ms, did not change MAP, and reduced P1 from 61.0 ± 5.3 to 51.5 ± 1.8 arbitrary units (AU), P2 from 41.3 ± 0.3 to 29.0 ± 1.8 AU, and MN from 171.1 ± 30.2 to 77.2 ± 9.6 AU of MAP. These indices, as well as HR and MAP, were similar for D and C animals 14, 30 and 120 days after STZ. Seven-day rats showed a negative correlation of urinary glucose with resting HR (r = -0.76, P = 0.03) as well as with the MN index (r = -0.83, P = 0.01). We conclude that rats with short-term diabetes mellitus induced by STZ presented modified autonomic control of HR and MAP which was reversible. The metabolic control may influence these results, suggesting that insulin treatment and a better metabolic control in this model may modify arterial pressure, HR and MAP variability

Cytokine production profile of heart-infiltrating T cells in Chagas' disease cardiomyopathy

The hallmark of chronic Chagas' disease cardiomyopathy (CCC) is the finding of a T cell-rich inflammatory mononuclear cell infiltrate in the presence of extremely few parasites in the heart lesions. The scarcity of parasites in affected heart tissue casts doubt on the direct participation of Trypanosoma cruzi in CCC heart tissue lesions, and suggests the possible involvement of autoimmunity. The cells in the infiltrate are presumably the ultimate effectors of tissue damage, and there is evidence that such cells recognize cardiac myosin in molecular mimicry with T. cruzi proteins rather than primary reactivity to T. cruzi antigens (Cunha-Neto et al. (1996) Journal of Clinical Investigation, 98: 1709-1712). Recently, we have studied heart-infiltrating T cells at the functional level. In this short review we summarize the studies about the role of cytokines in human and experimental T. cruzi infection, along with our data on heart-infiltrating T cells in human Chagas' cardiomyopathy. The bulk of evidence points to a significant production of IFN-g and TNF-a which may be linked to T. cruzi-induced IL-12 production

A comparative analysis of preprocessing techniques of cardiac event series for the study of heart rhythm variability using simulated signals

In the present study, using noise-free simulated signals, we performed a comparative examination of several preprocessing techniques that are used to transform the cardiac event series in a regularly sampled time series, appropriate for spectral analysis of heart rhythm variability (HRV). First, a group of noise-free simulated point event series, which represents a time series of heartbeats, was generated by an integral pulse frequency modulation model. In order to evaluate the performance of the preprocessing methods, the differences between the spectra of the preprocessed simulated signals and the true spectrum (spectrum of the model input modulating signals) were surveyed by visual analysis and by contrasting merit indices. It is desired that estimated spectra match the true spectrum as close as possible, showing a minimum of harmonic components and other artifacts. The merit indices proposed to quantify these mismatches were the leakage rate, defined as a measure of leakage components (located outside some narrow windows centered at frequencies of model input modulating signals) with respect to the whole spectral components, and the numbers of leakage components with amplitudes greater than 1%, 5% and 10% of the total spectral components. Our data, obtained from a noise-free simulation, indicate that the utilization of heart rate values instead of heart period values in the derivation of signals representative of heart rhythm results in more accurate spectra. Furthermore, our data support the efficiency of the widely used preprocessing technique based on the convolution of inverse interval function values with a rectangular window, and suggest the preprocessing technique based on a cubic polynomial interpolation of inverse interval function values and succeeding spectral analysis as another efficient and fast method for the analysis of HRV signals

Endogenous vasopressin and the central control of heart rate during dynamic exercise

The present article contains a brief review on the role of vasopressinergic projections to the nucleus tractus solitarii in the genesis of reflex bradycardia and in the modulation of heart rate control during exercise. The effects of vasopressin on exercise tachycardia are discussed on the basis of both the endogenous peptide content changes and the heart rate response changes observed during running in sedentary and trained rats. Dynamic exercise caused a specific vasopressin content increase in dorsal and ventral brainstem areas. In accordance, rats pretreated with the peptide or the V1 blocker into the nucleus tractus solitarii showed a significant potentiation or a marked blunting of the exercise tachycardia, respectively, without any change in the pressure response to exercise. It is proposed that the long-descending vasopressinergic pathway to the nucleus tractus solitarii serves as one link between the two main neural controllers of circulation, i.e., the central command and feedback control mechanisms driven by the peripheral receptors. Therefore, vasopressinergic input could contribute to the adjustment of heart rate response (and cardiac output) to the circulatory demand during exercise.

Post-exercise changes in blood pressure, heart rate and rate pressure product at different exercise intensities in normotensive humans

To evaluate the effect of exercise intensity on post-exercise cardiovascular responses, 12 young normotensive subjects performed in a randomized order three cycle ergometer exercise bouts of 45 min at 30, 50 and 80% of VO2peak, and 12 subjects rested for 45 min in a non-exercise control trial. Blood pressure (BP) and heart rate (HR) were measured for 20 min prior to exercise (baseline) and at intervals of 5 to 30 (R5-30), 35 to 60 (R35-60) and 65 to 90 (R65-90) min after exercise. Systolic, mean, and diastolic BP after exercise were significantly lower than baseline, and there was no difference between the three exercise intensities. After exercise at 30% of VO2peak, HR was significantly decreased at R35-60 and R65-90. In contrast, after exercise at 50 and 80% of VO2peak, HR was significantly increased at R5-30 and R35-60, respectively. Exercise at 30% of VO2peak significantly decreased rate pressure (RP) product (RP = HR x systolic BP) during the entire recovery period (baseline = 7930 ± 314 vs R5-30 = 7150 ± 326, R35-60 = 6794 ± 349, and R65-90 = 6628 ± 311, P<0.05), while exercise at 50% of VO2peak caused no change, and exercise at 80% of VO2peak produced a significant increase at R5-30 (7468 ± 267 vs 9818 ± 366, P<0.05) and no change at R35-60 or R65-90. Cardiovascular responses were not altered during the control trial. In conclusion, varying exercise intensity from 30 to 80% of VO2peak in young normotensive humans did not influence the magnitude of post-exercise hypotension. However, in contrast to exercise at 50 and 80% of VO2peak, exercise at 30% of VO2peak decreased post-exercise HR and RP.

The left ventricular contractility of the rat heart is modulated by changes in flow and a1-adrenoceptor stimulation

Myocardial contractility depends on several mechanisms such as coronary perfusion pressure (CPP) and flow as well as on a1-adrenoceptor stimulation. Both effects occur during the sympathetic stimulation mediated by norepinephrine. Norepinephrine increases force development in the heart and produces vasoconstriction increasing arterial pressure and, in turn, CPP. The contribution of each of these factors to the increase in myocardial performance needs to be clarified. Thus, in the present study we used two protocols: in the first we measured mean arterial pressure, left ventricular pressure and rate of rise of left ventricular pressure development in anesthetized rats (N = 10) submitted to phenylephrine (PE) stimulation before and after propranolol plus atropine treatment. These observations showed that in vivo a1-adrenergic stimulation increases left ventricular-developed pressure (P<0.05) together with arterial blood pressure (P<0.05). In the second protocol, we measured left ventricular isovolumic systolic pressure (ISP) and CPP in Langendorff constant flow-perfused hearts. The hearts (N = 7) were perfused with increasing flow rates under control conditions and PE or PE + nitroprusside (NP). Both CPP and ISP increased (P<0.01) as a function of flow. CPP changes were not affected by drug treatment but ISP increased (P<0.01). The largest ISP increase was obtained with PE + NP treatment (P<0.01). The results suggest that both mechanisms, i.e., direct stimulation of myocardial a1-adrenoceptors and increased flow, increased cardiac performance acting simultaneously and synergistically.

Evaluation of electromyographic activity and heart rate responses to isometric exercise. The role played by muscular mass and type

The purpose of the present study was to examine the relationship between the electromyographic (EMG) activity and heart rate (HR) responses induced by isometric exercise performed by knee extension (KE) and flexion (KF) in men. Fifteen healthy male subjects, 21 ± 1.3 years (mean ± SD), were submitted to KE and KF isometric exercise tests at 100% of maximal voluntary contraction (MVC). The exercises were performed with one leg (right or left) and with two legs simultaneously, for 10 s in the sitting position with the hip and knee flexed at 90o. EMG activity (root mean square values) and HR (beats/min) were recorded simultaneously both at rest and throughout the sustained contraction. The HR responses to isometric exercise in KE and KF were similar when performed with one and two legs. However, the HR increase was always significantly higher in KE than KF (P<0.05), whereas the EMG activity was higher in KE than in KF (P<0.05), regardless of the muscle mass (one or two legs) involved in the effort. The correlation coefficients between HR response and the EMG activity during KE (r = 0.33, P>0.05) and KF (r = 0.15, P>0.05) contractions were not significant. These results suggest that the predominant mechanism responsible for the larger increase in HR response to KE as compared to KF in our study could be dependent on qualitative and quantitative differences in the fiber type composition found in each muscle group. This mechanism seems to demand a higher activation of motor units with a corresponding increase in central command to the cardiovascular centers that modulate HR control.

Differential effects of isoproterenol on the activity of angiotensin-converting enzyme in the rat heart and aorta

The excessive stimulation of beta-adrenergic receptors in the heart induces myocardial hypertrophy. There are several experimental data suggesting that this hypertrophy may also depend, at least partially, on the increase of local production of angiotensin II secondary to the activation of the cardiac renin-angiotensin system. In this study we investigated the effects of isoproterenol on the activity of angiotensin-converting enzyme (ACE) in the heart and also in the aorta and plasma. Male Wistar rats weighing 250 to 305 g were treated with a dose of (±)-isoproterenol (0.3 mg kg-1 day-1, N = 8) sufficient to produce cardiac hypertrophy without deleterious effects on the pumping capacity of the heart. Control rats (N = 7) were treated with vehicle (corn oil). The animals were killed one week later. ACE activity was determined in vitro in the four cardiac chambers, aorta and plasma by a fluorimetric assay. A significant hypertrophy was observed in both ventricular chambers. ACE activity in the atria remained constant after isoproterenol treatment. There was a significant increase (P<0.05) of ACE activity in the right ventricle (6.9 ± 0.9 to 8.2 ± 0.6 nmol His-Leu g-1 min-1) and in the left ventricle (6.4 ± 1.1 to 8.9 ± 0.8 nmol His-Leu g-1 min-1). In the aorta, however, ACE activity decreased (P<0.01) after isoproterenol (41 ± 3 to 27 ± 2 nmol His-Leu g-1 min-1) while it remained unchanged in the plasma. These data suggest that ACE expression in the heart can be increased by stimulation of beta-adrenoceptors. However, this effect is not observed on other local renin-angiotensin systems, such as the aorta. Our data also suggest that the increased sympathetic discharge and the elevated plasma concentration of catecholamines may contribute to the upregulation of ACE expression in the heart after myocardial infarction and heart failure.

Reduced bone mineral density in men after heart transplantation

Heart transplantation is associated with rapid bone loss and an increased prevalence and incidence of fractures. The aim of the present study was to compare the bone mineral density (BMD) of 30 heart transplant (HT) recipients to that of 31 chronic heart failure (CHF) patients waiting for transplantation and to determine their biochemical markers of bone resorption and hormone levels. The BMD of lumbar spine and proximal femur was determined by dual-energy X-ray absorptiometry. Anteroposterior and lateral radiographs of the thoracic and lumbar spine were also obtained. The mean age of the two groups did not differ significantly. Mean time of transplantation was 25.4 ± 21.1 months (6 to 88 months). Except for the albumin levels, which were significantly higher, and magnesium levels, which were significantly lower in HT patients when compared to CHF patients, all other biochemical parameters and hormone levels were within the normal range and similar in the two groups. Both groups had lower BMD of the spine and proximal femur compared to young healthy adults. However, the mean BMD of HT patients was significantly lower than in CHF patients at all sites studied. Bone mass did not correlate with time after transplantation or cumulative dose of cyclosporine A. There was a negative correlation between BMD and the cumulative dose of prednisone. These data suggest that bone loss occurs in HT patients mainly due to the use of corticosteroids and that in 30% of the patients it can be present before transplantation. It seems that cyclosporine A may also play a role in this loss.

Altered heart rate and blood pressure variability in mice lacking the Mas protooncogene

Heart rate variability is a relevant predictor of cardiovascular risk in humans. A significant genetic influence on heart rate variability is suggested, although the genes involved are ill-defined. The Mas-protooncogene encodes a G-protein-coupled receptor with seven transmembrane domains highly expressed in testis and brain. Since this receptor is supposed to interact with the signaling of angiotensin II, which is an important regulator of cardiovascular homeostasis, heart rate and blood pressure were analyzed in Mas-deficient mice. Using a femoral catheter the blood pressure of mice was measured for a period of 30 min and 250 data values per second were recorded. The mean values and range of heart rate and blood pressure were then calculated. Neither heart rate nor blood pressure were significantly different between knockout mice and controls. However, high resolution recording of these parameters and analysis of the data by non-linear dynamics revealed significant alterations in cardiovascular variability in Mas-deficient animals. In particular, females showed a strong reduction of heart rate variability. Furthermore, the data showed an increased sympathetic tone in knockout animals of both genders. The marked alterations detected in Mas-deficient mice of both genders suggest that the Mas-protooncogene is an important determinant of heart rate and blood pressure variability.

A pulsatile flow model for in vitro quantitative evaluation of prosthetic valve regurgitation

A pulsatile pressure-flow model was developed for in vitro quantitative color Doppler flow mapping studies of valvular regurgitation. The flow through the system was generated by a piston which was driven by stepper motors controlled by a computer. The piston was connected to acrylic chambers designed to simulate "ventricular" and "atrial" heart chambers. Inside the "ventricular" chamber, a prosthetic heart valve was placed at the inflow connection with the "atrial" chamber while another prosthetic valve was positioned at the outflow connection with flexible tubes, elastic balloons and a reservoir arranged to mimic the peripheral circulation. The flow model was filled with a 0.25% corn starch/water suspension to improve Doppler imaging. A continuous flow pump transferred the liquid from the peripheral reservoir to another one connected to the "atrial" chamber. The dimensions of the flow model were designed to permit adequate imaging by Doppler echocardiography. Acoustic windows allowed placement of transducers distal and perpendicular to the valves, so that the ultrasound beam could be positioned parallel to the valvular flow. Strain-gauge and electromagnetic transducers were used for measurements of pressure and flow in different segments of the system. The flow model was also designed to fit different sizes and types of prosthetic valves. This pulsatile flow model was able to generate pressure and flow in the physiological human range, with independent adjustment of pulse duration and rate as well as of stroke volume. This model mimics flow profiles observed in patients with regurgitant prosthetic valves.

Quantitative Magnetic Resonance Imaging of the Liver and Heart In Iron Overload

Systemic iron overload (IO) is considered a principal determinant in the clinical outcome of different forms of IO and in allogeneic hematopoietic stem cell transplantation (alloSCT). However, indirect markers for iron do not provide exact quantification of iron burden, and the evidence of iron-induced adverse effects in hematological diseases has not been established. Hepatic iron concentration (HIC) has been found to represent systemic IO, which can be quantified safely with magnetic resonance imaging (MRI), based on enhanced transverse relaxation. The iron measurement methods by MRI are evolving. The aims of this study were to implement and optimise the methodology of non-invasive iron measurement with MRI to assess the degree and the role of IO in the patients. An MRI-based HIC method (M-HIC) and a transverse relaxation rate (R2*) from M-HIC images were validated. Thereafter, a transverse relaxation rate (R2) from spin-echo imaging was calibrated for IO assessment. Two analysis methods, visual grading and rSI, for a rapid IO grading from in-phase and out-of-phase images were introduced. Additionally, clinical iron indicators were evaluated. The degree of hepatic and cardiac iron in our study patients and IO as a prognostic factor in patients undergoing alloSCT were explored. In vivo and in vitro validations indicated that M-HIC and R2* are both accurate in the quantification of liver iron. R2 was a reliable method for HIC quantification and covered a wider HIC range than M-HIC and R2*. The grading of IO was able to be performed rapidly with the visual grading and rSI methods. Transfusion load was more accurate than plasma ferritin in predicting transfusional IO. In patients with hematological disorders, the prevalence of hepatic IO was frequent, opposite to cardiac IO. Patients with myelodysplastic syndrome were found to be the most susceptible to IO. Pre-transplant IO predicted severe infections during the early post-transplant period, in contrast to the reduced risk of graft-versus-host disease. Iron-induced, poor transplantation results are most likely to be mediated by severe infections.