Inflammatory activation during coronary artery surgery and its dose-dependent modulation by statin/ACE-inhibitor combination.

BACKGROUND: On-pump coronary artery bypass graft (CABG) surgery triggers an inflammatory response (IR) which may impair revascularization. The study aimed at (1) characterizing the temporal profile of the IR by assaying appropriate markers in both systemic and coronary blood, and (2) determining whether (and which doses of) cardiovascular drugs known to have antiinflammatory properties, namely statins and ACE-inhibitors (ACEI), inhibit the response. METHODS AND RESULTS: Patients scheduled for CABG (n=22) were randomized to statin/ACEI combination treatment at standard doses (STD, ramipril 2.5/simvastatin 20 mg, or atorvastatin 10 mg), or at high doses (HiDo, ramipril 10 mg, or enalapril 20 mg/simvastatin 80 mg, or atorvastatin 40 mg). Plasma levels of interleukin 6, tumor necrosis factor alpha, E-selectin, von Willebrand factor (vWF), and sVCAM-1 were serially assayed (ELISA) before, during, and after CABG. Blood was drawn from an artery, a systemic vein, and the coronary sinus. Myocardial perfusion scans were obtained before and 2 months after surgery in 19 out of 22 subjects. In the STD group both IL-6 and TNF displayed striking increases which were similar at all sites and peaked 10 to 60 minutes after aortic declamping. Such increases were drastically attenuated in the HiDo group. Instead, only modest increases in venous E-selectin, vWF, and sVCAM-1 were observed. Scintigraphic ischemia scores were entirely normalized after versus before CABG in the HiDo but not in the STD treatment group. CONCLUSIONS: On-pump CABG surgery is associated with an intense systemic inflammatory response, which can be almost completely prevented by early treatment with high (but not standard) doses of ACE-inhibitors and statins.

Adenosine A1 receptor expression during the transition from compensated pressure overload hypertrophy to heart failure.

OBJECTIVES: Myocardial adenosine is increased in pressure-overload hypertrophy (POH) and exerts important cardioprotective effects that delay transition to left ventricular failure. Adenosine-mediated signaling is attenuated in POH, but whether this depends on receptor or postreceptor defects is unknown. We therefore examined left ventricular adenosine A1-receptor gene and protein expression in experimental POH. METHODS: Six week-old Sprague-Dawley rats were subjected to abdominal aortic banding (group B) or sham operation (group S). Echocardiography and left ventricular catheterization were performed 10 weeks later under ketamine anesthesia. Left ventricular and lung weight indices were obtained postmortem. A1-Receptor mRNA and protein expression were measured in samples from left ventricular, right ventricular and aortic arch tissue. Group B rats were subgrouped as having compensated or decompensated hypertrophy according to the absence or presence of lung congestion (lung weight index below or above mean +/- 2SD compared with group S rats). RESULTS: Both mRNA and protein A1-receptor expression were significantly increased in compensated group B versus group S rats (by, respectively, 37 and 77%; both P < 0.01). This was not observed in decompensated group B rats. No consistent gene or receptor expression changes were observed in right ventricular or aortic tissues. CONCLUSIONS: In compensated POH, increased interstitial adenosine concentrations are accompanied by increased expression of the specific receptor mediating the major cardioprotective effects of this autacoid. Such overexpression is no longer detectable once the transition from POH to left ventricular failure has occurred. These observations may have pathophysiological and, in perspective, therapeutic relevance to the course of hypertensive heart disease.

Surgical animal model of ventricular hypertrophy.

In response to an increased afterload, the myocardium undergoes a complex adaptation by which wall stress is normalized and cardiac output is maintained. Although the consensus suggests that the increase of the myocardial mass is a necessary adaptive process to accommodate the increased workload, there is growing evidence that hypertrophy ultimately results in pathological remodeling and deterioration of cardiac function. Despite intense investigation, our understanding of the cellular mechanisms that are responsible for the initiation and the maintenance of this adaptation is largely incomplete and preventing or regressing left ventricular hypertrophy (LVH) is a major challenge. This chapter provides a detailed description of the procedures necessary to induce LVH by coarctation of the transverse aorta and to analyze the effects of the increased hemodynamic load on cardiac mass, cardiomyocyte size, and cardiac performance.

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.

Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of beta-adrenoceptor blockade.

OBJECTIVE: Racemic propranolol attenuates cardiac hypertrophy secondary to abdominal aortic banding-induced pressure overload by a mechanism independent of its effect on cardiac work load. This was only observed, however, using doses of propranolol that were much higher than those needed to induce beta-adrenoceptor blockade. Thus, the question remains as to whether the antihypertrophic effect of propranolol depends on its ability to antagonize cardiac beta-adrenoceptor-mediated action (positive chronotropic effect, trophic effect) or on beta-adrenoceptor-independent action. METHODS: In a rat model of chronic pressure overload induced by abdominal aortic banding, we evaluated the effects on left ventricular hypertrophy (LVH) of the propranolol isomers, L-propranolol and D-propranolol, which compared to L-isomer is approximately 50-fold less potent as a beta-adrenoceptor antagonist, but is similarly potent as a membrane-stabilizer, as well as of timolol, a non-selective beta-adrenergic antagonist devoid of membrane stabilizing activity, and disopyramide, which is a membrane stabilizer, but not a beta-adrenoceptor blocker. RESULTS: Compared to sham-operated rats, banded rats had 30% greater left ventricular to body weight (LVW/BW) ratio (P < 0.01). The increase in LVW/BW ratio was significantly attenuated by treatment with 40 and 80 (but not 10) mg/kg per day of L-propranolol. Left ventricular hypertrophy was also prevented by D-propranolol, 40 and 80 mg/kg per day, and disopyramide, 50 mg/kg per day, whereas timolol, 30 and 60 mg/kg per day, showed no antihypertrophic effect. In separate groups of banded rats in which the reduction in heart rate induced by propranolol (80 mg/kg per day) was prevented by chronic cardiac pacing at 375 b.p.m., hypertrophy was again prevented, indicating that the effects of L-propranolol on LVH are not related to a reduction in cardiac work load. CONCLUSIONS: In the aortic banding-induced model of LVH: (i) the antihypertrophic effect of propranolol is independent of its beta-adrenergic blocking activity; and Iii) since disopyramide and D-propranolol also proved to be able to antagonize banding-induced LVH, the hypothesis is proposed that membrane-stabilizing activity, among the ancillary properties of propranolol, most likely accounts for the antihypertrophic effect of this drug.

Effects of slow, controlled breathing on baroreceptor control of heart rate and blood pressure in healthy men.

BACKGROUND: Slow, controlled breathing has been shown by cross-spectral techniques to potentiate arterial baroreflex control of heart rate. However, crucial aspects of the effects of slow breathing on the arterial baroreflex remain unsettled, namely whether the major function of the arterial baroreflex (i.e. the control of blood pressure) is also potentiated and whether baroreflex function is differentially modulated according to the age of the individual. OBJECTIVE: To examine the bradycardic and depressor responses to selective carotid baroreceptor stimulation by the neck chamber technique (-15 and -30 mmHg neck suction) and the cross-spectral R-R interval/systolic blood pressure relationship (alpha index). METHODS: In 24 resting, supine healthy male volunteers (aged 19-66 years, mean +/-SEM 37.5 +/- 3.19 years), blood pressure (Finapres), R-R interval (electrocardiogram) and ventilation (impedance) were recorded continuously. Both assessments were performed during spontaneous breathing and during 6 cycles/min controlled ventilation in random order. RESULTS: The depressor and bradycardic responses to neck suction were significantly larger during slow breathing than in spontaneous breathing (+32 and +85%, respectively; both P < 0.01). The alpha index was also significantly larger during slow breathing (+62%; P < 0.01). Even after the volunteers were divided into older (> 50 years, n = 9) and younger (< 30 years, n = 9) groups, the baroreflex potentiation related to slow breathing was clearcut and significant for both the depressor (+46 and +24% older and younger volunteers; both P < 0.01) and the bradycardic (+130 and +73% older and younger volunteers; both P < 0.01) responses. When the assessment was made by computing the cross-spectral alpha index, a marked potentiation related to slow breathing was observed in younger volunteers (+99%; P < 0.01), whereas in older volunteers only a trend to an enhancement (by 32%; P < 0.055) was observed. CONCLUSIONS: Slow controlled breathing is associated with potentiation of both the depressor and the cardio-inhibitory components of the arterial baroreflex, the potentiation being largely similar regardless of the age of the individual.

Influence of left ventricular mass, uremia and hypertension on vagal tachycardic reserve.

BACKGROUND: Left ventricular (LV) hypertrophy, arterial hypertension and end-stage renal disease (ESRD) are associated with deranged cardiac parasympathetic regulation and increased cardiovascular risk. These conditions often co-exist but little is known about the relative contribution of LV mass, arterial blood pressure and ESRD to impaired cardiac vagal tone. We evaluated the vagal tachycardic reserve (VTR) in subjects with normal renal function (age 58.4 +/- 6.6 years, n = 19) and in patients under chronic hemodialysis (HD) (age 62.6 +/- 13.2 years, n = 30) having wide ranges of LV mass and blood pressure. METHODS: VTR was estimated from the tachycardic response to atropine (15 microg/kg intravenously) administered during a dipyridamole-atropine stress-echo test performed as part of the diagnostic work-up for identification of inducible myocardial ischemia. LV hypertrophy (defined as LV mass index > 125 g/m2 in both genders) was present in 20 HD patients and in nine control patients. Only patients free of inducible myocardial ischemia were included in the study. RESULTS: The atropine-mediated tachycardia was: (i) significantly smaller in HD patients than in control patients (34.7 +/- 7.6 versus 60.8 +/- 10.5 beats/min, P < 0.01); (ii) independently and inversely related to LV mass (multiple regression; partial coefficients, -0.139 in HD patients and -0.382 in controls, both P < 0.01) and to mean blood pressure (-0.171 in HD patients and -0.268 in controls, both P < 0.01). CONCLUSIONS: LV mass is the strongest (inverse) determinant of VTR. Blood pressure as well as the patient's renal status are also independent correlates of VTR, and the concomitance of LV hypertrophy and ESRD exacerbates the impairment of VTR.

Dynamic QT interval analysis in uraemic patients receiving chronic haemodialysis.

OBJECTIVE: To analyse the duration of the QT interval and its relationship with heart rate changes in patients with uraemia, before and during haemodialysis. METHODS: QT and RR intervals were measured automatically using a dedicated algorithm with 24-h Holter recordings in 29 patients (15 women) receiving chronic haemodialysis. QT corrected for heart rate (QTc) and the slope of QT/RR linear regression were calculated. Arterial blood pressure (ABP) was measured before and during haemodialysis. Plasma concentrations of K+, Mg2+ and Ca2+ were assessed before and after haemodialysis. RESULTS: ABP decreased significantly from baseline (102.7 +/- 11.0 mmHg) during the first (100.6 +/- 8.8 mmHg, P < 0.05), second (95.6 +/- 10.6 mmHg, P < 0.05), and third (94.9 +/- 10.3 mmHg, P < 0.05) hours of haemodialysis. QTc was longer during haemodialysis than during a 4-h period of no dialysis (447 +/- 28 ms compared with 429 +/- 22 ms, P < 0.001), and increased progressively during haemodialysis, with the greatest value during the last hour of haemodialysis (454 +/- 32 ms compared with 426 +/- 22 ms, P < 0.001). QT/RR slopes and correlation coefficients were lower during haemodialysis than during the period of no dialysis (0.13 +/- 0.08 compared with 0.20 +/- 0.07, P < 0.001 and 0.48 +/- 0.30 compared with 0.81 +/- 0.20, respectively; P < 0.001), suggesting a reduced ability to adapt the QT interval in response to changes in heart rate. The effects of haemodialysis on QT interval and the QT/RR relationship were greater in women than in men. QTc variations during dialysis were not correlated with changes in ABP, but were inversely related to changes in Ca2+ concentration (r2 = 0.35; P = 0.001). CONCLUSIONS: In patients with uraemia, the haemodialysis session induces a progressive increase in QT interval and modifies its relationship with heart rate. These effects may predispose some individuals to ventricular arrhythmias at the end of and immediately after the haemodialysis session.

Na+/H+ exchange inhibition attenuates left ventricular remodeling and preserves systolic function in pressure-overloaded hearts.

Cardiac hypertrophy is a homeostatic response to elevated afterload. Na+/H+ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na+/H+ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about +50%) and normal chamber size and function, whereas cariporide-treated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition.British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631

Adenosine A1 and A2A receptor cross-talk during ageing in the rat myocardium.

Adenosine (Ado), a naturally occurring autacoid, exerts cardioprotective effects against myocardial ischemia and reperfusion injury, through activation of its receptors type 1 (A1) and 2A (A2A). Since ageing involves a complex change in these effects, we evaluated A1 and A2A gene expression in left (LV) and right ventricle (RV) from 2-, 5-, 12-, and 21-month-old Sprague-Dawley rats. LV end-diastolic (EDD) and end-systolic (ESD) internal dimensions (mm) and LV fractional shortening (FS, %) were measured by M-mode echocardiography. Senescence was associated with a reduction in FS (42+/-1, 38+/-2, 39+/-2 and 35+/-2, in 2-, 5-, 12- and 21-month-old rats; p<0.02) and increases in EDD (7.5+/-0.2, 8.1+/-0.2, 8.5+/-0.2 and 8.8+/-0.2; p<0.001) and ESD (4.2+/-0.1, 4.4+/-0.2, 4.7+/-0.2 and 5.1+/-0.2; p=0.002). Ado A1 mRNA levels were highest in 12 and 21-month-old animals in both ventricles (LV: p<0.001; RV: p=0.001). By contrast, Ado A2A gene expression was lower in the aged LV (p<0.001), but higher in the aged RV (p<0.001). These modifications of Ado receptor gene expression and especially the increase in A1 receptor mRNA may partially explain the stronger antiadrenergic effects of Ado in the senescent heart.

Invited review: aging and the cardiovascular system.

Aging is associated with complex and diversified changes of cardiovascular structure and function. The heart becomes slightly hypertrophic and hyporesponsive to sympathetic (but not parasympathetic) stimuli, so that the exercise-induced increases in heart rate and myocardial contractility are blunted in older hearts. The aorta and major elastic arteries become elongated and stiffer, with increased pulse wave velocity, evidence of endothelial dysfunction, and biochemical patterns resembling early atherosclerosis. The arterial baroreflex is sizably altered in aging, but different components are differentially affected: there is a definite impairment of arterial baroreceptor control of the heart but much better preserved baroreceptor control of peripheral vascular resistance. Alterations at the afferent, central neural, efferent, and effector organ portions of the reflex arch have been claimed to account for age-related baroreflex changes, but no conclusive evidence is available on this mechanistic aspect. Reflexes arising from cardiopulmonary vagal afferents are also blunted in aged individuals. The cardiovascular and reflex changes brought about by aging may have significant implications for circulatory homeostasis in health and disease.

Modifications of the cardiovascular system with aging.

Aging is accompanied by significant cardiovascular modifications, both structural and functional. A slight degree of left ventricular hypertrophy develops, while the resting heart rate and early filling rate are somewhat decreased. In contrast, end-diastolic and end-systolic dimensions, stroke volume, and ejection fraction are largely unchanged. The effort tachycardic and inotropic responses are clearly attenuated, whereas the concomitant increase in end-diastolic diameter is enhanced. Large arterial conduits become less distensible and somewhat hypertrophic. Total blood volume is reduced, whereas total peripheral resistance is moderately increased. Neurohumoral systems relevant to cardiovascular regulation are nonuniformly affected by aging: the sympathetic nervous system is overactive and the circulating levels of vasopressin and atrial natriuretic factor are enhanced, while the activity of the renin-angiotensin system is blunted. Elderly individuals have altered cardiovascular homeostasis, with a typical propensity to postural and postprandial hypotension. "Spontaneous" blood pressure variability is increased, whereas heart rate variability is diminished. Vagally mediated chronotropic responses, including those dependent on baroreflex modulation, are attenuated, although end-organ (cardiac) parasympathetic responsiveness is exaggerated. Arterial baroreceptor control of blood pressure is largely preserved in advanced age, whereas cardiopulmonary-mediated reflex responses are definitely impaired.

Increased pulse wave velocity and not reduced ejection fraction is associated with impaired baroreflex control of heart rate in congestive heart failure.

BACKGROUND: It is known that baroreflex sensitivity (BRS) is impaired in cardiac patients with myocardial infarction (MI). Nevertheless, it is unknown whether factors other than a reduced ejection fraction play a role in the baroreflex impairment of these patients. METHODS AND RESULTS: Heart failure patients [congestive heart failure (CHF), n = 31, age 63 +/- 1.2 years, mean +/- SEM)], age-matched controls (n = 29) and coronary artery disease (CAD) patients without MI (n = 29) had RR interval and arterial blood pressure (BP) continuously monitored. Baroreflex function was assessed by the slope of the regression of RR interval, and BP responses to graded (-10, -20 and -40 mmHg) neck suction stimulation, the slope of bradycardic or tachycardic responses to spontaneous increases or reductions of SBP (sequence analysis) and the baroreflex efficiency index. Pulse wave velocity (PWV) was also measured.Compared with controls, CHF patients had RR interval and BP reflex responses to neck suction reduced by -36 and -54%, respectively (P < 0.01). By contrast, no differences were found between CHF and CAD patients. Similar reductions were observed for the sequence analysis (P < 0.01) in both CHF and CAD patients. Multiple regression analysis showed that in CHF and CAD patients, PWV and SBP and not ejection fraction were correlated with BRS. CONCLUSION: The baroreflex function is impaired in CHF patients, the extent and the degree of baroreflex impairment being similar to that of CAD patients without MI. In CHF and CAD patients, the baroreflex impairment correlates significantly with the increased PWV and not with ejection fraction.

Adrenergic origin of very low-frequency blood pressure oscillations in the unanesthetized rat.

Spectral analysis of cardiovascular signals has been extensively used to investigate circulatory homeostatic mechanisms. However, the nature of very low-frequency (VLF) fluctuations remains unclear. Because we previously observed enhanced VLF fluctuations in blood pressure (BP) in the sympathectomized rat (a model characterized by markedly increased plasma epinephrine levels), the aims of our study were to assess whether the genesis of VLF fluctuations in BP depends on circulating catecholamines and to determine which adrenergic receptor(s) and which membrane ion channel(s) are involved. We used continuous intra-arterial BP recordings from unanesthetized unrestrained rats to compute the power of VLF fluctuations in BP in the intact condition, during acute ganglionic blockade with hexamethonium, and after restoration of BP levels by infusion (in addition to hexamethonium) of adrenergic agonists (epinephrine, norepinephrine, and clonidine) or nonadrenergic vasoconstrictors (vasopressin). Effects of infusion of specific adrenergic receptor blockers (propranolol, prazosin, and yohimbine) with hexamethonium and catecholamines and infusion of various membrane ion channel blockers on VLF fluctuations in BP were also evaluated. Our results are as follows. 1) Ganglionic blockade drastically reduced BP levels and VLF fluctuations. 2) All vasoconstrictors restored BP levels, but only adrenergic vasoconstrictors generated striking VLF fluctuations in BP. 3) Catecholamine-induced fluctuations were abolished by alpha2-, but not alpha1- or beta-, adrenergic receptor blockade and by Ba2+-sensitive K+ channel or L-type Ca2+ channel, but not by other ion channel, blockers. We conclude that, in the conscious, unrestrained ganglion-blocked rat, catecholamine infusion generates VLF fluctuations in BP through stimulation of alpha2-receptors and activation of Ba2+-sensitive K+ channels. These fluctuations may have (patho)physiological relevance under conditions of disrupted circulatory homeostasis.

Survival benefits of different antiadrenergic interventions in pressure overload left ventricular hypertrophy/failure.

We observed previously that in rats with aortic banding (Bd), development of left ventricular (LV) hypertrophy is opposed by beta-blockade, whereas interventions interfering with alpha-adrenoceptor function also inhibit interstitial fibrosis. To assess whether these differential structural effects do translate into different effects on LV function and on heart failure mortality, Bd or sham Bd 8-week-old rats were randomized to vehicle treatment (Vh), chemical sympathectomy ([Sx] 6-hydroxydopamine, 150 mg/kg IP twice a week), beta-adrenoceptor blockade (propranolol [Pro], 40 mg/kg per day PO), or alpha-adrenoceptor blockade (doxazosin [Dox], 5 mg/kg per day PO). After monitoring survival for 10 weeks, the survivors were anesthetized to undergo echocardiography and intraarterial blood pressure measurement. Bd-Vh rats showed increased LV and lung weights, as well as LV dilation, depressed endocardial and midwall fractional shortening and a restrictive transmitral diastolic flow velocity pattern. Compared with Bd-Vh rats, all of the actively treated Bd rats showed less LV hypertrophy, LV dilation, and lung congestion but no less depression of midwall fractional shortening. In contrast, Sx and Dox but not Pro treatment were also associated with lesser degrees of diastolic dysfunction and, even more importantly, with a striking increase in survival (sham banded rats, 100%; Bd-Vh, 40%; Bd-Pro, 51%; Bd-Sx, 83%; and Bd-Dox, 82%). Although Pro, Sx, and Dox provide similar midterm protection from development of LV hypertrophy and dysfunction and from circulatory congestion, only Sx and Dox favorably affected mortality. These findings indicate that in the aortic banding rat model, alpha-adrenoceptors are importantly involved in the pathogenesis of cardiovascular deterioration and disease progression.

Enhanced baroreceptor control of the cardiovascular system by polyunsaturated Fatty acids in heart failure patients.

OBJECTIVES: The intention of this study was to test the hypothesis that, in heart failure patients, dietary supplementation of polyunsaturated fatty acids (PUFA) enhances arterial baroreceptor control of the cardiovascular system. BACKGROUND: Administration of PUFA reduces the risk of life-threatening arrhythmias in patients surviving myocardial infarction. This might result from potentiation of arterial baroreflexes, but whether or not PUFA enhance baroreflex function has never been studied in humans. METHODS: Patients with post-myocardial infarction left ventricular dysfunction underwent beat-to-beat blood pressure (BP) (Finapres, Ohmeda Inc., Englewood, Colorado) and R-R interval (electrocardiogram) recording; baroreceptor reflexes were assessed from the bradycardic and depressor responses to graded neck suction (NS) as well as by computation of the alpha "spontaneous" baroreflex sensitivity index. Assessments were repeated after prolonged treatment with PUFA (2 g/die, n = 15) or placebo (n = 10). RESULTS: Baseline BP and R-R interval were unaffected by PUFA. Both reflex depressor and bradycardic responses to NS increased after PUFA (respectively from -0.09 +/- 0.01 to -0.16 +/- 0.01 mm Hg x mm Hg(-1), p < 0.01, and from 1.25 +/- 0.9 to 1.76 +/- 1.1 ms x mm Hg(-1), p < 0.04) but not after placebo. The spontaneous baroreflex sensitivity increased in the PUFA (from 8.99 +/- 1.4 to 12.2 +/- 1.2 ms x mm Hg(-1), p < 0.02) but not in the placebo group. Polyunsaturated fatty acids (but not placebo) treatment also significantly increased R-R interval total variance and low-frequency and high-frequency spectral powers. CONCLUSIONS: Dietary PUFA supplementation markedly potentiates baroreflex function and enhances heart rate variability in patients with stable congestive heart failure.

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.

Sympathectomy or doxazosin, but not propranolol, blunt myocardial interstitial fibrosis in pressure-overload hypertrophy.

The adaptive changes that develop in the pressure-overloaded left ventricular (LV) myocardium include cardiomyocyte hypertrophy and interstitial fibrosis. Although the former is known to depend to a sizeable extent on sympathetic (over)activity, little information exists whether the same applies to the latter, ie, whether excess catecholamine exposure contributes to the imbalance between collagen deposition by fibroblasts and degradation by matrix metalloproteases (MMPs), eventually leading to LV collagen accumulation. Sprague-Dawley rats were subjected to abdominal aortic banding (B) or sham operation (S) and treated with beta-blockade (Bb, oral propranolol, 40 mg/kg per day), chemical sympathectomy (Sx, 6-hydroxydopamine, 150 mg/kg intraperitoneal twice per week) or vehicle (Vh). Ten weeks later, systolic blood pressure, LV weight, collagen abundance (computer-aided histology), zymographic matrix metalloproteinase (MMP)-2 activity and its specific tissue inhibitor concentration (TIMP-2) were measured. Both sympathectomy and beta-blockade failed to attenuate the banding-induced blood pressure elevation but significantly attenuated the attendant LV hypertrophy. As expected, pressure-overload hypertrophy was associated with interstitial fibrosis (collagen: 4.37+/-1.23% BVh versus 1.23+/-0.44% SVh, P<0.05), which was abolished by sympathectomy (2.55+/-1.31%, P=not significant versus SSx) but left unchanged by beta-blockade (4.11+/-1.23%, P<0.05 versus both SBb and BSx). beta-blockade, but not sympathectomy, was also associated with an increased TIMP-2/MMP-2 ratio (P<0.05), indicating reduced interstitial collagenolytic activity. In separate groups of banded and sham-operated rats, treatment with the alpha-receptor blocker doxazosin (10 mg/kg per day) displayed similar antifibrotic and biochemical effects as sympathectomy. Thus in the course of experimental pressure overload, the sympathetic nervous system plays a major pro-fibrotic role, which is mediated via alpha-adrenergic but not beta-adrenergic receptors.

Inhibition of left ventricular remodelling preserves chamber systolic function in pressure-overloaded mice.

Controversy exists whether the development of left-ventricular hypertrophy (LVH) is a mechanism able to prevent cardiac dysfunction under conditions of pressure overload. In the present study we re-assessed the long-term effects of attenuating LVH by using L- and D-propranolol, which are equally able to inhibit the development of LVH induced by aortic banding. The aortic arch was banded proximal to the left common carotid artery in 71 CD-1 mice that were then assigned randomly to receive L-propranolol, D-propranolol (both 80 mg/kg per day) or vehicle. Concurrently, sham-operated mice were given L-propranolol, D-propranolol or vehicle. LV dimension and performance were evaluated under isoflurane anaesthesia by cine-magnetic resonance imaging, echocardiography and cardiac catheterization up to 8 weeks after surgery. After 2 weeks of pressure overload, the vehicle-treated banded mice had enhanced LV weight, normal chamber size and increased relative wall thickness (concentric hypertrophy), whereas L-propranolol- or D-propranolol-banded mice showed a markedly blunted hypertrophic response, i.e. normal chamber size and normal relative wall thickness, as well as preserved systolic LV chamber function. After 4 weeks, the vehicle-treated banded mice showed LV enlargement with a reduced relative wall thickness (eccentric remodelling) and a clear-cut deterioration in LV systolic function. In contrast, L-propranolol- or D-propranolol-treated banded mice showed normal chamber size with a normal relative wall thickness and preserved systolic function. A distinct histological feature was that in banded mice, L-or D-propranolol attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. At the 8-week stage, LV dysfunction was present in propranolol-treated banded mice although it was much less severe than in vehicle-treated banded mice. It is concluded that (i) deterioration of LV systolic performance is delayed if LV hypertrophy is inhibited, (ii) banding-induced deterioration of LV systolic function is associated with LV eccentric remodelling and (iii) the antihypertrophic effect of propranolol is due to a selective action on cardiomyocytes rather than on collagen accumulation