Visceral sensitivity correlates with decreased regional gray matter volume in healthy volunteers: a voxel-based morphometry study.

Regional changes in brain structure have been reported in patients with altered visceral sensitivity and chronic abdominal pain, such as in irritable bowel syndrome. It remains unknown whether structural brain changes are associated with visceral sensitivity. Therefore, we present the first study in healthy individuals to address whether interindividual variations in gray matter volume (GMV) in pain-relevant regions correlate with visceral sensitivity. In 92 healthy young adults (52 female), we assessed rectal sensory and pain thresholds and performed voxel-based morphometry (VBM) to compute linear regression models with visceral sensory and pain thresholds, respectively, as independent variable and GMV in a priori-defined regions of interest (ROIs) as dependent variable. All results were familywise error (FWE) corrected at a level of PFWE<.05 and covaried for age. The mean (±SEM) rectal thresholds were 14.78±0.46mm Hg for first sensation and 33.97±1.13mm Hg for pain, without evidence of sex differences. Lower rectal sensory threshold (ie, increased sensitivity) correlated significantly with reduced GMV in the thalamus, insula, posterior cingulate cortex, ventrolateral and orbitofrontal prefrontal cortices, amygdala, and basal ganglia (all PFWE<.05). Lower rectal pain threshold was associated with reduced GMV in the right thalamus (PFWE=.051). These are the first data supporting that increased visceral sensitivity correlates with decreased gray matter volume in pain-relevant brain regions. These findings support that alterations in brain morphology not only occur in clinical pain conditions but also occur according to normal interindividual variations in visceral sensitivity.

Fear conditioning in an abdominal pain model: neural responses during associative learning and extinction in healthy subjects.

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement. In N = 21 healthy humans, visual conditioned stimuli (CS(+)) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS(-)) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness. Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS(+). During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS(-) was observed. In the reinstatement phase, a tendency for parahippocampal activation was found. Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain.

Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: an fMRI study in healthy placebo responders and nonresponders.

This functional magnetic resonance imaging study analysed the behavioural and neural responses during expectation-mediated placebo analgesia in a rectal pain model in healthy subjects. In N=36 healthy subjects, the blood oxygen level-dependent (BOLD) response during cued anticipation and painful rectal stimulation was measured. Using a within-subject design, placebo analgesia was induced by changing expectations regarding the probability of receiving an analgesic drug to 0%, 50%, and 100%. Placebo responders were identified by median split based on pain reduction (0% to 100% conditions), and changes in neural activation correlating with pain reduction in the 0% and 100% conditions were assessed in a regions-of-interest analysis. Expectation of pain relief resulted in overall reductions in pain and urge to defecate, and this response was significantly more pronounced in responders. Within responders, pain reduction correlated with reduced activation of dorsolateral and ventrolateral prefrontal cortices, somatosensory cortex, and thalamus during cued anticipation (paired t tests on the contrast 0%>100%); during painful stimulation, pain reduction correlated with reduced activation of the thalamus. Compared with nonresponders, responders demonstrated greater placebo-induced decreases in activation of dorsolateral prefrontal cortex during anticipation and in somatosensory cortex, posterior cingulate cortex, and thalamus during pain. In conclusion, the expectation of pain relief can substantially change perceived painfulness of visceral stimuli, which is associated with activity changes in the thalamus, prefrontal, and somatosensory cortices. Placebo analgesia constitutes a paradigm to elucidate psychological components of the pain response relevant to the pathophysiology and treatment of chronic abdominal pain.

A spectrum of knock-type Doppler signals in the intracranial vessels.

BACKGROUND AND PURPOSE: Knock-type Doppler signals (KTDS) are detectable by transcranial Doppler, and it has been hypothesized that they are related to an occlusion of a small perforating artery and microvascular ischemia. However, the nature of KTDS has not been prospectively defined. We aimed at describing the spectral and power motion Doppler characteristics of KTDS and ultrasound exposure conditions that lead to their appearance. METHODS: Consecutive patients referred with symptoms of stroke or transient ischemic attacks to our cerebrovascular ultrasound laboratory were screened for the presence of KTDS. The presence of microvascular ischemia was assessed using brain MRI. RESULTS: Among 327 patients with cerebrovascular symptoms, 46 (14%) had KTDS. KTDS were found more frequently in posterior circulation vessels (55% vertebral artery, 21.5% basilar artery, and 6% posterior cerebral artery). There was no association between ultrasound identification of KTDS and the presence of brain ischemia in the distribution of any vessel (OR, 0.37; 95% CI, 0.09-1.53; P=0.171) on univariate logistic regression analyses. KTDS was not related to the presence of microvascular ischemia on brain MRI (OR, 1.12; 95% CI, 0.55-2.29; P=0.761). We described the range of spectral and power motion Doppler appearances of KTDS and experimentally demonstrated the most likely underlying mechanism being a large vessel wall movement artifact. CONCLUSIONS: Although KTDS can be distinguished from other spectral flow signals, they can be found in normal vessels, they do not seem to be associated with the vessel affected by ischemia, and they should not be overinterpreted.

Predictors of early postoperative atrial fibrillation after off-pump myocardial revascularization.

OBJECTIVE: : We determined the incidence and the predisposing factors of atrial fibrillation (AF) after aorta nontouch coronary artery bypass grafting without extracorporeal circulation. METHODS: : From February 2001 to November 2005, 1359 patients (1159 men, 85.3%) of mean (±SD) age 64.8 (±9.8) years, who underwent off-pump coronary artery bypass grafting (OP-CAB), were prospectively enrolled. Demographics, perioperative data, and comorbidities were recorded in all patients. A 24-hour rhythm monitoring was performed in all patients until hospital discharge. RESULTS: : Among 1359 patients, 273 (20.1%) had development of atrial fibrillation in the early postoperative period. Patients with AF had higher mean (±SD) age, 68.3 (±8.8) years, compared with control subjects [63.9 (±9.9)] (P ≤ 0.0005). Univariate analysis showed that apart from age, history of arterial hypertension (P ≤ 0.02), chronic obstructive pulmonary disease (P ≤ 0.02), and the use of bilateral internal mammary arteries (P ≤ 0.01) were predisposing factors for the development of AF. Logistic regression analysis showed that age, history of arterial hypertension, and the use of bilateral internal mammary arteries were predisposing factors for early postoperative AF after OP-CAB. CONCLUSIONS: : Atrial fibrillation occurred in approximately 20% of patients undergoing OP-CAB, mainly in older patients with arterial hypertension who received bilateral internal mammary artery grafts.

External reshaping of the left ventricle in off-pump surgery.

BACKGROUND: : Dyskinetic areas of the lateral and inferior left ventricular (LV) wall are frequently encountered in patients with coronary artery disease. In clinical practice, all of the techniques described for the restoration of shape and function of the LV require cardiopulmonary bypass. A new technique of LV external reshaping that aims to obtain a near-normal ventricular conical shape is described. This technique is performed during an off-pump coronary artery bypass graft (CABG) operation. It is used mainly on the inferior and lateral walls of the ventricle, but also on the anterolateral wall when warranted. This technique can be considered an alternative to classic aneurysmectomy in high-risk cases. METHODS: : All patients underwent total arterial revascularization without aortic manipulation. Intraoperative transesophageal echocardiography was used in all cases to define the dilated akinetic/dyskinetic area. This area was effectively plicated using interrupted mattress sutures reinforced with Teflon felt or pericardial strips. This technique allows near normalization of the geometry of the ventricle and LV end-diastolic volume reduction. In cases of preexisting mitral regurgitation (MR), a reduction of the MR was observed after lateral wall restoration. From September 2002 to April 2005, the external reshaping technique was applied on 56 cases among 949 off-pump CABG cases (5.9%). A detailed transthoracic echocardiogram was obtained preoperatively. The mean ejection fraction of all enrolled patients was 31.2 ± 7%. The location of the plication was: lateral wall in 22, inferior wall in 16, and anterolateral wall in 18. The average number of coronary anastomoses was 2.6. Twelve patients were found to have 2-3+ MR. All patients were followed up during a period of 35 months. RESULTS: : One patient died due to severe right ventricular dysfunction. Seven patients developed atrial fibrillation, and one had ventricular tachycardia. During the follow-up period, we observed a reduction of left ventricular end-diastolic diameter and a parallel augmentation of ejection fraction (mean 42.2 ± 4%). The ventricular cavity's architecture was normalized. Among the 12 patients with MR, an improvement of regurgitation was noted in 10 (from 2-3+ to 1-2+). One patient died during the follow-up period, and 1 patient required reoperation due to persistent severe MR. CONCLUSIONS: : The external reshaping of the LV during beating heart surgery is technically feasible, has promising results, and can be performed without major complications.

Arterial stiffness assessed by pulse wave analysis in essential hypertension: relation to 24-h blood pressure profile.

BACKGROUND: Arterial stiffness is a risk factor for cardiovascular morbidity and mortality and appears to be increased in arterial hypertension. The purpose of the present study was to relate systemic arterial stiffness assessed by pulse wave analysis to variables of 24-h ambulatory blood pressure monitoring (ABPM) in patients with essential hypertension. METHODS: Seventy-two subjects with untreated mild to moderate arterial hypertension underwent evaluation with 24-h ambulatory blood pressure monitoring. In the same subjects, applanation tonometry and pulse wave analysis was performed for evaluation of systemic arterial stiffness expressed as augmentation index and estimated aortic pulse wave velocity. RESULTS: Clinic systolic blood pressure, mean heart rate during 24-h blood pressure monitoring and height were independent predictors of augmentation index and estimated aortic pulse wave velocity. The 41 patients with blunted reduction in nighttime blood pressure (nondippers) showed higher mean systolic blood pressure (p=0.02), lower systolic and diastolic blood pressure variability (p<0.001), higher pulse pressure during 24-h monitoring (p=0.05) and higher estimated aortic pulse wave velocity (p=0.03), indicating stiffer arteries in this group. CONCLUSIONS: These results suggest that blood pressure change from day- to nighttime is an important determinant of arterial stiffness assessed by pulse wave analysis; this association could contribute to the higher cardiovascular risk in nondippers.

Time rate of blood pressure variation is associated with increased common carotid artery intima-media thickness.

The extent of target-organ damage has been positively associated with the magnitude of blood pressure (BP) variability in essential hypertension. However, the clinical implications of the rate of BP changes have never been investigated. We evaluated the association between the rate of systolic BP (SBP) variation derived from ambulatory BP monitoring (ABPM) data analysis and the extent of common carotid artery (CCA) intima-media thickness (IMT) in normotensive (n=280) and in uncomplicated hypertensive subjects (n=234). The 24-hour rate of SBP variation was significantly (P<0.001) higher in hypertensive (0.608 mm Hg/min; 95% confidence interval [CI], 0.595 to 0.622) than in normotensive individuals (0.567 mm Hg/min; 95% CI, 0.555 to 0.578), even after adjusting for baseline characteristics, day-night BP changes, 24-hour heart rate (HR), SBP, and HR variability. In the entire group of patients, multiple linear regression models revealed independent determinants of CCA-IMT in the following rank order: age (P<0.001), 24-hour rate of SBP variation (P<0.001), male gender (P=0.004), cholesterol (P=0.009), and smoking (P=0.014). A 0.1 mm Hg/min increase in the 24-hour rate of SBP variation was associated to an increment of 0.029 mm (95% CI, 0.018 to 0.040) in CCA-IMT independent of BP and HR levels, BP and HR variability, and dipping status. The rate of SBP variation during the morning BP surge correlated independently (P<0.001) to larger CCA-IMT values after adjustment for baseline characteristics and other ABPM parameters. Thus, the rate of BP fluctuations is greater in hypertensive patients and correlates to increased CCA-IMT. This finding indicates that steeper BP variations may produce a greater stress on the vessel wall and consequently result in medial hypertrophy of the large arteries.

Cardiac hypertrophy in hypertension: relation to 24-h blood pressure profile and arterial stiffness.

BACKGROUND: In subjects with essential hypertension peripheral blood pressure profile contributes to the pathogenesis of left ventricular hypertrophy. It is not known if central arterial pressure is superior to peripheral blood pressure profile for predicting left ventricular hypertrophy. In the present study 24-h blood pressure profile and central hemodynamics were examined to evaluate mechanical loading factors as determinants of cardiac hypertrophy in mild to moderate untreated essential hypertension. METHODS: Forty-eight untreated subjects with mild to moderate essential hypertension were examined by echocardiography for evaluation of left ventricular mass, 24-h ambulatory blood pressure monitoring (ABPM), and applanation tonometry of the radial artery with pulse wave analysis for evaluation of central hemodynamics. RESULTS: Left ventricular mass showed a statistically significant correlation with age, clinic systolic blood pressure, mean heart rate and heart rate variability during 24-h ABPM, augmentation pressure and index and central systolic blood pressure. In a multiple regression analysis including clinic systolic blood pressure, central systolic pressure, mean systolic pressure and pulse pressure during ambulatory monitoring as well as age, independent predictors of left ventricular mass were only age (P=0.006) and central systolic blood pressure (P=0.04). In conclusion, pulse wave analysis is a valuable method in predicting cardiac hypertrophy in untreated mild to moderate essential hypertension. Central systolic blood pressure should be taken into account for planning therapeutic strategies for prevention of left ventricular hypertrophy in hypertensive patients.

Pulse pressure in acute stroke is an independent predictor of long-term mortality.

The management of blood pressure (BP) during the acute phase of stroke remains a matter of debate. The aim of the present study was to evaluate a possible association between long-term mortality and BP values in acute stroke by means of BP monitoring. We studied a consecutive series of 198 first-ever acute stroke patients. BP monitoring was initiated in all subjects within 24 h of ictus. One year after stroke onset, 34 (17.7%) patients had died. Multivariate Cox regression analysis revealed only age, level of consciousness on admission, lacunar stroke and 24-hour pulse pressure (24-hour PP) as significant outcome predictors. The hazards ratio for 1-year mortality associated with every 10 mm Hg increase in 24 h PP was 1.39 (95% CI: 1.04-1.86, p = 0.028). The present results demonstrate that increasing 24-hour PP levels in patients with acute stroke are independently associated with higher long-term mortality. This may have implications in acute stroke BP management and warrants further investigation.

Association between 24-h blood pressure monitoring variables and brain oedema in patients with hyperacute stroke.

OBJECTIVE: To assess the effects of blood pressure (BP) values on oedema formation following hyperacute stroke. DESIGN: Prospective observational study. SETTING AND PATIENTS: Acute stroke-unit in University hospital. A total of 240 consecutive first-ever ischaemic or haemorrhagic stroke patients were recruited within 3 h of ictus. METHODS Casual and 24-h BP values were measured. Known stroke risk factors and clinical findings on admission were documented. Patients were imaged with computed tomography (CT) scan within 24 h from stroke onset and 5 days later in order to determine the presence of brain oedema. Patients who received antihypertensive medication during the BP monitoring were excluded. RESULTS: The main outcome measure was brain oedema formation, which was present in 78 (32.5%) patients. The 24-h systolic (SBP), diastolic (DBP) and mean BP values, 24-h pulse pressure and heart rate values were significantly higher in patients with brain oedema than in the reference group (stroke patients without brain swelling). On multiple variable analysis, containing clinical, demographic and BP monitoring variables, 24-h SBP remained significantly (P = 0.019) associated with brain oedema. The odds ratio for oedema formation associated with each 10-mmHg increase in 24 h SBP was 1.25 (95% confidence intervals: 1.04-1.51). During the first 27 h after onset SBP course showed a spontaneous decline in the reference group, which was not documented in patients with brain oedema. CONCLUSION: Elevated 24-h SBP values in the acute stroke period are associated with subsequent brain oedema formation.

Oral L-arginine improves endothelial dysfunction in patients with essential hypertension.

BACKGROUND: L-Arginine is a nitric oxide precursor, which augments endothelium-dependent vasodilatation in hypercholesterolemic humans and animals. Endothelium-dependent vasodilation is attenuated in patients with hypertension; however the effects of oral L-arginine on endothelial function of the conduit arteries in patients with essential hypertension have not previously been investigated. METHODS: In a prospective randomized double blind trial, 35 patients with essential hypertension received either 6 g L-arginine (18 subjects) or placebo (17 subjects). Patients were examined for flow-mediated endothelium-dependent dilatation of the brachial artery before and 1.5 h after administration of L-arginine or placebo. At the end of the protocol the nitrate-induced, endothelium-independent vasodilatation was evaluated. RESULTS: Two groups of L-arginine and placebo were similar regarding age, sex, blood lipids, smoking, diabetes, coronary artery disease, body mass index, intima-media thickness of the common carotid artery, clinics blood pressure and baseline brachial artery parameters. Administration of L-arginine or placebo did not change significantly heart rate, blood pressure, baseline diameter, blood flow or reactive hyperemia. L-Arginine resulted in a significant improvement of flow-mediated dilatation (1.7+/-3.4 vs. 5.9+/-5.4%, P=0.008) while placebo did not significantly change this parameter (3.0+/-2.7 vs. 3.1+/-2.2%, P=ns). The effect of L-arginine on flow-mediated dilatation was significantly different from the effect of placebo (P=0.05). L-Arginine did not significantly influence nitrate-induced dilatation (16+/-6.9 vs. 17.7+/-6.7%, P=ns). CONCLUSIONS: Oral administration of L-arginine acutely improves endothelium-dependent, flow-mediated dilatation of the brachial artery in patients with essential hypertension. The long-term effects of L-arginine in these patients require further investigation.

A new pattern for using both thoracic arteries to revascularize the entire heart: the pi-graft.

We present a complex graft for total arterial revascularization based on bilateral skeletonized internal thoracic arteries (ITA). The lower two-thirds of the free right ITA is anastomosed to the proximal segment of the left in situ ITA using the T-graft technique (Tector-Barner-Calafiore). The free, transected distal part of the left ITA is then anastomosed end-to-side on free right ITA (T-on-T anastomosis). In addition, the technique may use another graft extending the proximal third of the in situ right ITA with the free radial artery for right-sided revascularization. The entire operation can be performed off-pump to avoid any procedure on the ascending aorta.