To evaluate the circulating levels of remodeling biomarkers procollagen type 1 C-terminal propeptide (PICP), human cartilage glycoprotein-39 (YKL-40), plasma renin activity (PRA), aldosterone (Aldo) ...as well as clinical and echocardiographic parameters in patients with heart failure with reduced ejection fraction (HFrEF), before and after treatment with Sacubitril/Valsartan (S/V).
A total of 26 consecutive patients with HFrEF on stable clinical conditions were studied. Clinical, echocardiographic parameters and circulating biomarkers were measured at baseline, after 30 and 60 days of S/V treatment. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased, from 126 ± 15 to 113 ± 4 mmHg (p < 0.001) and from 77 ± 11 to 72 ± 9 mmHg (p = 0.005), respectively, at the end of study. Concomitantly, left ventricular ejection fraction (LVEF) increased by 22.8% from 29.5 ± 5% to 36.2 ± 5%, (p < 0.001) and indexed left ventricular end-systolic volume (LVESVi) decreased by 12% from 38.6 ± 8.7 ml/m
to 34.0 ± 10.0 ml/m
. (p = 0.007). Circulating levels of PICP, YKL-40, PRA and Aldo decreased by - 42.2%, - 46.8%, - 79.1% and - 76.7%, respectively (p < 0.001 for all), the decrements being already maximal within 30 days of S/V treatment. No significant changes of plasma electrolytes and creatinine were observed during the study (all p > 0.05).
A decrease of circulating markers of inflammation and fibrosis during chronic treatment with S/V is associated with an improvement of hemodynamic and echographic parameters in patients with HRrEF. These data are compatible with an anti-fibrotic and anti-inflammatory effect of S/V, that may contribute to the beneficial outcomes of the drug in this clinical setting.
BACKGROUNDPrevious studies have shown that obesity is characterized by a sympathetic overactivity coupled with an insulin resistance state and a baroreflex impairment. The present study was set out ...to compare the effects of peripheral versus central obesity on sympathetic, metabolic and reflex function.
METHODSIn 36 lean subjects (age 35.8 ± 1.4 years, mean ± SEM), 20 subjects with peripheral obesity (PO) and 26 subjects with central obesity (CO), all age-matched and with normal blood pressure values, we measured beat-to-beat arterial blood pressure (Finapres), heart rate (HR, ECG), homeostasis model assessment (HOMA) index, plasma norepinephrine (NE, high-performance liquid chromatography) and postganglionic muscle sympathetic nerve traffic (MSNA, microneurography) at rest and during baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively.
RESULTSBoth HOMA index, NE and MSNA values were significantly increased (P < 0.01) in obese as compared with lean individuals. Subjects with CO displayed MSNA and HOMA values significantly greater than those found in individuals with PO (65.4 ± 2.0 versus 47.9 ± 1.9 bs/100hb and 2.85 ± 0.10 versus 2.43 ± 0.11 a.u., respectively, P < 0.05 for both). Both in male and female subjects with CO or PO, MSNA, HOMA index and waist-to-hip ratio were significantly related to each other. Baroreceptor-HR and -MSNA control was significantly (P < 0.01) impaired in obese as compared with lean subjects, the degree of impairment being similar in CO and PO.
CONCLUSIONSThese data suggest that CO is characterized by a sympathetic activation greater for magnitude than that detectable in PO. This appears not to be related to gender or to baroreflex mechanisms but rather to metabolic factors, i.e. to the greater insulin resistance characterizing CO.
Previous studies have shown that essential hypertension and obesity are both characterized by sympathetic activation coupled with a baroreflex impairment. The present study was aimed at determining ...the effects of the concomitant presence of the 2 above-mentioned conditions on sympathetic activity as well as on baroreflex cardiovascular control. In 14 normotensive lean subjects (aged 33.5±2.2 years, body mass index 22.8±0.7 kg/m mean±SEM), 16 normotensive obese subjects (body mass index 37.2±1.3 kg/m), 13 lean hypertensive subjects (body mass index 24.0±0.8 kg/m), and 16 obese hypertensive subjects (body mass index 37.5±1.3 kg/m), all age-matched, we measured beat-to-beat arterial blood pressure (by Finapres device), heart rate (HR, by ECG), and postganglionic muscle sympathetic nerve activity (MSNA, by microneurography) at rest and during baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Blood pressure values were higher in lean hypertensive and obese hypertensive subjects than in normotensive lean and obese subjects. MSNA was significantly (P <0.01) greater in obese normotensive subjects (49.1±3.0 bursts per 100 heart beats) and in lean hypertensive subjects (44.5±3.3 bursts per 100 heart beats) than in lean normotensive control subjects (32.2±2.5 bursts per 100 heart beats); a further increase was detectable in individuals with the concomitant presence of obesity and hypertension (62.1±3.4 bursts per 100 heart beats). Furthermore, whereas in lean hypertensive subjects, only baroreflex control of HR was impaired, in obese normotensive subjects, both HR and MSNA baroreflex changes were attenuated, with a further attenuation being observed in obese hypertensive patients. Thus, the association between obesity and hypertension triggers a sympathetic activation and an impairment in baroreflex cardiovascular control that are greater in magnitude than those found in either of the above-mentioned abnormal conditions alone.
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.
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).
In early post-MI CHF, sympathectomy only partially attenuated LV dysfunction and entirely prevented baroreflex sensitivity impairment that arises from enhanced sympathetic activity.
Thirteen borderline hypertensives were investigated at rest and during dynamic exercise, before and after therapy with nadolol (40-80 mg/day for 7-28 days), in order to evaluate regulation of the ...number of lymphocyte beta-receptors. Systolic blood pressure and the heart rate were measured before and after 15 min of bicycle exercise, both with and without nadolol therapy; blood samples were withdrawn for adrenaline, noradrenaline and lymphocyte beta-receptor determinations. Nadolol induced a significant decrease in systolic blood pressure and the heart rate at rest, while plasma catecholamines and lymphocyte beta-receptors did not change significantly. Of the physiological responses to dynamic exercise (increases in systolic blood pressure, heart rate, plasma noradrenaline levels and adrenaline and lymphocyte beta-receptors), only the rise in beta-receptors was entirely prevented, and the increase in the heart rate was significantly attenuated by nadolol. It is suggested that the lack of a rise in the number of beta-receptors during exercise may contribute to the blunted exercise-induced tachycardia in patients taking nadolol.
Background/Aims: Cirrhotic patients with ascites are characterized by a marked activation of the sympathetic and the renin-angiotensin-aldosterone system. Total paracentesis is associated with a ...short-lived suppression of the renin-angiotensin-aldosterone system. Little information exists as to whether this favourable effect is parallelled by sympathoinhibition.
Methods: In 16 Child C cirrhotic patients (age: 57.1±6.2 years, mean±SEM) with tense ascites we assessed the time course of the effects of total paracentesis followed by intravenous albumin (6–8 g/l of ascites) on beat-to-beat mean arterial pressure (Finapres), heart rate, plasma norepinephrine, epinephrine (high performance liquid chromatography) and muscle sympathetic nerve activity (microneurography, peroneal nerve). Measurements were obtained under baseline conditions, during staged removal of ascitic fluid (250 ml/min) and 24 h later. The patient remained supine throughout the study period.
Results: Total paracentesis (10.6±1.3 l) induced a decrease in mean arterial pressure (from 95.0±2.6 mmHg to 88.2±3.2 mmHg,
p<0.01), in heart rate (from 82.5±3.3 beats/min to 77.1±2.8 beats/min,
p<0.01) and a reduction in plasma norepinephrine values (from 782±133 pg/ml to 624±103 pg/ml,
p<0.01), which were substantially maintained 24 h later. In eight patients muscle sympathetic nerve activity did not change during paracentesis (from 65±7.1 bursts/min to 65±7.4 bursts/min,
p=NS), but a marked reduction was observed 24 h later (48.4±5.6 bursts/min,
p<0.01).
Conclusions: These data provide the first evidence that total paracentesis exerts an acute marked sympathoinhibitory effect. Whether this is a long-lasting phenomenon and to what extent plasma expansion with albumin contributes to this effects need to be further addressed.
The effects of recombinant human erythropoietin (rHuEPO) administration on blood pressure and urinary albumin excretion were studied in normotensive Wistar-Kyoto rats (WKY), in spontaneously ...hypertensive rats (SHR), and in SHR rats treated with an angiotensin converting enzyme inhibitor (SHR-ACEi). Rats were housed in metabolic cages and treated with rHuEPO (150 U/kg body weight bw three times a week) for 6 weeks. Control animals received the vehicle only (0.25 mL of physiological saline). An angiotensin converting enzyme inhibitor was administered in the drinking water for 6 weeks (spirapril 5 mg/kg bw). Systolic blood pressure (SBP), and 24 h urinary albumin excretion (UAE) were measured once a week. No significant differences in SBP were observed between rHuEPO and vehicle-treated normotensive animals at the end of the treatment (171.9 ± 4.9
v
172.1 ± 5.6 mm Hg, respectively). After 6 weeks, SBP was significantly higher in SHR and SHR-ACEi groups treated with rHuEPO than in control groups (239.8 ± 7.3 and 243.0 ± 7.3 mm Hg
v
218.1 ± 6.0 and 187.9 ± 4.6 mm Hg, respectively); UAE was significantly higher in groups treated with rHuEPO than in control groups (WKY: 265.9 ± 19.5
v
127.0 ± 12.3 μg/100 g bw, SHR: 1668.4 ± 564.6
v
234.8 ± 22.9 μg/100 g bw, and SHR-ACEi: 1522.7 ± 448.3
v
143.0 ± 18.9 μg/100 g bw, respectively). We concluded that erythropoietin treatment causes an increase in arterial pressure in SHR only, and an increase in UAE in both normotensive and hypertensive rats. The albuminuric effect was not entirely dependent on increased blood pressure. The treatment with an angiotensin converting enzyme inhibitor did not modify either the proteinuric or the pressor effects.
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