Luca Mircoli

Heart rate-dependence of arterial distensibility in vivo.

Objectives Viscous and inertial components contribute to arterial distensibility and compliance in vitro. The purpose of our study was to determine whether this phenomenon is of relevance in vivo, namely, whether arterial compliance is altered by an increase in heart rate Design Arterial diameter was assessed by an echo-Doppler device in a common carotid and femoral artery, namely, in a large elastic and a muscle artery. The studies were performed in 12-week-old pentobarbitone-anaesthetized Wistar-Kyoto rats subjected to atrial pacing via a transjugular unipolar catheter at five different randomly sequenced rates (280, 310, 340, 370 and 400 beats/min). After each stage, spontaneous sinus rhythm was allowed to return. Blood pressure was measured via a catheter inserted into the carotid or femoral artery contralateral to the vessels in which the diameter was measured. Arterial compliance and distensibility values were derived according to the Langewouters formula Results A progressive increase in heart rate caused by pacing was accompanied by progressive and marked reductions in carotid artery compliance and distensibility. When quantified by the area under the distensibilitypressure or compliance-pressure curve the reduction was in the range 15-43%. Although a tendency to a similar phenomenon was observed in the femoral artery, in the latter vessel the reduction in distensibility and compliance was less marked and statistically insignificant Conclusions In the anaesthetized rat acute increases in heart rate are accompanied by reductions in arterial compliance and distensibility. The effect is greater in elastic than in muscle arteries

Effect of Sympathectomy on Mechanical Properties of Common Carotid and Femoral Arteries

Sympathetic stimulation is accompanied by a reduction of arterial distensibility, but whether and to what extent elastic and muscle-type arterial mechanics is under tonic sympathetic restraint is not known. We addressed this issue by measuring, in the anesthetized rat, the diameters of the common carotid and femoral arteries with an echo-Doppler device (NIUS 01). Blood pressure was measured by a catheter inserted contralaterally and symmetrically to the vessel where the diameter was measured. Arterial distensibility over the systolic-diastolic pressure range was calculated according to the Langewouters formula. Data were collected in 10 intact (vehicle pretreatment) and 9 sympathectomized (6-hydroxydopamine pretreatment) 3-month-old Wistar-Kyoto rats. Compared with the intact animals, sympathectomized rats showed a marked increase in arterial distensibility over the entire systolic-diastolic pressure range. When quantified by the area under the distensibility-pressure curve, the increase was 59% and 62% for the common carotid and femoral arteries, respectively (P<.01 for both). In the femoral but not in the common carotid artery, sympathectomy was accompanied also by an increase in arterial diameter (+18%, P<.05 versus intact). Therefore, in the anesthetized normotensive rat, sympathetic activity exerts a tonic restraint on large-artery distensibility. This restraint is pronounced in elastic vessels and even more pronounced in muscle-type vessels.

Heart rate-dependent stiffening of large arteries in intact and sympathectomized rats

In the anesthetized rat, acute increases in heart rate are accompanied by a reduction in arterial distensibility, which is a significant phenomenon in elastic-type vessels such as the common carotid but much less evident in muscle-type vessels such as the femoral artery. Because the sympathetic nervous system importantly reduces arterial distensibility, the present study aimed to determine whether sympathetic influences (1) are involved in the heart rate-dependent changes in arterial distensibility and (2) exert differential effects on elastic-type versus muscle-type arteries. To address this issue, 9 sympathectomized (6-hydroxydopamine) and 10 vehicle-treated, 12-week-old, pentobarbitone-anesthetized Wistar-Kyoto rats were subjected to atrial pacing via a transjugular catheter at 5 different randomly sequenced rates (280, 310, 340, 370, and 400 bpm). After each step, spontaneous sinus rhythm was allowed to return to normal. Common carotid and femoral artery diameters were measured by an echo Doppler device (NIUS 01), and blood pressure was measured via catheter inserted into the contralateral vessel. Arterial distensibility was calculated over the systolic-diastolic pressure range according to the Langewouters formula. In the common carotid artery, progressive increases in heart rate determined progressive and marked reductions of distensibility (range, 15% to 43%) in sympathectomized and intact rats. In the femoral artery, the stiffening effect of tachycardia was present in sympathectomized rats (range, 21% to 42%), at variance with the inconsistent changes observed in intact rats. In conclusion, our experiments support the notions (1) that in predominantly elastic-type arteries, the stiffening effect of tachycardia is exerted independently of sympathetic modulation of the vessel wall properties and (2) that in predominantly muscle-type arteries, removal of sympathetic influences unmasks the stiffening effect of tachycardia.

Age-dependent expression of fibrosis-related genes and collagen deposition in the rat myocardium

OBJECTIVES We sought to characterize the evolution, during maturational growth and early ageing, of the messenger abundance of four genes involved in cardiac fibrosis regulation (procollagens alpha2(I) and alpha1(III), transforming growth factors beta1, and beta3) and corroborate it with the alterations in collagen deposition in cardiac interstitium and around coronary arteries. METHODS Messenger RNA was quantified in LV and RV of 2-, 6-, 12- and 19-month-old male Sprague-Dawley rats (n = 5 per group) with Northern blot analysis. Collagen deposition was quantified with a semi-automated image analyser on Sirius red-stained sections of LV tissue. RESULTS There was an age-related monotonous decrease of procollagen type I (COL-I) transcript abundance in LV (p < 0.001) but not in RV. Procollagen type III (COL-III) expression decreased rapidly during maturational growth, both in LV and RV. On the other hand, collagen deposition in myocardial interstitium and around coronary arteries was slightly augmented during the maturational period of life (2-12 months), but with a higher rate during early ageing (up to 19 months). This was not accompanied by a significant thickening of the wall of coronary arteries. Transforming growth factor beta1, (TGF-beta1) and transforming growth factor beta3 (TGF-beta3) transcript abundance showed no major variations during ageing. CONCLUSIONS These results reflect a striking ventricular difference regarding the age-dependent expression of COL-I. The expression of TGF-beta(s), pleiotropic factors known to influence collagen pathway at different levels, does not seem to be profoundly altered during ageing. The discrepancy between protein and COL-I and COL-III mRNA levels indicates differences in age-related mRNA stability and/or regulation of collagen translation.

Granulocyte colony‐stimulating factor attenuates left ventricular remodelling after acute anterior STEMI: results of the single‐blind, randomized, placebo‐controlled multicentre STem cEll Mobilization in Acute Myocardial Infarction (STEM‐AMI) Trial

The aim of this study was to assess the effect of granulocyte colony‐stimulating factor (G‐CSF) on left ventricular (LV) function and volumes in patients with anterior ST‐elevation myocardial infarction (STEMI) and depressed LV ejection fraction (EF).

Lowering of elevated ambulatory blood pressure by HMG-CoA reductase inhibitors

Controversial results were reported as to a possible blood pressure-lowering effect of statins. This may relate to methodological limitations (blood pressure measuring techniques) or to putative different effects of statins in different biologic conditions (cholesterol or blood pressure levels, age, etc). Patients with cholesterol >200 mg/dL and no previous statin treatment underwent 24-hour ambulatory blood pressure (ABP) monitoring and were classified as normotensives or hypertensives according to their ABP. They were randomized to statin (n = 51, simvastatin or pravastatin, 10-20 mg/d; atorvastatin, 5-10 mg/d) or control treatment (n = 23, soy lecithin, 20 g/d) for 2 months, after which ABP assessment was repeated. No consistent treatment-related reduction in ABP was observed in lecithin-treated patients (either hypertensives or normotensives) or in statin-treated normotensive patients (−0.7 ± 5.1/−1.0 ± 4.6 mm Hg, both P = ns). In contrast, statin-treated hypertensive patients showed lower systolic and diastolic blood pressure (−5.7 ± 5.8/−3.5 ± 3.9 mm Hg, both P < 0.001), the effect was entirely accounted for by reduced daytime values with no change in nighttime values, and it was unrelated to the concomitant statin-induced cholesterol reduction. Statins moderately but significantly lower blood pressure in patients with high (but not with normal) ABP; the effect is confined to the daytime period and is unrelated to the extent of the cholesterol lowering.

Nitric Oxide–Dependent Vasodilation in Young Spontaneously Hypertensive Rats

Conflicting evidence exists on the possible impairment of tonic nitric oxide (NO) mediated vasodilation as a causative factor in the genesis of human as well as experimental hypertension. We evaluated the tonic NO-dependent vasodilation from the pressor response to NO synthesis inhibition by NG-monomethyl-L-arginine (L-NMMA) in 9 conscious, chronically instrumented spontaneously hypertensive rats (SHR) at 12 weeks of age, ie, during the early established hypertensive stage. Nine age-matched Wistar-Kyoto rats (WKY) were used as controls. The pressor responses to L-NMMA (100 mg . kg-1 IV bolus plus 1.5 mg . kg-1 . min-1 infusion for 60 minutes) as well as to non NO-dependent pressor stimuli, namely, vasopressin (2, 4, and 8 ng . kg-1) and phenylephrine (0.5, 1, and 2 microg . kg-1) given as IV boluses, were assessed both under control conditions and during suppression of autonomic reflexes by hexamethonium (30 mg . kg-1 IV bolus+1.5 mg . kg-1 . min-1 infusion). Rather than being reduced, the pressor responses to L-NMMA were 39% and 71% larger in the control and areflexic conditions, respectively, than those observed in WKY (both P<0.01). A similar pattern was observed for the pressor responses to vasopressin (+37% and +68% in the control and areflexic conditions, respectively; both P<0.01) and phenylephrine, (+20% and +52%; both P<0.05). Additional groups of 6-week-old prehypertensive SHR (n=11) and age-matched WKY (n=11) were subjected to an identical protocol: in these animals, the pressor responses to L-NMMA were similar in each strain, as were the pressor responses to vasopressin and phenylephrine in both control and areflexic conditions. In conclusion, our observations indicate that during the developmental phase of hypertension in the SHR model, namely, during the prehypertensive as well as the early established hypertensive stage, NO-dependent vasodilation is preserved (if not enhanced) so that a putative impairment of this function provides no significant pathogenic contribution to the onset of hypertension in this experimental model.

Lack of autonomic contributions to tonic nitric oxide-mediated vasodilatation in unanesthetized free-moving rats.

Objective To clarify the controversial issue of whether autonomic influences modulate vascular nitric oxide-mediated vasodilatation or even directly contribute to production of nitric oxide (NO) via nitroxidergic fibers. Methods Chronic venous and arterial catheters were implanted in Wistar-Kyoto rats (n = 65) for continuous blood pressure measurement, drug administration and blood sampling. Tonic NO-dependent vasodilatation in the conscious free-moving animal was evaluated as the pressor response to inhibition of NO synthesis by intravenous L-monomethylarginine (a 100 mg/kg intravenous bolus plus 0.5 mg/kg per min infusion for 30 min). Experiments were performed under control conditions, chemical sympathectomy by 6-hydroxy-dopamine, ganglionic blockade by hexamethonium, and surgical denervation of sino-aortic baroreceptors. Results Baseline mean arterial pressure was 100 ± 4 mmHg (mean ± SEM) in control rats and 73 ± 3, 62 ± 5, and 105 ± 10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. The peak increase in mean arterial pressure after administration of L-monomethylarginine was 38 ± 3 mmHg in control rats and 51 ± 3, 50 ± 6, and 63 ± 10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. Epinephrine and norepinephrine levels in rats of separate groups of unanesthetized control, sympathectomized and ganglion-blocked animals were measured by high-performance liquid chromatography from an arterial blood sample, the results indicating drastic reductions in levels of both catecholamines in the ganglion-blocked (but not in the sympathectomized) rats compared with those in the control rats. Conclusions Tonic NO-dependent vasodilatation can normally be maintained in the unanesthetized unrestrained rat irrespective of autonomic or humoral adrenergic influences.

Preservation of the Baroreceptor Heart Rate Reflex by Chemical Sympathectomy in Experimental Heart Failure

Background—The mechanisms underlying impaired baroreflex sensitivity in congestive heart failure (CHF) are incompletely understood. The purpose of the present study was to test the hypothesis that this alteration depends on the marked degree of sympathetic overactivity known to characterize the CHF syndrome. Methods and Results—Eight-week-old rats were subjected to induction of postmyocardial infarction CHF obtained by coronary ligation (Lig), chronic chemical sympathectomy by 6-hydroxydopamine (Sx), both interventions (Sx-Lig), or neither intervention (Veh-Sham, sham surgery, and vehicle administration). Four weeks after infarction, in conscious state, baroreflex sensitivity was assessed from the bradycardic responses to graded phenylephrine-induced elevations in blood pressure (BP). Left ventricular (LV) diameter was assessed by echocardiography, and plasma catecholamines were assayed to estimate sympathetic activity. Lungs were eventually excised and weighed (LW). CHF was associated with the following: (1) no changes in BP and heart rate; (2) sympathetic overactivity (norepinephrine, 320.2±53.8 pg/mL for Veh-Lig versus 173.4±20.5 pg/mL for Veh-Sham, P <0.01), prevented by Sx (181.2±35.5 pg/mL for Sx-Lig versus 159.8±33.1 pg/mL for Sx-Sham, P =NS); (3) LV enlargement (10.3±0.7 mm for Veh-Lig versus 6.8±0.6 mm for Veh-Sham, P <0.01), irrespective of Sx (9.7±0.7 mm for Sx-Lig versus 6.6±0.5 mm for Sx-Sham, P <0.01); (4) pulmonary congestion (LW, 7.55±0.40 mg per gram of body weight for Veh-Lig versus 5.21±0.44 mg per gram of body weight for Veh-Sham, P <0.01), marginally attenuated by Sx (6.54±0.28 mg per gram of body weight for Sx-Lig versus 4.98±0.22 mg per gram of body weight for Sx-Sham, P <0.05); (5) reduction in baroreflex sensitivity (0.443±0.032 ms/mm Hg for Veh-Lig versus 0.860±0.420 ms/mm Hg for Veh-Sham, P <0.01), entirely prevented by Sx (1.217±0.058 ms/mm Hg for Sx-Lig versus 1.345±0.093 ms/mm Hg for Sx-Sham, P =NS). Conclusions—In early post-MI CHF, sympathectomy only partially attenuated LV dysfunction and entirely prevented baroreflex sensitivity impairment that arises from enhanced sympathetic activity.

Altered blood pressure variability in patients with congestive heart failure

OBJECTIVE Congestive heart failure (CHF) is characterized by sympathetic overactivity but reduced variability of heart interval and sympathetic nerve activity; little information exists, however, about the alterations in blood pressure variability in this syndrome, especially during excitatory manoeuvres such as tilting or exercise. DESIGN AND METHODS Nine patients with CHF (age 62+/-1 years, NYHA class II-III, ejection fraction 33+/-1%, peak VO2 14.1+/-3.2 ml/min per kg body weight [mean +/- SEM]) and eight healthy control subjects (age 58+/-1 years) with normal left ventricular function were studied. Blood pressure (Finapres), R-R interval (ECG) and respiration (nasal thermistor) were recorded during 15-min periods of supine rest, 70 degree head-up tilting, submaximal bicycling exercise and post-exercise recovery. Total variance and the power of the spectral components of blood pressure (HF, respiratory-related; LF, 0.03-0.14 Hz; and VLF, 0.02-0.003 Hz) were measured. RESULTS Compared with control subjects, CHF patients have, first, a normal overall blood pressure variability during supine rest but a failure to increase this variability in response to head-up tilt and exercise; second, a suppressed LF spectral component of blood pressure at rest and in response to head-up tilt and exercise; and third, reappearance of LF blood pressure power during postexercise recovery. CONCLUSIONS In CHF patients, overall blood pressure variability and its LF spectral component are altered at rest and during sympathoexcitatory manoeuvres. Somewhat paradoxically, however, the depressed LF blood pressure power is partially restored during a 15-min recovery period, indicating that at least part of the CHF-related alterations of blood pressure variability have the potential to revert back towards normal under appropriate physiological circumstances.