Jürgen Klingelhöfer

Relationship Between Circadian Blood Pressure Patterns and Progression of Early Carotid Atherosclerosis A 3-Year Follow-Up Study

BackgroundArterial hypertension is a major risk factor for cardiovascular damage. The results of several studies suggest that target organ damage is greater in hypertensive persons with high blood pressure variability. Methods and ResultsDuring 3.3 years of follow-up, we studied the relationship between circadian blood pressure changes and the progression of early carotid atherosclerosis in 286 patients aged >55 years. Blood pressure patterns were evaluated with a long-term blood pressure monitor, and the extent of atherosclerosis was measured as the intima-media wall thickness (IMT) of the common carotid artery. Patients were subdivided according to blood pressure variability. The progression of IMT was significantly greater in the patients with increased systolic blood pressure variability (0.11 mm/y [95% CI 0.09 to 0.14] versus 0.05 mm/y [0.03 to 0.08];P <0.005) even after adjustment for other risk factors. Multivariate regression analysis revealed the daytime systolic blood pressure variability to be the best predictor for the progression of IMT. Raised daytime systolic blood pressure variability (>15 mm Hg) is associated with an increased relative risk of the development of early atherosclerosis (3.9 [1.4 to 11.1];P <0.01) and of cardiovascular events (1.87 [1.08 to 3.20];P <0.01). ConclusionsThe daytime systolic blood pressure variability is a strong predictor of early carotid atherosclerosis progression and is useful to define the risk-benefit ratio of therapeutic approaches.

Prognostic relevance of pathological sympathetic activation after acute thromboembolic stroke

Objective: To evaluate the prognostic impact of early pathologic sympathetic activation after stroke. Methods: The authors examined 112 consecutive patients (mean age, 69 years; 60 men) with their first brain infarction. A pathologic sympathetic activation was presumed if the initial norepinephrine level exceeds 300 pg/mL. In addition, involvement of the insular cortex, nighttime blood pressure changes, and several cardiovascular risk factors were determined. One-year outcome measures were mortality rate, cardiovascular and cerebrovascular events, and activities of daily living (Barthel index and Rankin score). Results: Norepinephrine levels greater than 300 pg/mL, nighttime blood pressure increases, and insular involvement were associated with a lower Barthel index (p < 0.005) at the 1-year follow-up. By stepwise logistic regression analysis, insular infarction, serum norepinephrine concentration, right-sided infarction, and nighttime blood pressure increase were significant and independent predictors of an unfavorable functional outcome. Cox regression analysis showed a higher rate of cardiovascular and cerebrovascular events (hazard ratio, 2.9; 95% CI, 1.07; 6.83; p < 0.04) in patients with initially increased norepinephrine concentrations. Conclusions: The involvement of the insular cortex, the occurrence of a pathologic nighttime blood pressure increase, and an initially increased serum norepinephrine concentration are independent predictors of poor long-term outcome.

Changes of circadian blood pressure patterns after hemodynamic and thromboembolic brain infarction.

We investigated the changes of circadian blood pressure patterns after thromboembolic and hemodynamic brain infarction and evaluated the relation between circadian blood pressure variation, infarct location, and activation of the autonomic nervous system after thromboembolic stroke. Methods Repeated 24-hour blood pressure measurements were performed in 45 patients with proven first-ever brain infarctions of different origins. Evaluation of serum norepinephrine concentration, prolongation of the QT interval, and degree of cardiac arrhythmias were used to determine the extent of sympathetic activation after thromboembolic stroke. Results Whereas circadian blood pressure variation was significantly increased after hemodynamic infarction compared with a control group (diastolic, −25.2±4.5% versus −13.8±6.5%; P<.005), a clearly reduced variation was observed after thromboembolic infarction (diastolic, −5.2±6.9%). Blood pressure variation was positively related to serum norepinephrine concentration (r=.79; P<01) after thromboembolic infarction. Patients with involvement of the insular cortex showed a nocturnal rise of blood pressure significantly more frequently (66.7% versus 11.8%; p<.005) and had higher norepinephrine levels (540±110 pg/mL versus 290±178 pg/mL; P<.01) than patients without insular cortex infarction, indicating increased sympathetic activity. This was associated with a significantly more frequent occurrence of QT prolongation and cardiac arrhythmias. Conclusions The observed differences in circadian blood pressure patterns may (1) help to distinguish the pathophysiological basis of the stroke, (2) help to explain worsening in some cases of hemodynamic stroke, (3) confirm the importance of the insular cortex for sympathetic activation, and (4) identify subgroups of patients with increased risk of myocardial infarction and arrhythmia.

Assessment of intracranial hemodynamics in sleep apnea syndrome.

Background and Purpose: Sleep apnea syndrome may lead to changes in cerebral hemodynamics due to altered alveolar ventilation. We investigated the dynamics of CO2‐ and blood pressure‐regulated alterations of cerebral blood flow velocities during apneic episodes and evaluated CO2 reactivity during different sleep stages. Methods: A computer‐assisted pulsed Doppler system (2 MHz) was used for continuous overnight recordings of middle cerebral artery flow patterns together with simultaneous polysomnography, continuous blood pressure recordings, and measurements of end‐expiratory CO2 in six patients with sleep apnea syndrome. Results: Increases in mean flow velocity of 19‐219% and in blood pressure of 12.5‐83.1% could be observed during the apneic episodes, with maximum increases during rapid eye movement (REM) sleep. CO2 reactivity was in the normal range (4.4±1.2%) in the waking state and was markedly increased during sleep stages 1 and 2 (p<0.005 compared with awake). The greatest increase was found during REM sleep, with a rise of up to three times the waking value (p<0.0001 compared with sleep stage 2). Conclusions: The changes of mean flow velocity could be interpreted as reactive adaptation processes because of CO2 and blood pressure increases corresponding to apnea. The increased CO2 reactivity during sleep may indicate a “hypersensitivity” of intracranial vascular CO2 or pH receptors and a disturbance of central catecholaminergic and cholinergic systems. The pronounced velocity changes during apneic episodes and the concomitant alterations of vessel wall tension might lead to microangiopathies and macroangiopathies due to chronic strain on the brain vessels. (Stroke 1992;23:1427‐1433)

Prophylaxis of Thrombotic and Embolic Events in Acute Ischemic Stroke With the Low-Molecular-Weight Heparin Certoparin Results of the PROTECT Trial

Background and Purpose— Patients with stroke are at substantial risk of thromboembolic complications and therefore require antithrombotic prophylaxis. To show the noninferiority of the low-molecular-weight heparin certoparin to unfractionated heparin (UFH) for the prevention of thromboembolic complications, we performed a randomized, double-blind, active-controlled multicenter trial in patients with acute ischemic stroke. Methods— Overall, 545 patients were randomized within 24 hours of stroke onset to treatment with certoparin (3000 U anti-Xa OD; n=272) or UFH (5000 U TID; n=273) for 12 to 16 days. Patients with paresis of a leg and an National Institutes of Health Stroke Scale score of 4 to 30 points were included. The primary end point was a composite outcome of proximal deep vein thrombosis, pulmonary embolism, or death related to venous thromboembolism during treatment. Computed tomography was performed at trial entry, after 7 days, and when clinical deterioration occurred. Results— The per-protocol analysis revealed 17 (7.0%) primary events in the certoparin group compared with 24 (9.7%) in the UFH group, thereby demonstrating noninferiority (P=0.0011), confirmed by intention-to-treat analysis (6.6% versus 8.8%; P=0.008). Major bleeding occurred during treatment in 3 patients allocated to certoparin (1.1%) and 5 patients allocated to UFH (1.8%). Conclusions— Certoparin (3000 U anti-Xa OD) is at least as effective and safe as UFH (TID) for the prevention of thromboembolic complications in patients with acute ischemic stroke.

Noninvasive Prediction of Intracranial Pressure Curves Using Transcranial Doppler Ultrasonography and Blood Pressure Curves

Background and Purpose Until now the assessment of intracranial pressure (ICP) required invasive methods. The objective of this study was to introduce an approach to a noninvasive assessment of continuous ICP curves. Methods The intracranial compartment was considered a “black box” system with an input signal, the arterial blood pressure (ABP), and an output signal, the ICP. A so-called weight function described the relationship between ABP and ICP curves. Certain parameters, called transcranial Doppler (TCD) characteristics, were calculated from the cerebral blood flow velocity (FV) and the ABP curves and were used to estimate this weight function. From simultaneously sampled FV, ABP, and (invasively measured) ICP curves of a defined group of patients with severe head injuries, the TCD characteristics and the weight function were computed. Multiple regression analysis revealed a mathematical formula for calculating the weight function from TCD characteristics. This formula was used to generate the ICP simulation. FV, ABP, and ICP recordings from 11 patients (mean age, 46±14 years) with severe head injury were studied. In each patient, ICP was computed by a simulation procedure, generated from the data of the remaining 10 patients. The simulation period was 100 seconds. Results Corresponding pressure trends with a mean absolute difference of 4.0±1.8 mm Hg between computed and measured ICP were observed. Shapes of pulse and respiratory ICP modulations were clearly predicted. Conclusions These results demonstrate that this method constitutes a promising step toward a noninvasive ICP prediction that may be clinically applicable under well-defined conditions.

Adaptive Noninvasive Assessment of Intracranial Pressure and Cerebral Autoregulation

Background and Purpose— A mathematical model has previously been introduced to estimate noninvasively intracranial pressure (nICP). In the present multicenter study, we investigated the ability of model to adapt to the state of cerebral autoregulation (SCA). This modification was intended to improve the quality of nICP estimation and noninvasive assessment of pressure reactivity of the cerebrovascular system. Methods— We studied 145 patients after severe head injuries or stroke. All patients had direct ICP, arterial blood pressure (ABP), and transcranial Doppler middle cerebral artery blood flow velocity (FV) monitored. The SCA was assessed by moving correlation (Mx index) of cerebral perfusion pressure (CPP=ABP−ICP) and cerebral blood flow velocity and correlation of ABP and ICP (PRx index). nICP was calculated from ABP and FV waveforms. When nICP was used instead of ICP, the SCA was continuously estimated, and the model was dynamically adapted to the SCA. Results— High and moderate correlations between invasively (Mx, PRx) and noninvasively (nMx, nPRx) estimated autoregulation indexes were observed (Mx:R =0.90, P <0.001; PRx:R =0.62, P <0.001). Values of Mx and nMx indicated contradictory SCA in 4 of 167 evaluated recordings; values of PRx and nPRx were contradictory in 27 recordings. When the model was adapted to the SCA, the mean error of ICP estimation decreased significantly (P <0.005). Conclusions— Continuous adaptation of the model to SCA improves the accuracy of noninvasive estimation of ICP and ICP dynamics. The same model provides a noninvasive and continuous assessment of SCA.

Changes of circadian blood pressure patterns and cardiovascular parameters indicate lateralization of sympathetic activation following hemispheric brain infarction

The effects of left- and right-sided hemispheric brain infarction on variability in circadian blood pressure and cardiovascular measures were investigated in 35 patients to test for asymmetry of the sympathetic consequences of stroke. No significant differences regarding age, size of infarction or extent and frequency of damage to the insular cortex could be detected between the two groups. Patients with right-sided infarction showed a significantly reduced circadian blood pressure variability [diastolic: -1% (95% CI -4 to 1) vs -6% (-9 to -2);P < 0.05] and a higher frequency of nocturnal blood pressure increase (47% vs 35%;P < 0.05) as compared with patients with left-sided infarction. Right-sided infarction was also associated with higher serum noradrenaline concentrations [546 pg/ml (95% CI 415–677) vs 405 pg/ml (266–544);P < 0.05], and ECG more frequently showed QT prolongation (53% vs 35%;P < 0.05) and cardiac arrhythmias (67% vs 20%;P < 0.005). However, irrespective of the hemisphere damaged, patients with insular infarction showed the most pronounced changes of these parameters. In addition, two patients with right-sided strokes (13%) involving the insula, but none with a left-sided infarction, developed myocardial infarction. These findings suggest lateralization of sympathetic activation with right-sided dominance for sympathetic effects following hemispheric stroke.

Reduced Progression of Early Carotid Atherosclerosis After Antibiotic Treatment and Chlamydia pneumoniae Seropositivity

Background—Chlamydia pneumoniae (Cp) infection has been associated with atherosclerosis, and a beneficial effect of antibiotic therapy on future cardiovascular events was described. Methods and Results—We evaluated the effect of roxithromycin therapy (150 mg twice daily for 30 days) on the progression of the intima-to-media thickness (IMT) of the common carotid artery using duplex ultrasonography in a prospective and randomized trial with a follow-up of 2 years in 272 consecutive patients with ischemic stroke aged over 55 years in whom the first IMT measurement and Cp testing (IgG and IgA) were performed at least 3 years before the roxithromycin treatment. Cp IgG antibodies (≥1:64) were initially found in 123 (45%) patients and IgA antibodies (≥1:16) in 112 (41%) patients. During the 3 years before antibiotic therapy, Cp-positive patients showed an enhanced IMT progression, even after adjustment for other cardiovascular risk factors (0.12 [95% CI, 0.11 to 0.14] versus 0.07 [0.05 to 0.09] mm/year;P <0.005). The 62 Cp-positive patients given roxithromycin showed a significantly decreased IMT progression after 2 years compared with the Cp-positive patients without therapy (0.07 [0.045 to 0.095] versus 0.11 [0.088 to 0.132] mm/year;P <0.01). No significant difference in the occurrence of future cardiovascular events was found between both groups during follow-up. No change of IMT was observed in Cp-negative patients given roxithromycin (n=74) compared with those without therapy (0.06 [0.03 to 0.09] versus 0.07 [0.05 to 0.09] mm/year). Conclusions—Our findings suggest a positive impact of antibiotic therapy on early atherosclerosis progression in Cp-seropositive patients with cerebrovascular disease.

Enhanced Progression of Early Carotid Atherosclerosis Is Related to Chlamydia pneumoniae (Taiwan Acute Respiratory) Seropositivity

Background —Chlamydia pneumoniae (Cp) infection has been associated with atherosclerosis and has been proposed as a possible additional cardiovascular risk factor. However, the relationship between Cp seropositivity and the progression of early carotid atherosclerosis is not unequivocally clarified. Methods and Results —We evaluated the association between serological detection of Cp IgG and/or IgA antibodies and the progression of the intima-media thickness (IMT) of the common carotid artery using duplex ultrasonography in a prospective study with a follow-up of 3 years in 272 consecutive patients with cerebrovascular disease. Cp-seropositive patients showed a significantly enhanced progression of the IMT even after adjustment for other cardiovascular risk factors (0.12 mm/y [95% CI 0.11 to 0.14] versus 0.07 mm/y [0.05 to 0.09];P <0.005). Patients with increased C-reactive protein (≥0.5 mg/dL) and Cp seropositivity showed the most pronounced IMT progression. Multivariate regression analysis revealed Cp seropositivity to be an independent risk factor for progression of early carotid atherosclerosis. Cox proportional-hazard regression analysis demonstrated a significantly increased rate of cerebrovascular and cardiovascular events in patients with Cp seropositivity, particularly in patients with increased C-reactive protein levels. Conclusions —Our data support the importance of chronic inflammation and infection for the early stages of atherosclerotic development.