Heart rate variability and progression of coronary atherosclerosis.

Low heart rate (HR) variability is associated with increased risk of cardiovascular morbidity and mortality, but the causes and mechanisms of this association are not well known. This prospective study was designed to test the hypothesis that reduced HR variability is related to progression of coronary atherosclerosis. Average HR and HR variability were analyzed in 12-hour ambulatory ECG recordings from 265 qualified patients participating in a multicenter study to evaluate the angiographic progression of coronary artery disease in patients with prior coronary artery bypass surgery and low high-density lipoprotein cholesterol concentrations (<1.1 mmol/L). Participants were randomized to receive a placebo or gemfibrozil therapy. The progression of coronary atherosclerosis was estimated by quantitative, computer-assisted analysis of coronary artery stenoses from the baseline angiograms and from repeated angiograms performed an average of 32 months later. The progression of focal coronary atherosclerosis of the patients randomized to placebo therapy was more marked in the tertile with the lowest standard deviation of all normal to normal R-R intervals (SDNN, 74+/-13 ms; mean decrease in the per-patient minimum luminal diameter -0.17 mm; 95% confidence interval [CI], -0.23 to -0.12 mm) than in the middle tertile (SDNN, 107+/-7 ms; mean decrease -0.05 mm; 95% CI, -0.08 to -0.01 mm) or highest tertile (SDNN, 145+/-25 ms; mean change 0.01 mm; 95% CI, -0. 04 to 0.02 mm) (P<0.001 between the tertiles). This association was abolished by gemfibrozil. SDNN was lower (P<0.001) and minimum HR was faster (P<0.01) in the patients with marked progression than in those with regression of focal coronary atherosclerosis. In multiple regression analysis including HR variability, minimum HR, demographic and clinical variables, smoking, blood pressure, glucose, lipid measurements and lipid-modifying therapy, progression of focal coronary atherosclerosis was independently predicted by the SDNN (beta=0.24; P=0.0001). Low HR variability analyzed from ambulatory ECG predicts rapid progression of coronary artery disease. HR variability provided information on progression of focal coronary atherosclerosis beyond that obtained by traditional risk markers of atherosclerosis.

Gender difference in autonomic and hemodynamic reactions to abrupt coronary occlusion.

OBJECTIVES: We sought to determine whether there are gender-related differences in autonomic and hemodynamic responses to abrupt coronary occlusion. BACKGROUND: The risk of sudden death before hospital admission is higher in men with an acute myocardial infarction. The reasons for this gender-related difference are not well understood. Cardiovascular autonomic regulation modifies the outcome of acute coronary events, and there are gender differences in the autonomic regulation of heart rate (HR) in normal physiologic circumstances. METHODS: We analyzed the changes in HR, HR variability and blood pressure and the occurrence of ventricular ectopic beats during a 2-min coronary occlusion in 140 men and 65 women referred for single-vessel coronary angioplasty. The ranges of nonspecific responses were determined by analyzing a control group of 19 patients with no ischemia during a 2-min balloon inflation in a totally occluded coronary artery. RESULTS: Women more often had ST segment changes (p < 0.01) and chest pain (p < 0.05) during the occlusion. Significant bradycardia or increase in HR variability as a sign of vagal activation occurred more often in women than in men (31% vs. 13%, p < 0.01 and 25% vs. 11%, p < 0.05, respectively). Coronary occlusion also more often caused (28% vs. 11%, p < 0.01) a decrease in blood pressure in women. The most pronounced female preponderance was in the incidence of Bezold-Jarisch-type reaction (i.e., simultaneous bradycardia and decrease in blood pressure [16% vs. 0.7%, p < 0.0001]). Logistic regression models developed to analyze the significance of gender while controlling for baseline variables and signs of ischemia identified female gender to be an independent predictor of bradycardic reactions (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.7, p < 0.01), hypotensive reactions (OR 2.6, 95% CI 1.1 to 6.0, p < 0.05) and Bezold-Jarisch-type response (OR 22.2, 95% CI 2.5 to 200, p < 0.01). Significance of female gender as a protector against early coronary occlusion-induced ventricular ectopic beats emerged as having borderline significance (OR 0.4, CI 0.1 to 1.1, p = 0.07). CONCLUSIONS: Vagal activation is more common in women than in men during abrupt coronary occlusion and may have beneficial antiarrhythmic effects, modifying the outcome of acute coronary events.

Baroreflex sensitivity in drug-treated systemic hypertension.

Baroreflex sensitivity is impaired in patients with systemic hypertension. The persistence of abnormal baroreflex sensitivity despite adequate blood pressure control may be one of the reasons why the effect of antihypertensive therapy on coronary artery disease mortality has been less than expected on the basis of the achieved blood pressure levels.

Sex-related differences in autonomic modulation of heart rate in middle-aged subjects.

BACKGROUND: Women have worse outcomes when they experience acute myocardial infarction (MI), but the reasons for this sex-related difference are not well understood. Because cardiovascular neural regulation plays an important role in cardiac mortality, we studied possible sex-related differences in the autonomic modulation of heart rate (HR) in middle-aged subjects without known heart disease. METHODS AND RESULTS: Baroreflex sensitivity (BRS) and HR variability were studied in randomly selected, age-matched populations of middle-aged women (n = 186; mean age, 50 +/- 6 years) and men (n = 188; mean age, 50 +/- 6 years) without hypertension, diabetes, or clinical or echocardiographic evidence of heart disease. BRS measured from the overshoot phase of the Valsalva maneuver was significantly lower in women (8.0 +/- 4.6 ms/mm Hg, n = 152) than in men (10.5 +/- 4.6 ms/mm Hg, n = 151) (P < .001), and the low-frequency component of HR variability measured from ECG recordings also was lower in women (P < .001), whereas the high-frequency component was higher in women than in men (P < .001). The ratio between the low-and high-frequency oscillations also was lower in the women (P < .001). The increase of HR and decrease of high-frequency component of HR variability in response to an upright posture were smaller in magnitude in women than in men (P < .01 for both). After adjustment for differences in the baseline-variables, such as blood pressure, HR, smoking, alcohol consumption, and psychosocial score, the sex-related differences in BRS and HR variability still remained significant (P < .001 for all). Women with estrogen replacement therapy (n = 46) had significantly higher BRS and total HR variance than the age-matched women without hormone treatment (P < .01 for both), and the BRS and HR variability of the women with estrogen therapy did not differ from those of the age-matched men. CONCLUSIONS: Baroreflex responsiveness is attenuated in middle-aged women compared with men, but the tonic vagal modulation of HR is augmented. Hormone replacement therapy appears to have favorable effects on the cardiovascular autonomic regulation in postmenopausal women.

Dispersion of the QT interval and autonomic modulation of heart rate in hypertensive men with and without left ventricular hypertrophy.

Left ventricular hypertrophy is an independent risk factor for sudden cardiac death in hypertension, but the mechanisms of electrical instability associated with hypertrophy are not well known. We studied dispersion of the QT interval, an index of inhomogeneity of repolarization, and heart rate variability, a measure of cardiac autonomic modulation, in a randomly selected population of 162 men with systemic hypertension and made comparisons between the patients with echocardiographic evidence of left ventricular hypertrophy (left ventricular mass index > or = 131 g/m2, n = 44) and those without hypertrophy (left ventricular mass index < 131 g/m2, n = 118). The heart rate-corrected QT dispersion (67 +/- 37 versus 53 +/- 21 milliseconds, P < .05) and QT apex dispersion (55 +/- 22 versus 44 +/- 16 milliseconds, P < .01) were significantly longer in the patients with left ventricular hypertrophy than in those without hypertrophy. Thirteen of the 44 patients (30%) with hypertrophy versus 7 of the 118 patients (6%) without hypertrophy had an abnormally long QT apex dispersion ( > 70 milliseconds) (P < .001). The time and frequency domain measures of heart rate variability did not differ significantly between the patient groups with and without left ventricular hypertrophy. The measures of heart rate variability were not related to QT dispersion or left ventricular mass index but had a negative correlation with blood pressure values (eg, r = -.30 between the low-frequency component of heart rate variability and systolic pressure, P < .001). Age, body mass index, antihypertensive medication, and the other demographic variables were similar between the groups, but the patients with left ventricular hypertrophy had higher systolic (P < .01) and diastolic (P < .01) pressures compared with the patients without hypertrophy. Left ventricular hypertrophy in hypertensive men is associated with inhomogeneity of the early phase of ventricular repolarization, favoring susceptibility to reentrant ventricular tachyarrhythmias. Abnormalities in cardiac autonomic function, which may trigger a spontaneous onset of arrhythmias, are related to elevated blood pressure but not specifically to left ventricular hypertrophy.

Heart rate variability in systemic hypertension.

Low heart rate (HR) variability is a risk factor for cardiac mortality in various patient populations, but it has not been well established whether patients with long-standing hypertension have abnormalities in the autonomic modulation of HR. Time and frequency domain measures of HR variability were compared in randomly selected, age-matched populations of 188 normotensive and 168 hypertensive males (mean age 50 +/- 6 years for both). The standard deviation of the RR intervals was lower in the hypertensive subjects than in the normotensive ones (52 +/- 19 vs 59 +/- 20 mss; p <0.01), and the very low and low-frequency spectral components of HR variability analyzed as absolute units were reduced in the hypertensive patients relative to the normotensive controls (p <0.001 for both). Hypertensive subjects also had blunted changes of the normalized low- and high-frequency components in response to an upright (sitting) posture (NS) as compared with normotensive subjects (p <0.001 for both). Multiple regression analysis showed the standard deviation of the RR intervals to be predicted most strongly by systolic blood pressure, both in the patients with hypertension (beta--0.20, p=0.01) and in the normotensive subjects (beta--0.28, p=0.0002). After adjustment for the baseline differences in blood pressure and body mass index, none of the absolute measures of the HR variability or the responses of the normalized units of HR variability to a change in the body posture differed between the hypertensive subjects and normotensive controls. These data show that long-standing hypertension results in reduced overall HR variability and blunted autonomic responses to a change in body posture. Altered autonomic modulation of HR in hypertension is mainly due to elevated blood pressure and obesity in males with long-standing hypertension as compared with normotensive subjects.

Abnormalities in beat-to-beat dynamics of heart rate before the spontaneous onset of life-threatening ventricular tachyarrhythmias in patients with prior myocardial infarction.

BACKGROUND: Beat-to-beat analysis of RR intervals can reveal patterns of heart-rate dynamics, which are not easily detected by summary measures of heart-rate variability. This study was designed to test the hypothesis that alterations in RR-interval dynamics occur before the spontaneous onset of ventricular tachyarrhythmias (VT). METHODS AND RESULTS: Ambulatory ECG recordings from 15 patients with prior myocardial infarction (MI) who had spontaneous episodes of sustained VT during the recording and VT inducible by programmed electrical stimulation (VT group) were analyzed by plotting each RR interval of a sinus beat as a function of the previous one (Poincaré plot). Poincaré plots were also generated for 30 post-MI patients who had no history of spontaneous VT events and no inducible VT (MI control subjects) and for 30 age-matched subjects without heart disease (normal control subjects). The MI control subjects and VT group were matched with respect to age and severity of underlying heart disease. All the healthy subjects and MI control subjects showed fan-shaped Poincaré plots characterized by an increased next-interval difference for long RR intervals relative to short ones. All the VT patients had abnormal plots: 9 with a complex pattern, 3 ball-shaped, and 3 torpedo-shaped. Quantitative analysis of the Poincare plots showed the SD of the long-term RR-interval variability (SD2) to be smaller in all VT patients (52+/-14 ms; range, 31 to 75 ms) than in MI control subjects (110+/-24 ms; range, 78 to 179 ms, P<.001) or the normal control subjects (123+/-38 ms, P<.001), but the SD of the instantaneous beat-to-beat variability (SD1) did not differ between the groups. The complex plots were caused by periods of alternating sinus intervals, resulting in an increased SD1/SD2 ratio in the VT group. This ratio increased during the 1-hour preceding the onset of 27 spontaneous VT episodes (0.43+/-0.20) compared with the 24-hour average ratio (0.33+/-0.19) (P<.01). CONCLUSIONS: Reduced long-term RR-interval variability, associated with episodes of beta-to-beat sinus alternans, is a highly specific sign of a propensity for spontaneous onset of VT, suggesting that abnormal beat-to-beat heart-rate dynamics may reflect a transient electrical instability favoring the onset of VT in patients conditioned by structurally abnormal hearts.

Effect of beta blockade on heart rate variability during vessel occlusion at the time of coronary angioplasty.

Beta blockers modify cardiovascular neural regulation, which may contribute to their protective effect against sudden cardiac death. To evaluate the effects of beta blockade on cardiovascular autonomic reactions caused by acute coronary occlusion in humans, heart rate (HR) variability was analyzed in the time and frequency domains immediately before and during balloon occlusion of a coronary artery in 116 patients randomly assigned to either chronic beta-blocker therapy (beta-blocker group) or no beta blockade (control group) during elective 1-vessel coronary angioplasty. Coronary occlusion (mean 112 seconds) caused a significant increase in both the high- and low-frequency components of HR variability in the control group (n = 58), from 2.7 +/- 1.6 to 3.4 +/- 1.7 (logarithmic units, p < 0.001) and from 4.3 +/- 1.3 to 4.8 +/- 1.5 (p < 0.01), respectively, whereas in the beta-blocker group (n = 58), the high-frequency power did not change during occlusion, but the low-frequency power increased from 3.9 +/- 1.4 to 4.4 +/- 1.4 (p = 0.01). Changes in high- and low-frequency components and HR were related to the change in systolic blood pressure during occlusion in the beta-blocker group (r = 0.53, p < 0.001; r = 0.34, p < 0.05; and r = -0.41, p < 0.01, respectively), but not in the control group (r = -0.17, r = -0.14, and r = 0.24, respectively). Thus, beta blockade attenuates the initial vagal activation associated with acute coronary occlusion and seems to maintain baroreflex-mediated cardiovascular control. The maintained integrity of baroreflex regulation and the alleviation of extreme autonomic reactions during beta blockade may modify the clinical outcome of acute coronary occlusion in a beneficial way.

Significance of perfusion of the infarct related coronary artery for susceptibility to ventricular tachyarrhythmias in patients with previous myocardial infarction.

OBJECTIVE: To study the significance of perfusion of the infarct related coronary artery for susceptibility to ventricular tachyarrhythmias in patients with a remote myocardial infarction. SETTING: Tertiary referral cardiac centre. METHODS: Angiographic filling of the infarct related artery was assessed in a consecutive series of 85 patients with different susceptibilities to ventricular tachyarrhythmias after previous (> 3 months) Q wave myocardial infarction: 30 patients had a history of cardiac arrest (n = 16) or sustained ventricular tachycardia (n = 14), and sustained ventricular tachyarrhythmia was inducible in these by programmed electrical stimulation (arrhythmia group); 47 patients had no clinical arrhythmic events and no inducible ventricular tachyarrhythmias during programmed ventricular stimulation (control group). Eight patients without a history of any arrhythmic events were inducible into ventricular tachycardia. RESULTS: The patients in the arrhythmia group were older (63 (SD 8) years) than the control patients (59 (6) years, P < 0.05), and had larger left ventricular volumes in cineangiography (P < 0.01), but ejection fraction, severity of left ventricular wall motion abnormalities, previous thrombolytic therapy, and time from previous infarction did not differ between the groups. Patients with susceptibility to ventricular tachyarrhythmias more often had a totally occluded infarct related artery on angiography (77%) than patients without arrhythmia susceptibility (21%) (P < 0.001), and complete collateral filling of the infarct artery in cases without complete anterograde filling was less common in the arrhythmia group than in the control group (P < 0.001). Patients without a history of malignant arrhythmia but with inducible ventricular tachyarrhythmia also had no or poor perfusion of the infarct artery more often than the patients without inducible arrhythmia (P < 0.001). Logistic multiple regression showed that no or poor anterograde or collateral filling of the infarct related artery was the most powerful predictor of susceptibility to ventricular tachyarrhythmias (P < 0.001). Left ventricular size and function were not independently related to arrhythmic susceptibility. CONCLUSIONS: No or poor angiographic filling of the infarct related artery is closely associated with susceptibility to ventricular tachyarrhythmias late after acute myocardial infarction, suggesting that perfusion of the infarct artery will modify favourably the electrophysiological substrate of the infarct scar independently of the myocardial salvage achieved by early reperfusion.

Effects of perfusion of the infarct-related artery on risk markers of life-threatening arrhytmias in patients with prior myocardial infarction

Programmed electrical stimulation (PES), angiographic studies, Holter recording, 12-lead ECG and signal averaged ECG (SAECG, n=63) were performed in 109 consecutive patients with a prior Q-wave myocardial infarction (MI). Sixty-five patients (59 por cento) had TMI-class ) or 1 antegrade perfusion without significant collateral filling of the infarct related artery (IRA) (=poor persuion) and forty four (41 por cento) had either good antegrade or collateral perfusion of the IRA. The severity of corony artery disease or ejection fraction did not differ between the patients with poor or good perfusion of IRA. Heart rate variability and presence of late potentials on SAECG were also similar between the groups. but the dispersion of the QT interval was prolonged in the patients with poor perfusion of IRA (86 +/- 35 ms vs. 69 +/- 27 ms, p<0.01). The patients with poor perfusion of IRA had more often a clinical history of VT compared to those with good perfusion (68 por cento vs 9 por cento, p<0.01). Patets with good filling of the IRA after a prior MI have a low risk for VT, suggesting that preserved perfusion of the infarct scar stabilizes the electrophysiologic substrate.

Stenosis severity and the occurrence of ventricular ectopic activity during acute coronary occlusion during balloon angioplasty.

To elucidate the incidence and determinants of early ventricular arrhythmias (VA) during acute coronary occlusion, continuous electrocardiographic, heart rate, and blood pressure recordings were performed in 152 patients during standardized balloon occlusions of significant (50% to 95%) coronary artery stenoses. A control group of 13 patients with chronic total occlusion of a coronary artery was also studied. None of them developed VA during balloon inflation in the preexisting total occlusion of the artery. Balloon occlusion of a coronary artery was associated with occurrence of ventricular ectopy in 18 patients (VA group, 12%). The VA group had milder stenosis severity (72% vs 81%, p < 0.001) than the rest of the patients, and none of them had visible collaterals to the occluded vessel. The VA group also had ST-segment deviations more often (p < 0.05) during occlusion than patients with no VA. Occlusion of the left anterior descending artery caused VA more often (p < 0.05) than occlusion of the left circumflex or right coronary artery. No clinical or hemodynamic variable or medication was associated with the occurrence of VA. In stepwise logistic regression analysis, the only significant predictors of ventricular ectopic activity were the stenosis severity and the anterior site of coronary occlusion. Even a nonstenotic plaque can be so fragile that it is prone to rupture. The present findings suggest that such an occlusion may result in electrical instability more easily than occlusion of a more advanced coronary lesion.

Impaired low-frequency oscillations of heart rate in patients with prior acute myocardial infarction and life-threatening arrhythmias.

Myocardial infarction results in abnormal cardiac autonomic function, which carries an increased risk of cardiac mortality, but it is not well known whether autonomic dysfunction itself predisposes patients to life-threatening arrhythmias or whether it merely reflects the severity of underlying ischemic heart disease. To determine the significance of abnormalities of cardiovascular neural regulation on the risk for ventricular tachycardia (VT), heart rate (HR) variability in the time and frequency domain were compared in a case-control study between 30 patients with a prior myocardial infarction and a history of sustained VT (n = 18) or cardiac arrest (n = 12) (VT group) and 30 patients with a prior myocardial infarction but no arrhythmic events (control group). The patient groups were carefully matched with respect to age, sex, location, ejection fraction, number of prior infarctions, number of diseased coronary arteries, and beta-blocking medication. In all patients in the VT group, inducibility into sustained VT was achieved, but none of the control patients had inducible nonsustained or sustained VT during programmed electrical stimulation. Patients in the VT group had a significantly lower SD of the RR intervals (p < 0.01), and reduced ultra low-, very low-, and low-frequency power spectral components of HR variability (p < 0.001 for all) than controls, but the high-frequency component of HR variability did not differ significantly between groups. In multiple regression analysis, reduced very low-frequency power of HR variability was the strongest independent predictor of VT susceptibility.(ABSTRACT TRUNCATED AT 250 WORDS)

Diurnal fluctuations in human ventricular and atrial refractoriness.

The relative significance of the direct and indirect effects of autonomic tone on diurnal fluctuations in human ventricular and atrial refractoriness are not well known. In this study, the circadian rhythms of ventricular and atrial effective refractory periods (ERPs) were measured by noninvasive programmed stimulation in ten patients (mean age 62 +/- 10 years) who had a permanent dual chamber pacemaker for complete atrioventricular (AV) block. The ERP was measured at 4-hour intervals during spontaneous sinus rhythm with ventricular pacing (day 1) and during constant-rate dual chamber pacing (day 2). Cosinor analysis showed the ventricular ERP to have a significant diurnal rhythm in sinus rhythm (amplitude, 12 msec; 95% confidence intervals 1-24 msec) but not during constant-rate pacing (amplitude, 4 msec; 95% confidence intervals -3-12 msec). The atrial ERP had a significant rhythm at times of both spontaneous sinus rate (amplitude, 19 msec; confidence intervals 13-24 msec) and constant heart rate (amplitude, 11 msec; confidence intervals 1-21 msec) with acrophase during the sleeping hours. The increase in heart rate during dual chamber pacing resulted in a more marked decrease in the average 24-hour ERP in the ventricle than in the atrium (46 +/- 9 msec vs 12 +/- 6 msec, P < 0.01). Thus, refractoriness is more rate dependent in the ventricle than in the atrium, and autonomic influences on ventricular refractoriness are mainly indirect, via fluctuations in the sinus rate, but atrial refractoriness is also affected by direct neural influences and/or other rate independent factors.

Heart rate variability during repeated arterial occlusion in coronary angioplasty.

Acute coronary occlusion may cause severe autonomic reactions that can modify the clinical presentation of acute ischemic events. To evaluate whether adaptation in these autonomic reactions exists during repeated short coronary occlusions, heart rate (HR) and its variability in the time and frequency domains were analyzed in 70 patients with significant (50% to 95%) coronary artery stenosis immediately before and during 2 identical balloon occlusions of the vessel (mean 110 seconds). Reactions were compared with the range of nonspecific changes formed by analyzing a control group (n = 13) with no ischemia during balloon inflation in a totally occluded coronary artery. Thus, neither occlusion caused significant changes in HR or HR variability in 29 patients (41%). Vagal activation, as seen by an abnormal increase in HR variability or bradycardia, or both, was observed in 24 patients (34%). HR reactions in this group (p < 0.05) were significantly attenuated during the second occlusion. An opposite reaction (i.e., abnormal decrease in HR variability or tachycardia, or both) was observed in 17 patients (24%). A nonsignificant tendency for attenuation of the reactions was also seen in this group. Severity of chest pain, frequency of ST-segment shifts, or narrowing of pulse pressure were comparable during the 2 occlusions. Thus, a preceding short vessel occlusion-reperfusion cycle seems to attenuate autonomic HR reactions, especially vagal reactions, during subsequent coronary occlusion. Alleviation of extreme autonomic reactions may modify the clinical outcome of coronary occlusion in a beneficial way.

Effect of preocclusion stenosis severity on heart rate reactions to coronary occlusion.

Autonomic mechanisms may have an important role in the clinical presentation of acute coronary occlusion. This research was designed to evaluate the effect of preocclusion stenosis severity on the immediate autonomic heart rate (HR) responses to a subsequent acute occlusion of the coronary artery. HR and its variability in the time and frequency domains were analyzed in patients with mild to moderate (< or = 85%) (group 1, n = 19) and severe (> 85%) (group 2, n = 18) left anterior descending coronary artery stenosis immediately before and during balloon occlusion (mean 108 seconds). The ranges of nonspecific responses were determined by analyzing HR reactions in a control group (n = 13) with no ischemia during balloon inflation of a totally occluded coronary artery. An abnormal increase in HR variability and/or bradycardia as a sign of vagal activation occurred in 6 patients (32%) in group 1 and in 3 patients (17%) in group 2. A significant decrease in HR variability or tachycardia, or both, was observed in 5 patients (26%) in group 1, but in none of the patients in group 2. Compared with the control group, the balloon occlusion of mild to moderate stenosis caused abnormal HR reactions more often than did occlusion of tight stenosis (58% vs 17%, p < 0.05). Balloon occlusions in group 1 caused chest pain (p < 0.01), ST-segment changes (p < 0.001), and narrowing of pulse pressure (p < 0.05) more often than did occlusions of severe stenoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian rhythms of frequency domain measures of heart rate variability in healthy subjects and patients with coronary artery disease. Effects of arousal and upright posture.

BACKGROUND: Altered neural regulation of the cardiovascular system may be an important factor for various manifestations of ischemic heart disease. This research was designed to compare the circadian rhythm of cardiac neural regulation and autonomic responses to arousal and upright posture between patients with uncomplicated coronary artery disease (CAD) and age-matched subjects with no evidence of heart disease. METHODS AND RESULTS: Twenty-four-hour heart rate variability (HRV) in the frequency domain was analyzed in 20 male patients (mean age, 52 +/- 7 years) with angiographic evidence of CAD without prior myocardial infarction and in 20 healthy men (mean age, 51 +/- 8 years) with no clinical, echocardiographic, or exercise ECG evidence of heart disease. None of the 24-hour average frequency-domain components of HRV differed significantly between the two groups. Healthy subjects had a significant circadian rhythm of normalized units of high-frequency (HF) power of HRV with higher values during sleep. Normalized units of low-frequency (LF) power and the LF/HF ratio also showed a significant circadian rhythm in healthy subjects, with higher values during the daytime. No significant circadian rhythms in any of the normalized spectral components of HRV were observed in patients with CAD, and the night-day difference in LF/HF ratio was smaller in the patients with CAD than in the healthy subjects (0.5 +/- 1.4 versus 1.8 +/- 0.7, P < .001). Awakening when in the supine position resulted in a significant increase in the LF/HF ratio (P < .01) in the healthy subjects, but no significant changes in HRV were observed after awakening in patients with CAD. Assumption of upright position resulted in a comparable decrease in the components of HRV between the groups. CONCLUSIONS: The circadian rhythm of cardiac neural regulation is altered in patients with uncomplicated CAD. Reduced autonomic responses to sleep-wake rhythm suggest that the modulation of cardiac autonomic function by stimuli from the central nervous system is impaired in CAD.

Mitochondrial DNA deletions in dilated cardiomyopathy: a clinical study employing endomyocardial sampling.

OBJECTIVES: The aim of this study was to assess the occurrence of the two most commonly encountered mitochondrial DNA (mtDNA) deletions in the hearts of patients with idiopathic dilated cardiomyopathy. BACKGROUND: The mutation frequency of mtDNA is high, and sporadic cases of cardiomyopathies associated with mtDNA deletions have been described. Reports of increases in mtDNA deletions with advancing age also exist. METHODS: We studied 15 consecutive patients with typical signs of idiopathic dilated cardiomyopathy, without a family history, together with 16 control hearts obtained at autopsy from patients who died of noncardiac causes. The patients underwent both right and left heart catheterization, during which endomyocardial biopsy samples were taken. The mtDNA in these samples and in the control hearts was analyzed by the polymerase chain reaction technique for the occurrence and proportion of 5- and 7.4-kilobase (kb) deletions (Cambridge sequence map positions from nucleotides 8469 to 13447 and 8637 to 16084, respectively). RESULTS: The 5-kb mtDNA deletion was observed in the hearts of all of the patients with idiopathic dilated cardiomyopathy, accounting for 0.32 +/- 0.05% (mean +/- SEM) of the total mtDNA. The 7.4-kb deletion was found in 7 of the 15 patients with idiopathic dilated cardiomyopathy and comprised 0.28 +/- 0.08% of the total. The 5- and 7.4-kb deletions were detected in 12 and 9 control hearts, respectively, quantitatively similar to the patients with idiopathic dilated cardiomyopathy. A sigmoidal age dependency of the mtDNA deletions was found both in the patients with cardiomyopathy and in the control hearts, but after elimination of the confounding age variable, there was no difference between these groups. CONCLUSIONS: Because of the similarity of the age-dependent increase in the frequency of mtDNA deletions in cardiomyopathic and control hearts, the deletions have no causal relation with idiopathic dilated cardiomyopathy. The present results confirm the notion of an increase in mtDNA deletions with advancing age and show that endomyocardial tissue sampling is a feasible method for detecting mtDNA defects in affected hearts.

Responses of heart rate variability to coronary occlusion during coronary angioplasty.

Signs of sympathetic activation are frequent during the early hours of anterior wall acute myocardial infarction, whereas parasympathetic reflexes predominate in inferior wall acute myocardial infarction. To assess the immediate autonomic responses to acute coronary occlusion, the high-frequency power and root-mean-square successive difference, frequency and time domain measures of heart rate (HR) variability were analyzed in 73 cases of significant (50 to 95%) coronary artery stenosis immediately before and during balloon occlusion (mean 99 seconds). The range of nonspecific changes was formed on the basis of a control group with no ischemia during dilatations of 16 totally occluded coronary arteries. Balloon occlusion of the left anterior descending artery (n = 35) caused an abnormal increase in the measures of HR variability as a sign of vagal activation in 8 patients (23%), and a significant decrease in HR variability in 4 (11%). Occlusion of the left circumflex artery (n = 19) caused an increase in HR variability in 5 patients (26%), and a decrease in 2 (11%). Right coronary artery occlusion (n = 19) caused an increase in HR variability in 5 patients (26%) and a decrease in 4 (21%). Thus, coronary occlusion causes immediate changes in HR variability in greater than one third of patients with coronary artery disease. The direction of these initial HR variability changes cannot be predicted by the site of coronary occlusion.

Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen.

OBJECTIVE: Non-enzymatic glycosylation of proteins occurs in diabetes and advanced glycosylated end products can accumulate in long lived proteins such as vascular collagen and reduce the elasticity of vessel walls. To evaluate the potential association of advanced glycosylated end products in collagen with diminished arterial elasticity in diabetes, 14 diabetic and 14 age and sex matched non-diabetic patients with coronary artery disease were studied. METHODS: Arterial elasticity was assessed in terms of carotid to femoral pulse wave velocity and by measuring the change in ascending aortic diameter induced by pulse pressure. Collagen linked fluorescence, a measure of advanced glycosylated end products, was determined from tissue specimens of the skin, ascending aorta, and right atrial appendage taken during coronary bypass surgery. RESULTS: As a sign of diminished arterial elasticity, carotid to femoral pulse wave velocity was raised (p < 0.01) and change in ascending aortic diameter tended to be diminished (p = 0.09) in the diabetic patients. Collagen linked fluorescence was increased (p < 0.05) in the myocardium of the diabetic group, but the difference in skin and aorta was not significant. Collagen linked fluorescence between the aorta, skin, and myocardium correlated with each other (r = 0.64-0.77). Collagen linked fluorescence in the aorta and myocardium correlated with carotid to femoral pulse wave velocity (r = 0.63 and r = 0.67, respectively) in the diabetic group but not in the control group. CONCLUSIONS: These data suggest that non-enzymatic glycosylation of matrix proteins, and specifically collagen, may modify arterial elasticity in diabetic patients with coronary artery disease.