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Adequate sympathetic nervous system activation is essential for the compensatory mechanisms of blood pressure maintenance during the hemodialysis (HD) procedure. Chronic sympathetic nervous system overactivity, however, may lead to the development of hypertension and cardiovascular disease in HD patients. The present review focuses on recent findings on the sympathetic nervous system activity in these patients. Sympathetic overactivity has been demonstrated directly by muscle sympathetic nerve activity recordings (MSNA) in chronic renal disease, but only rarely in HD patients. In the latter, sympathetic activity has mostly been assessed using indirect methodology. Decreased heart rate variability, increased blood pressure variability (BPV), and suppressed baroreflex function are believed to represent chronic sympathetic overactivity in HD patients. The HD procedure and ultrafiltration are associated with enhanced sympathetic activity and baroreflex activation. During most episodes of intradialytic hypotension, the baroreflex is adequately activated; sympathetic withdrawal with bradycardia, however, has been reported during excessive hypovolemia. Sympathetic overactivity is also believed to be a mechanism associated with intradialytic hypertensive episodes and refractory hypertension. While successful renal transplantation is associated with improvement of heart rate variability (HRV), improvement and restoration of baroreflex function, persistent sympathetic overactivity has been documented in transplanted patients using MSNA recordings. Decreased HRV and baroreflex function have been reported to be associated with increased mortality and morbidity in HD patients. The predictive value of sympathetic outflow assessed by MSNA has yet to be determined. Optimization of HD treatment, pharmacological interventions, and renal sympathetic denervation are several approaches targeting sympathetic overactivity to improve cardiovascular morbidity and mortality.

Patients with posttraumatic stress disorder (PTSD) experience psychological and physiological distress. However, imaging research has mostly focused on the psychological aspects of the disorder. Considered an expression of distress, heart rate (HR) in PTSD is often elevated. In the current study, we sought to identify brain regions associated with increased HR in PTSD. Nine patients with PTSD and six healthy trauma survivors were scanned while resting, clenching teeth, and listening to neutral and traumatic scripts. Brain function was evaluated using H2O15 positron emission tomography (PET). HR was monitored by electrocardiogram. Data were analyzed using statistical parametric mapping (SPM). Subjects with PTSD exhibited a significant increase in HR upon exposure to traumatic scripts, while trauma survivors did not. Correlations between regional cerebral blood flow and HR were found only in patients with PTSD, in orbitofrontal, precentral and occipital regions. Neither group showed correlation between rCBF and HR in the amygdala or hippocampus. These preliminary results indicate that "top down" central nervous system regulation of autonomic stress response in PTSD may involve associative, sensory and motor areas in addition to regions commonly implicated in fear conditioning.

Objectives The role of the baroreflex function in the pathogenesis of hemodialysis-associated hypotension is controversial. Complex demodulation technique (CDM), providing continuous assessment of the amplitude of cardiovascular oscillation over time, is particularly suitable to assess dynamic changes in autonomic nervous system and baroreceptor sensitivity (BRS) during dialysis. In the present study, CDM was used to determine the effects of dialysis treatment on BRS and to characterize BRS changes during acute intradialytic hypotension. Methods Continuous beat-to-beat blood pressure and interbeat intervals (IBIs) were monitored in 93 chronic patients without (n = 70) and with (n = 26) hypotension during 96 dialysis sessions. The amplitudes of SBP and DBP, IBIs, and BRS change in the low-frequency (around center frequency of 0.09 Hz) and high-frequency (around center frequency of 0.30 Hz) ranges were followed during the whole dialysis session. Results Hemodialysis treatment was associated with increased low-frequency BRS, especially in sessions without hypotension. Hypotensive episodes were associated with significant increases in both low-frequency BRS and high-frequency BRS, mainly in patients with severe hypotension. The magnitude of the increase in baroreflex indices was proportional to the decrease in blood pressure. Low-frequency IBI/high-frequency IBI ratio, a marker of sympatho-vagal balance, did not significantly change during hypotension. Conclusion Our study shows that the baroreflex mechanism is preserved and adequately activated during intradialytic hypotension. Other factors, such as ischemic heart disease, left ventricular dysfunction, and inadequate arteriolar tone, rather than failure of baroreflex function, are more likely to be responsible for dialysis-induced hypotension.

Background. Renal transplantation improves the uraemic autonomic dysfunction and heart rate variability (HRV). The effects of successful transplantation on blood pressure variability (BPV) and baroreflex function are not well defined. Methods. BPV, HRV and baroreceptor indices were determined in (1) 52 non-diabetic chronic haemodialysis patients, (2) 44 transplanted patients, 24 in the first year after renal transplantation (≤I year) and 20 at least 1 year (>1 year) after renal transplantation, and (3) 41 control individuals with normal renal function, age-matched to (1) and (2). Power spectrum analysis of interbeat intervals (IBI) and systolic blood pressure (SBP) was performed in the low-frequency (LF 0.04-0.15 Hz) and the high-frequency (HF 0.15-0.40 Hz) bands. Spontaneous baroreceptor sensitivity (BRS) was determined by the sequence (slope) and spectral (a coefficient) techniques. Results. In haemodialysis patients, BPV was increased, while HRV, BRS slope and LF a and HF a coefficients were markedly decreased as compared to control individuals. Renal transplantation was associated with normalization of BPV at short term (≤1 year) and long term and with improvement of HRV at a long-term (> 1 year) follow-up. In patients with long-standing functioning grafts (>1 year), baroreceptor indices were significantly increased and returned to values similar to those of the control subjects. Conclusions. Our data show that renal transplantation improves blood pressure and HRV and restores baroreflex function to near normal range on the long-term follow-up. These effects may contribute to the improvement of blood pressure control and survival after successful transplantation.

Autonomic nervous system dysfunction and dialysate sodium (Na) concentration are believed to play a role in the pathogenesis of hemodialysis-related hypertension. The present study was undertaken to determine whether increases in blood pressure in hemodialysis patients are associated with changes in heart rate variability (HRV), a measure of the autonomic nervous system function, and long-term exposure to increased dialysate Na concentration.Baseline clinical, biochemical data and HRV of patients undergoing increased Na profiling dialysis (High-Na, n = 9) and on conventional treatment (Control, n = 11) were compared with those obtained after one year of study.After one year, the mean predialysis systolic blood pressure (SBP) increased in seven patients of the High-Na and in five of the Control group, and decreased or remained unchanged in the remaining subjects. Initial HRV was significantly higher in patients with increased SBP, and it increased further in these patients after one year. At the end of the study, post-dialysis plasma Na, osmolality, and weight gains were significantly higher in the High-Na group. No significant correlation, however, was found between individual changes in intradialytic sodium elimination and the alterations in blood pressure.These data suggest that the dialysate sodium concentration, a most important determinant of interdialytic weight gain and fluid balance, is only partly correlated with long-term changes in blood pressure. An increased blood pressure over time may develop in a subset of hemodialysis patients with higher HRV, suggestive of increased sympathetic activity.

Background. The pathogenesis of haemodialysisinduced hypotension is multifactorial and may include autonomic nervous system dysfunction. The present study was undertaken to (i) determine heart rate variability (HRV) in chronic haemodialysis patients without and with haemodynamic instability (hypotensionprone) during ultrafiltration and (ii) identify patients at risk and the predictors of dialysis-related hypotension. Methods. HRV was evaluated in 56 chronic haemodialysis patients without (stable; n ¼ 27) and with symptomatic hypotension episodes (unstable; n ¼ 29) during daytime, haemodialysis and night-time periods. Logistic regression analysis was performed in a model that included clinical and biochemical data and HRV measurements. Results. HRV was significantly reduced in haemodynamically unstable as compared with the stable patients. LF/HF ratio, an index representative of sympathovagal balance, was significantly lower in unstable patients, especially in those with ischaemic heart disease and diabetes mellitus. In a logistic regression model including clinical data and HRV measurements, ischaemic heart disease and left ventricular systolic dysfunction were found to be the main predictors of haemodynamic instability. Conclusions. These data suggest that haemodynamic instability is strongly associated with a decreased HRV and an impaired sympathovagal balance, suggesting disturbed autonomic control in uraemic patients with cardiac damage. Patients with ischaemic heart disease, reduced left ventricular systolic function and decreased HRV may be at the highest risk to be haemodynamically unstable during haemodialysis. The role of early detection and treatment of ischaemic heart disease in preventing symptomatic hypotensive episodes in these patients remains to be determined.

Repeated pattern ventricular arrhythmia (RPVA) is often observed in electrocardiogram recordings as a repeated sequence of a fixed number of normal sinus QRS complexes interposed between ventricular ectopic beats. The number of interposed sinus complexes is defined as the order of the repeated pattern ventricular arrhythmia. Regions of orders as a function of sinus RR and coupling intervals and duration of refractory periods of normal conduction and reentry pathways were derived from a computer model that simulates a reentry mechanism. Refractory periods of both the normal and reentry conduction pathways could be estimated from electrocardiogram measured time intervals. A variable relationship of RR intervals for different orders was found among patients. According to the reentry model, these order changes were more likely to occur with changes in the reentry refractory period than with heart rate changes. The longer RR intervals of interpolated beats in some patients were also explained by the model.

Purpose. To utilize power spectral analysis (PSA) of heart rate variability (HRV) as a pharmacodynamic (PD) measure of atropine parasympathetic effect, and to model the kinetics of action.

Background In patients with acute myocardial infarction (MI), early fibrinolytic therapy results in improved survival and preservation of ventricular function. The purpose of the study was to determine whether very early treatment also reduces the development of congestive heart failure. Methods and Results During the years 1984 to 1989, 358 consecutive patients with acute MI were treated with streptokinase, 161 within the first 1.5 hours from the onset of chest pain (group A) and 197 within 1.5 to 4.0 hours (group B). In 68, fibrinolysis was initiated in the prehospital setting pioneered by our group. Symptoms related to heart failure including dyspnea on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, nocturia, and peripheral edema, in addition to pulmonary edema events, were assessed during 5 years of follow-up. The evaluation was based on medical records and a detailed questionnaire, which was filled in by the investigators. A favorable significant effect of very early thrombolysis on the development of most of these limiting symptoms appeared 3 months after hospital discharge and persisted thereafter (P

By graphically identifying patterns of ventricular ectopic beat (VEB) interval characteristics, we sought to enhance arrhythmia analysis, especially in long-term ECG monitoring. Coupling intervals as a function of preceding sinus RR intervals (CI/RR diagrams) with the aid of coupling interval and interectopic interval histograms were analyzed in 172 patients with frequent VEBs. Four distinct types of CI/RR diagrams were observed: horizontal-elongated (25 patients), linear (4 patients), triangular (37 patients), and clusters separated by dot-sparse areas (17 patients). In 89 patients, no definite pattern was discerned. The patients with elongated diagrams were significantly younger, had fixed coupling, uniform QRS complexes, and lacked periodicities in their interectopic interval histograms. The linear pattern was detected in a small group with rate-related VEBs. In the group with a triangular pattern, 30% of the patients exhibited interectopic periodicities suggesting parasystole. The patients with dot-sparse areas in the CI/RR diagrams had more variable coupling and predominantly more multiform QRS complexes. We conclude that CI/RR diagrams in conjunction with coupling interval and interectopic interval histograms enhance arrhythmia analysis by identifying patterns, such as those consistent with either fixed coupling, rate dependence, parasystole, or multiform VEBs.

Changes in heart rate preceding ventricular ectopic beats may be used to identify clinical subsets of patients. We evaluated RR interval patterns preceding ventricular ectopic beats with a rate enhancement method which estimates ventricular ectopic beat dependence on the sinus RR interval preceding the ventricular ectopic beat and the dynamic heart rate trend, which is based on the slope of the five RR intervals preceding the ventricular ectopic beat. Using these two methodologies in 176 patients with frequent ventricular ectopic beats we identified several unique subsets of patients: (1) bradycardia-enhanced patients were younger with a high proportion of males and longer, more variable coupling intervals; (2) tachycardia-enhanced patients exhibited sleep suppression of ventricular ectopic beats and had shorter, less variable coupling intervals; (3) patients with predominantly no change in RR preceding the ventricular ectopic beat were significantly older, with greater prevalence of cardiovascular disease and reduced sinus RR variability, indicating decreased autonomic nervous system activity. These two methods may serve as a basis for further investigations regarding the treatment and prognosis of ventricular ectopic beats.

Objective—To evaluate the stability of short recordings of heart rate variability (HRV) with time, and the association of HRV with age and sex. Design—Five minute Holter recordings were made twice over a two month interval (tracking study). In addition, HRV was measured in a cross sectional study. Setting—Residents of 11 Israeli kibbutzim were examined in their settlements. Subjects—32 men and 38 women (aged 31-67) participated in the tracking study and 294 (aged 35-65) were involved in the cross sectional study. Main outcome measures—Time and frequency domain analyses on Holter recordings were undertaken in two breathing conditions: spontaneous and controlled breathing (15 respirations per minute). Regression was used to assess the relations of sex, age, heart rate, and logarithmically transformed HRV indices. Results—HRV measures were highly consistent with time with correlations of 0.76-0.80 for high frequency and total power. Geometric mean total power declined with age by 45% in men and 32% in women, and was lower by 24% among women than among men (all p ⩽ 0.005). Men had a 34% higher very low and low frequency power and a higher ratio of low to high frequency power (p

The objective of this study was to assess the familial aggregation of heart rate variability (HRV), a readily measurable noninvasive reflection of cardiac autonomic function. Familial correlations were analyzed in 451 kibbutz members aged 15–97 years belonging to 80 kindreds. Five-minute duration Holter recordings made during silent supine spontaneous breathing and metronomic breathing were analyzed in the time and frequency domains. The present analysis considers the familial correlations and the heritability estimates of two time-domain indices, the standard deviation (SD) of the R-R interval (RR), reflecting total variability, and the root mean square of successive differences in RR intervals (RMSSD), reflecting vagal (parasympathetic) tone. During free breathing, age- and sex-adjusted correlations between parents and their children (r=0.24 for both indices) and between adult siblings above 30 years of age (r=0.24 and r=0.34 for SD and RMSSD, respectively) were statistically significant, whereas spouse correlations (r=–0.04, r=–0.02 for SD and RMSSD, respectively) and correlations in younger siblings (r=–0.22 and r=0.01, respectively) were not. Significant heritability estimates were demonstrated for the two indices (h 2=0.41 for SD and h 2=0.39 for RMSSD). These findings suggest that familial aggregation of HRV characteristics is determined mostly by genetic factors and less so by environmental factors and provide a basis for continuing the investigation into the underlying genetic influences on HRV.

The long term impact of pre-hospital thrombolysis in acute myocardial infarction on the subsequent development of heart failure symptoms was investigated in 362 consecutive patients. The pre hospital strategy, used in 61 patients, allowed for very early administration of streptokinase, within 1.2±0.6 (mean±S.D.) hours from pain onset. In contrast, 294 patients treated in hospital received lytic treatment within 2.0±0.9 hours. The pre hospital group showed faster reperfusion, as measured by the time to peak creatine kinase and to ST segment recovery, but only a slightly better ventricular function, as compared to hospital treated patients. Heart failure symptoms were significantly reduced in the pre hospital group during hospitalization and at long term follow up: there were less dyspnea, fatigue, orthopnea, nocturnal dyspnea, nocturia, peripheral edema and episodes of pulmonary edema. Angina was reduced as well. We conclude that the initial benefit of prehospital thrombolysis translates into long term reduction of heart failure symptoms, thus improving quality of life.

RR variability (HRV), an independent predictor of death following myocardial infarction, may also be related to other features of coronary artery disease. We evaluated its ability to differentiate among sedentary patients with chest pain ≥45 years of age demonstrating either normal or abnormal myocardial perfusion with rest and exercise thallium-210 tomographic imaging. The major HRV difference between 48 men and 50 women with normal perfusion was a significantly higher high frequency power in women. No significant differences in mean HRV values were found between the 57 men with abnormal perfusion scans and the 48 men with normal perfusion. In both men and women with normal perfusion scans, duration of exercise was significantly related to age. In men with abnormal scans, impaired myocardial perfusion alters the relationship between exercise duration and age, and a group of individuals with diminished HRV and low levels of physical fitness, regardless of age, can be identified. Despite these latter selective findings, we conclude that HRV is not a sensitive indicator to differentiate patients with normal and abnormal myocardial perfusion.

Objectives. We sought to compare the angiographic outcome of diabetic patients (treated with insulin or oral hypoglycemic agents) after successful coronary angioplasty with that in nondiabetic patients. The analysis included the outcome of the dilated (restenosis) and nondilated narrowings (disease progression). Background. Recent data have confirmed that diabetes mellitus is an important risk factor for long-term adverse events. These adverse events are more common after balloon angioplasty than after bypass surgery (Bypass Angioplasty Revascularization Investigation [BARI]). Methods. We examined retrospectively 353 coronary angiograms of 248 patients (55 diabetic, 193 nondiabetic) who were referred for diagnostic angiography >1 month after successful angioplasty (1.4 ± 0.6 [mean ± SD] repeat angiograms/patient). Restenosis and disease progression/regression were compared between groups by means of quantitative angiography. Results. Baseline clinical and angiographic characteristics were similar in both groups. There was a nonsignificant trend for a higher restenosis rate of dilated narrowings in diabetic patients. There were no significant changes between diabetic and nondiabetic patients in the rates of progression and regression of narrowings that were not dilated during the initial angioplasty. The main difference was in the rate of appearance of new narrowings: There was a 22% increase in the number of narrowings on the follow-up angiogram in diabetic patients (38 new, 174 preexisting narrowings) compared with 12% (86 new, 734 preexisting narrowings) in nondiabetic patients (p Conclusions. The combination of diabetes mellitus and an artery that was instrumented during balloon angioplasty is additive and increases the risk of formation of new narrowing in that artery. This finding may explain the high adverse event rates observed in diabetic patients in the angioplasty arm of the BARI study, most of whom had angioplasty performed in at least two arteries.

A group of algorithms has been developed to investigate the characteristics of beat-to-beat intervals preceding and following the onset and termination of repeated pattern ventricular arrhythmias (RPVA) such as bigeminy and trigeminy. Eighty-five patients, each with more than 3000 ventricular ectopic beats in a 24-hour Holter recording and with more than 10 episodes of RPVA, were evaluated. A statistically significant prolongation of sinus intervals preceding the onset of bigeminy and trigeminy and shortening of postectopic intervals after the onset were observed. In addition, shortening of postectopic intervals before the termination of bigeminy and trigeminy and lengthening of sinus intervals following their termination were also seen. A significant presence of these characteristics was not observed in arrhythmias with a greater number of sinus beats between ectopic beats. These dynamics provide information which may be utilized in the assessment of mechanisms involved in the onset and termination of RPVA.

Angioplasty in patients with unstable coronary artery disease is associated with higher complication rates compared with patients with stable disease. In this report we describe our results from a group of patients with unstable disease (unstable angina pectoris and postmyocardial infarction) where a strategy of delaying angioplasty for5 days after admission was undertaken. Included are 2069 consecutive patients: 1197 treated for stable angina pectoris and 872 treated during admission for unstable angina or myocardial infarction. There was no difference between the two groups in angioplasty success (92.1% stable, 92.3% unstable), failure to dilate without complication (6.4% stable, 6.1% unstable), or in the rate of major complications: death (0.5% stable, 1.1% unstable), Q-wave myocardial infarction (0.9% stable, 1.1% unstable), and emergency coronary artery bypass (0.6% stable, 0.3% unstable). The duration of hospitalization following angioplasty was longer in the unstable group (5.6 +/- 8.1 days vs. 4.2 +/- 4.1 days; p0.001) because of longer duration of heparin infusion. There was no difference between groups in minor complications such as groin hematoma and pseudoaneurysm, renal failure, or infections. It was concluded that delaying angioplasty in unstable patients for5 days after admission is a safe and effective therapeutic strategy for this group of patients. The need for prolonged heparin infusion after angioplasty is increased in unstable patients and thus the duration of hospitalization after the procedure is longer.

This report describes the effect of age and gender on the results of balloon angioplasty using current technique and indications. A consecutive group of 2,067 patients who underwent angioplasty at a single institution after 1990 is described. Angioplastic success was 92.2% and similar among men and women and the various age groups. Sixteen patients (0.8%) died, and mortality among women was significantly higher (1.4 vs. 0.6%, p0.001). There were no age or gender differences in the rate of Q-wave myocardial infarction and the need for coronary artery bypass. Minor complications such as groin complications (10.5% women, 5.0% men; p0.001) and infections (6.4% women, 3.7% men; p0.05) were more common in women, and as a result the duration of hospitalization after angioplasty was longer. The length of hospitalization after angioplasty was longer with advanced age, mainly as a result of higher groin complications (p0.001), infections (p0.01) and renal failure (p0.05). We conclude that using current indications and technique, angioplasty can be performed safely with a high success rate. Mortality is higher among women. The length of hospitalization after angioplasty is longer in women and, at advanced age, due to higher rate of minor complications.

Background Continuous systolic blood pressure (SBP) and interbeat intervals (IBI) recordings reveal sequences of consecutive beats in which SBP and heart rate change in opposite direction, representing negative feedback baroreflex mechanisms, as well as sequences in which SBP and heart rate change in the same direction (non-baroreflex), believed to represent feedforward control mechanisms. The present study was undertaken to assess the relationship between baroreflex and non-baroreflex sequences in end stage renal insufficiency. Methodology/Principal Findings Continuous beat-to-beat SBP and IBI monitoring was performed in patients on chronic hemodialysis (HD, n=72), in age-matched patients after renal transplantation (TX, n=41) and healthy (control) individuals (C, n=34). The proportion of baroreflex and nonbaroreflex episodes and the b coefficients (the regression line slope of SBP-IBI correlation) were determined using a newly developed 1 minute sliding window method, the classical sequence technique and the "Z" coefficient method. Analysis using the 1 minute sliding window showed an increased proportion of baroreflex episodes in controls and HD, and predominance of nonbaroreflex episodes in TX. An increased proportion of nonbaroreflex episodes in TX patients relative to HD was also revealed by the "Z" method. Baroreflex and nonbaroreflex b coefficients obtained by all methods were markedly decreased in HD. This alteration was reversed at least partly in TX. In HD, both baroreflex and nonbaroreflex b coefficients were inversely correlated to age and CRP levels; in TX, the nonbaroreflex b coefficient was influenced by the type of calcineurin inhibitor. Conclusion/Significance Renal status affects the contribution of baroreflex and nonbaroreflex mechanisms and the strength of SBP-IBI relationship. The predominant contribution of nonbaroreflex mechanisms in TX may be suggestive of enhanced central sympathetic control. Our data may be relevant for understanding of the pathogenesis and selection of appropriate treatment of post-transplant hypertension.

This study examines the effect of coronary angioplasty on the progression and appearance of new disease in sites of the coronary tree that were not dilated by the balloon. We examined 355 pairs of coronary angiograms from 252 patients. The study consisted of consecutive patients who were referred for catheterization1 month after successful angioplasty. Progression/regression and the appearance of new narrowings at sites not dilated by angioplasty were determined. The life-table method was used to determine outcome, and any event (progression, regression, and new narrowing) was analyzed according to the time of occurrence. The angioplasty artery was compared with the non-angioplasty artery and the effect of restenosis was determined by comparing arteries with and without restenosis. Progression/regression rates were not significantly different in angioplasty and non-angioplasty arteries. More new narrowings were identified in the angioplasty artery (p0.01). With regard to narrowings located in the angioplasty artery, progression was more common, regression less common, and the appearance of new narrowings more common in arteries with restenosis than in non-angioplasty arteries or arteries without restenosis. We believe that mechanical trauma to the artery during angioplasty could accelerate disease progression and the appearance of new narrowings in angioplasty arteries, whereas normalization of flow rate and pattern, especially in arteries without restenosis, attenuates the rate of progression and the appearance of new narrowings in these arteries. The final outcome depends on the balance between these factors.

The angiographic appearance of the coronary arteries were examined in 302 patients with stable angina pectoris and compared to 308 patients with acute myocardial infarction, who received high-dose intravenous thrombolytic therapy, in order to elucidate the underlying angiopathological picture in the two diseases. In each group coronary lesions were present in proximal segments of the arteries and were closely related to bifurcations. Lesions were more extensively distributed in the coronary tree in patients with stable angina and they had an average of 5.4 lesions per patient, compared to the acute myocardial infarction group who had only 2.4 lesions. Also, in the acute myocardial infarction patients, four-fifths of the culprit arteries were patent, 104 (34%) had a ruptured plaque, 22 (7%) had an ulcerated plaque and in 190 (62%) the lesions were eccentric. The study shows that patients with myocardial infarction who are suitable for thrombolysis have a unique coronary angiographic picture and the acute episode is caused by sudden rupture of a localized atheromatous plaque which initiates an obstructive thrombotic cascade.

Background The mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes. Methodology/Principal Findings Continuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of- dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension. Conclusion/Significance Our data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of- dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension.

The effect of immediate recoil on the results of balloon angioplasty was examined in a group of 416 patients (596 lesions) who underwent successful coronary angioplasty. Immediate recoil was responsible for loss of 0.42 +/- 0.64 mm from the potentially achievable lesion diameter, and represented 23% of the actual gain in diameter. The immediate recoil was determined mainly by the degree of arterial stretch, which is best represented by the balloon to normal artery size ratio (correlation coefficient 0.49, p0.0001). Classic risk factors for coronary artery disease did not affect immediate recoil, except for a trend toward lower values in patients with history of hypercholesterolemia. There was a tendency for lower recoil in patients with residual coronary thrombus and in those who underwent angioplasty within 1 week of acute myocardial infarction. Recoil was larger in the left anterior descending artery than in the circumflex or the right coronary artery. Patients with more immediate recoil developed more restenosis (50% stenosis at follow-up). However the late loss of luminal diameter due to the restenotic process was smaller in those who had larger initial recoil. It is concluded that immediate recoil after balloon angioplasty is an elastic phenomenon that is related mainly to the degree of arterial stretch. The relative importance of immediate recoil in determining the late outcome of coronary angioplasty is at least as important as the late restenotic process.

In order to assess early changes in heart rate variability, we studied 81 patients with acute myocardial infarction during the initial 24 hours after thrombolytic therapy. The standard deviation of the mean heart rate and the low (0 to 0.05 Hz), mid (0.05 to 0.20 Hz), and high (0.20 to 0.35 Hz) frequency band power were evaluated with 24-hour ECG Holter recordings. We found diminished variance in the time domain and reduced power spectrum in the frequency domain compared with a group of 41 normal subjects (p < 0.01). Patients with anterior infarction had significantly (p < 0.01) higher heart rates and lower heart rate variability values than patients with inferior infarction. Reduction in heart rate variability occurred within the first 8 hours in patients with anterior infarction; a significant fall (p < 0.03) was especially noted in the high-frequency band after a decline in ST-segment elevation. Heart rate variability alterations in patients with inferior infarction were most evident in the final 8-hour interval. These findings may be viewed in terms of sympathovagal imbalance and may be related to clinical signs of intense autonomic nervous system activity that are observed early in the course of acute anterior and inferior myocardial infarction.

The angiographic appearance of the coronary arteries was examined in 308 patients with acute myocardial infarction (AMI) who received highdose intravenous thrombolytic therapy. Coronary angiography was performed on day 7 after admission to the hospital. Patients had an average of 2.4 discrete arterial narrowings or obstructions. The narrowings were proximal and related to bifurcations. Four fifths of the culprit arteries were patent; 104 (34%) had a ruptured plaque, 22 (7%) had an ulcerated plaque, and in 190 (62%) the lesions were eccentric. Patients differed from a comparable, previously studied, control series of 302 patients with chronic stable angina pectoris who had more extensive disease. They had 5.7 narrowings/patient, also located proximally and at bifurcations, but more widely distributed in the coronary tree. Patients with AMI who are suitable for thrombolysis have a unique coronary angiographic picture. The data confirm that AMI is caused by sudden rupture of a localized atheromatous plaque that initiates an obstructive thrombotic cascade.

The day vs night values of variables that may be related to the autonomic nervous system were compared in 50 individuals without obvious heart disease. Using ambulatory electrocardiographic monitoring and heart rate variability analysis, it was found that in contrast to daytime, nocturnal heart rate and total heart rate variability were reduced and low (0–0.05 Hz) and high (0.2–0.35 Hz) frequency power of nocturnal heart rate variability were increased, whereas mid-frequency (0.05–0.2 Hz) power was reduced. In addition, nocturnal episodes of trapezoidal-shaped waveforms of heart rate increase were present primarily at night and ST was elevated to a greater extent at night. Many of these factors were related to age and tentatively, despite the small sample size, reflect an age-related diminished autonomic nervous system response. These results serve to establish a circadian basis for comparison when evaluating disease states such as ischemic heart disease and its prognosis.

Background: Patients with diabetes mellitus (D) (both insulin-requiring D [IRD] and non-IRD) who undergo angioplasty have worse long-term outcome than do non-D patients. Few data are available in the literature that explain these findings. Hypothesis: The study was undertaken to compare restenosis and progression of coronary disease after angioplasty in IRD patients, in non-IRD patients, and in non-D patients. Methods: Diabetic patients who underwent coronary angioplasty were separated into two subgroups: IRD and non-IRD patients. Their angiographic outcome was compared with non-D patients. We examined retrospectively 353 coronary angiograms of patients who were referred for diagnostic angiography > 1 month after successful angioplasty. Quantitative angiography was used to determine the outcome in dilated narrowings (restenosis) and in nondilated narrowings (disease progression). Results: Baseline clinical and angiographic characteristics were similar in all groups. Restenosis rate was higher in IRD (61 %) than in non-IRD (36%) and non-D (35%) patients (p = 0.04). Late luminal loss after angioplasty was two times greater in IRD patients than in the other two groups (p=0.01). Disease progression of nondilated narrowings was significantly more prominent in non-IRD than in non-D patients: Diameter stenoses were similar in the initial angiogram, but narrowings were significantly more severe (p=0.02) in the final angiogram (70 ± 27% and 60 ± 33%, respectively). New narrowings were more common in non-IRD than in non-D patients: there was a 23% increase in the number of narrowings in the follow-up angiogram in non-IRD patients compared with only 12% in non-D patients (p < 0.003). These new narrowings were more common (p=0.01) in angioplasty arteries (57 narrowings on 420 arteries—13.6%) than in nonangioplasty arteries (54 narrowings on 639 arteries—8.5%). Conclusion: Restenosis is more common in IRD patients and explains the high rate of adverse cardiac events within the first year after coronary intervention in these patients (mainly target lesion revascularization). Disease progression (including new narrowings) is the main determinant of patient outcome > 1 year after coronary intervention and is accelerated in non-IRD compared with non-D patients.

Analysis of heart rate variability with Holter monitoring during the acute phase of myocardial infarction is often difficult due to excessive artifacts and arrhythmias. Detection of noisy epochs of data or arrhythmias and their substitution by interpolation has enabled further analysis on epochs which otherwise would have been discarded. The present paper discusses various strategies for artifact and arrhythmia detection. Although none of the methods solved all varieties of artifacts, a method based on differences from both moving mean and from the last normal value performs well in the majority of cases.

A method for trend subtraction and its effect on long-term monitoring of the low-frequency range of the heart rate variation is described. Slow trend removal is used prior to applying an autoregressive power spectral analysis to Holter heart rate data. Careful application of this trend removal algorithm reveals important changes in slow periodic heart rate fluctuations that are related to the activity of the automatic nervous system. These changes are otherwise masked by nonperiodic alterations. >

We studied heart rate variability in rats by power scaling spectral analysis (PSSA), autoregressive modeling (AR), and detrended fluctuation analysis (DFA), assessed stability by coefficient of variation between consecutive 6-h epochs, and then compared cross-correlation among techniques. These same parameters were checked from baseline conditions through acute and chronic disease states (streptozotocin-induced diabetes) followed by therapeutic intervention (insulin). Cross-correlation between methods over the entire time period was r = 0.94 (DFA and PSSA), r = 0.81 (DFA and AR), and r = 0.77 (AR and PSSA). Under baseline conditions the scaling parameter measured by DFA and PSSA and the high-frequency (HF) component measured by AR fluctuated around an average value, but these fluctuations were different for the three methods. After diabetes induction, a strong correlation was found between the HF power and the short-term scaling parameter. Despite their differences in methodology, DFA and PSSA assess changes in parasympathetic tone as detected by autoregressive modeling.

Decreased heart rate variability (HRV) is associated with a worse prognosis in a variety of diseases and disorders. We evaluated the determinants of short-period HRV in a random sample of 149 middle-aged men and 137 women from the general population. Spectral analysis was used to compute low-frequency (LF), high-frequency (HF) and total-frequency power. HRV showed a strong inverse association with age and heart rate in both sexes with a more pronounced effect of heart rate on HRV in women. Age and heart rate-adjusted LF was significantly higher in men and HF higher in women. Significant negative correlations of BMI, triglycerides, insulin and positive correlations of HDL cholesterol with LF and total power occurred only in men. In multivariate analyses, heart rate and age persisted as prominent independent predictors of HRV. In addition, BMI was strongly negatively associated with LF in men but not in women. We conclude that the more pronounced vagal influence in cardiac regulation in middle-aged women and the gender-different influence of heart rate and metabolic factors on HRV may help to explain the lower susceptibility of women for cardiac arrhythmias.

The present study was undertaken to compare heart rate variability (HRV) values in patients on maintenance hemodialysis with no evidence of ischemic or hypertensive heart diseases to those of age- and gender-matched healthy individuals and those of patients after renal transplantation. To assess the effects of a common confounding factor, HRV values were also determined in patients with systemic amyloidosis, in chronic hemodialysis, and after successful renal transplantation. Spectral analyses of RR intervals from continuous electrocardiogram recordings were performed to quantify ultra low frequency, very low frequency, low frequency, and high frequency powers. HRV determinations were all significantly reduced in uremic patients undergoing hemodialysis compared with the healthy control subjects, especially in those with systemic amyloidosis. Renal transplantation normalized HRV in most patients; HRV, however, remained reduced in isolated amyloidosis patients with cardiac or adrenal involvement. HRV circadian day/night differences were preserved in hemodialysis patients and after renal transplantation in those without amyloidosis but not in those with amyloidosis. These data suggest that reduced HRV in chronic hemodialysis patients may precede other manifestations of cardiovascular disease. In uremic patients with amyloidosis, a more severe form of autonomic failure may occur. Successful transplantation corrects HRV abnormalities in most patients, suggesting that the autonomic dysfunction of uremia is caused by humoral factors reversed by the normalization of the renal function.

The present study employs a computer simulation of the timing of normal and abnormal ventricular activation according to a re-entry model. A wide variety of arrhythmia patterns similar to those obtained in clinical settings may be simulated by using an algorithm which is based on parameters such as the sinus RR interval (RR), the refractory period, the coupling interval between normal activation and re-entry and the coupling interval between one re-entry and a subsequent re-entry (CV). By varying RR and CV the results of the simulation may show transition between different types of arrhythmia such as ventricular tachycardia, bigeminy, trigeminy and more widely separated ventricular ectopic beats such as in concealed bigeminy. The algorithm provides a basis for the study of re-entry, a major mechanism in the genesis of ventricular arrhythmias.

We evaluated the long-term angiographic outcome of balloon angioplasty by comparing original and follow-up target coronary narrowing. Rather than using restenosis to determine outcome, as in most angioplasty studies, we took an unusual approach and analyzed outcome in terms that are commonly used in progression and regression studies after medical interventions. Quantitative angiographic measurements were undertaken in 315 narrowings with an initial diameter stenosis90% before and after angioplasty and at follow-up. Angiographic deterioration (10% increase in follow-up diameter stenosis) was identified in 44 (14%) narrowings. Angiographic deterioration was not influenced by age, sex, risk factors, lipid profile, or the indication for angioplasty. Deterioration was also not predicted by the severity, length, or the location of the narrowing. The deteriorating narrowings had a higher recoil after dilatation compared with narrowings with angiographic improvement (21% +/- 31% vs 12% +/- 17%, p = 0.006); the residual stenosis after angioplasty was therefore higher. The late loss was also significantly increased compared with narrowings with angiographic improvement (65% +/- 26% vs 8% +/- 24%, p0.001). We conclude that the incidence of angiographic deterioration of coronary disease as a result of restenosis is uncommon but not negligible. Interventional cardiologists should resist the temptation to dilate mild, silent coronary narrowings because the procedure might have an unfavorable angiographic (and probably clinical) effect.

Regularity or complexity characteristics of RR interval variations have attained importance in the evaluation of a variety of pathological conditions. Regular periodic fluctuations in heart rate are considered indicators of loss of control in the cardiovascular system and of disturbances in pulmonary function. Methods to detect such loss of cardiopulmonary function have been developed mainly through linear and non-linear system analysis. Both approaches were tested in the present study. MBW, which is the ratio between maximal power spectrum (PS) amplitude and its 3-db bandwidth (BW) in the 0-0.1 Hz frequency range, was calculated and compared for different examples derived from 24 h Holter recordings and for sinusoidal function mixed with varying degrees of noise. Approximate entropy (ApEn), a measure derived from non-linear system analysis has been tested for the same data and compared with the MBW ratio. The results show that MBW effectively differentiates regular and non-regular epochs while ApEn differentiates them in a less optimal manner especially in cases where higher degrees of noise are present but regularity is still observed visually.

Myocardial damage in acute myocardial infarction is a time-dependent process. We examined the influence of very early thrombolytic therapy, comparing prehospital to hospital administration, in a consecutive group of patients with myocardial infarction on mortality, complications and the preservation of left ventricular function. Seven hundred sixty patients received early thrombolytic therapy: 114 at home (time delay to treatment 1.4 +/- 0.8 h) and 646 in hospital (2.1 +/- 1.0 h). Sixteen patients died in hospital and significant hemorrhage occurred in 15 (including three patients with hemorrhagic stroke). There was no difference between groups in hospital mortality or rate of complications. The duration of ischemia was shorter in patients with prehospital therapy (pain duration: 3.3 +/- 2.1 vs. 4.0 +/- 2.2; P0.05, and time to recovery of the ST segment in the electrocardiogram: 4.3 +/- 3.3 vs. 6.6 +/- 6.3; P0.002). Peak plasma creatine kinase was earlier in patients with prehospital therapy (11.2 +/- 5.0 vs. 13.0 +/- 5.8; P0.002), although there was no difference between groups in the absolute peak plasma level. Left ventricular function was assessed by contrast ventriculography 1 week after admission (616 patients). Ventricular function was better in patients with prehospital therapy: (ejection fraction of 58 +/- 13% vs. 54 +/- 15%; P0.05 and a left ventricular dysfunction index of 534 +/- 515 vs. 691 +/- 519 units; P0.05). We conclude that prehospital thrombolytic therapy is feasible and safe. Reperfusion is achieved earlier and more myocardium can be salvaged using this strategy without increasing the rate of complications.

The variability in heart rate is related to the activity of the autonomic nervous system, which influences the heart rate either directly or via the peripheral circulation. In this study direct measurement of peripheral circulation parameters and their variability was obtained by means of photoplethysmography which provides assessment of the blood volume in the tissue and its increase during systole by measuring the light absorption in the tissue. Both blood volume and systolic blood volume increase showed oscillations in very low frequency, about 0.02 Hz and in relative high frequency, about 0.3 Hz, which is related to respiration. In comparison to the variability of the heart rate the high frequency oscillation has lower amplitude but the low frequency oscillation is much higher.

Coronary restenosis after balloon angioplasty is a slow process that develops over a few months. In some patients, with an initially successful angioplasty, an artery that originally had only moderate stenosis becomes totally occluded as a result of restenosis. This report describes 16 such patients out of 415 dilated lesions with late angiographic follow-up. Ten patients presented with stable angina pectoris, 5 had unstable angina and only one was admitted with a small myocardial infarction. Visible collaterals were present in 15 patients. Except for the patient who sustained myocardial infarction, none of the late angiograms showed the typical morphological features of acute lesion. We conclude that total coronary occlusion late after successful angioplasty of an artery that was moderately narrowed is rare. The 'restenotic' occlusion is a slow process that stimulates collateral formation and thus the risk of myocardial infarction is small.

The role of plasma lipoproteins in the pathogenesis of coronary atherosclerosis has been well defined. 1 Restenosis after coronary angioplasty is often described as a form of accelerated atherosclerosis due to phenotypic modification and proliferation of medial muscle myocytes. 2 A few recent studies investigated the role of lipoproteins in restenosis, but the results were conflicting. 3–5 Modification of lipoprotein profile can halt the progression and even induce regression of coronary atherosclerosis 6,7 ; whether it can also decrease the rate of restenosis is not clear. In this investigation, we examined the effect of the different lipoprotein fractions on the development of restenosis, using the absolute and relative amounts of late loss of luminal diameter as a continuous measure of restenosis.

Patients with diabetes mellitus are excessively vulnerable to myocardial ischemia and often suffer from autonomic cardiac dysfunction. They are also known to have specific capillary pathology and abnormalities of substances essential for the neoangiogenic cascade. These background data led us to the hypothesis that the severity of ischemic heart disease in diabetes is attributable (at least in part) to microcirculatory and autonomic inadequacy caused by microangiopathy and failure of postischemic adaptive neoangiogenesis. To test this hypothesis we compared myocardial capillaries, autonomic nerve endings of 19 diabetics, 30 normoglycemics with ischemic heart disease, and 9 valve replacements serving as nonischemic controls. Right atrial appendages obtained during coronary bypass surgery were utilized for light, fluorescent, and electron microscopic morphometry. Although in this series there were no significant differences in the clinical and laboratory hemodynamic values between the ischemic normoglycemic and diabetic patients, the latter showed marked capillary and nerve terminal pathology, and their capillary density as well as capillary to myofiber ratios were significantly lower. In addition, the mean capillary area, volume fraction, and intercapillary distance were higher in diabetics. The mean area of the nerve varicosities was also smaller, and this was correlated with capillary density. We concluded that the findings support the hypothesis that cardiac vulnerability in diabetes is connected with inadequate adaptive neoangiogenesis and that this seems to be associated with atrophic changes in the nerve terminals.

Perioperative myocardial ischemia was evaluated in 36 consecutive carotid endarterectomy procedures carried out on patients with a high (72.2%) prevalence of ischemic heart disease. The procedures were performed under cervical plexus block plus a prophylactic intravenous nitroglycerin infusion. Findings of myocardial ischemia on perioperative (48 hours) continuous electrocardiogram recordings were correlated with preoperative cardiac status, perioperative continuous intra-arterial blood pressure measurements, and postoperative cardiac outcome. In two patients, ST segment analysis was un-interpretable because of bundle-branch blocks. Altogether, 64 episodes of significant ST segment depression were detected in 18 (52.9%) of the remaining procedures. In 8 (23.5%) procedures, ST segment depressions occurred either during carotid artery clamping at the time of the largest rise in blood pressure or within 2 hours of declamping, when blood pressure tended to decline. There were four (11.7%) postoperative cardiac events: three myocardial infarctions (one 0 wave and two non-Q wave) and one episode of unstable angina pectoris. All four patients with cardiac events had early signs of myocardial ischemia either at the time of cross-clamping, or soon after declamping of the carotid artery. All myocardial infarctions developed following prolonged (>10 hours) myocardial ischemia, starting with the first 20 hours after surgery. Thus, ST segment depression occurring during clamping or soon after carotid declamping was associated with cardiac complications (sensitivity 100% and specificity 86.6%) and suggests the possible usefulness of on-line ST segment trend monitoring.

Atheromatous coronary artery disease progresses by atheroma accretion, plaque rupture and thrombus formation, with or without spontaneous fibrinolysis [1–3]. The natural history may be altered by modifying risk factors in an attempt to induce regression [4], or treated by mechanical means such as balloon angioplasty, directional coronary atherectomy or drills, or flow modulated by the insertion of an aorto coronary bypass graft with or without endarterectomy [5, 6].

Multiresolution representations of the heart rate variability (HRV) using the wavelet transforms are proposed to characterize the autonomic nervous system regulation of cardiovascular activity during carotid surgery. Results suggest that the power in all frequency bands was low during the surgery and increased after the declamping of the carotid artery.

Parasympathetic autonomie nervous system activity is reflected in the high frequency (HF) range of heart rate fluctuations. The proper selection of the limits of this HF frequency range is important for following parasympathetic activity under different physiologic or pathologic conditions. A low cut-off frequency of 0.15 Hz allows power from lower frequencies components which are not solely connected with the parasympathetic system to enter into calculations of HF activity. This error of HF power estimation causes, for instance, masking of increased true HF activity during sleep. A low cut-off frequency of 0.2 Hz remedies such problems while only rarely leading to errors due to peak HF power at frequencies lower than 0.2 Hz.