Description: Background— Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension. Methods and Results— A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±20.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 10 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/90; P for all 〈0.001), respectively. In patients with true treatment resistance there was a significant reduction with RDN in 24-hour SBP (–10.1/–10.2/–11.7 mm Hg, P 〈0.001), diastolic BP (–4.8/–4.9/–7.4 mm Hg, P 〈0.001), maximum SBP (–11.7/–10.0/–6.1 mm Hg, P 〈0.001) and minimum SBP (–6.0/–9.4/–13.1 mm Hg, P 〈0.001) at 3, 6, and 12 months, respectively. There was no effect on ambulatory BP monitoring in pseudoresistant patients, whereas office BP was reduced to a similar extent. RDN was equally effective in reducing BP in different subgroups of patients. Office SBP at baseline was the only independent correlate of BP response. Conclusions— RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00664638 and NCT00888433.

Description: Background Elevated heart rate represents an independent risk factor for cardiovascular outcome in patients with heart disease. In the sinoatrial node, rate increase is mediated by β 1 adrenoceptor mediated activation of the Gα s pathway. We hypothesized that genetic inactivation of the stimulatory Gα s protein in the sinoatrial node would provide sinus rate control and would prevent inappropriate heart rate acceleration during β-adrenergic activation. Methods and Results Domestic pigs ( n =10) were evenly assigned to receive either Ad-small interfering RNA (siRNA)-Gα s gene therapy to inactivate Gα s or adenovirus encoding for green fluorescent protein (Ad-GFP) as control. Adenoviruses were applied through virus injection into the sinoatrial node followed by epicardial electroporation, and heart rates were evaluated for 7 days. Genetic inhibition of Gα s protein significantly reduced mean heart rates on day 7 by 16.5% compared with control animals (110±8.8 vs 131±9.4 beats per minute; P 〈0.01). On β-adrenergic stimulation with isoproterenol, we observed a tendency toward diminished rate response in the Ad-siRNA-Gα s group (Ad-siRNA-Gα s , +79.3%; Ad-GFP, +61.7%; n =3 animals per group; P = 0.294). Adverse effects of gene transfer on left ventricular ejection fraction (LVEF) were not detected following treatment (LVEF Ad-siRNA-Gαs , 66%; LVEF Ad-GFP , 60%). Conclusions In this preclinical proof-of-concept study targeted Ad-siRNA-Gα s gene therapy reduced heart rates during normal sinus rhythm compared with Ad-GFP treatment and prevented inappropriate rate increase after β-adrenergic stimulation. Gene therapy may provide an additional therapeutic option for heart rate reduction in cardiac disease. ( J Am Heart Assoc . 2012;1:jah3-e000372 doi: 10.1161/JAHA.111.000372)

Description: An imbalance between proangiogenic (vascular endothelial growth factor) and antiangiogenic (soluble fms-like tyrosine kinase 1) factors plays an important role in hypertension associated with reduced uteroplacental perfusion (RUPP). Exercise has been shown to stimulate proangiogenic factors, such as vascular endothelial growth factor, in both the pregnant and nonpregnant state; thus, we hypothesized that exercise training would attenuate both angiogenic imbalance and hypertension attributed to RUPP. Four groups of animals were studied, RUPP and normal pregnant controls and normal pregnant and RUPP+exercise training. Exercise training attenuated RUPP-induced hypertension ( P 〈0.05), decreased soluble fms-like tyrosine kinase 1 ( P 〈0.05), increased VEGF (P〈0.05), and elevated the soluble fms-like tyrosine kinase 1:vascular endothelial growth factor ratio. The positive effects of exercise on angiogenic balance in the RUPP rats were confirmed by restoration ( P 〈0.05) of the RUPP-induced decrease in endothelial tube formation in human umbilical vascular endothelial cells treated with serum from each of the experimental groups. Placental prolyl hydroxylase 1 was increased ( P 〈0.05) in RUPP+exercise training rats. Decreased trolox equivalent antioxidant capacity in the placenta, amniotic fluid, and kidney of the RUPP rats was reversed by exercise. RUPP-induced increase in renal thiobarbituric acid reactive species was attenuated by exercise. The present data show that exercise training before and during pregnancy attenuates placental ischemia-induced hypertension, angiogenic imbalance, and oxidative stress in the RUPP rat and reveals that increased prolyl hydroxylase 1 is associated with decreased soluble fms-like tyrosine kinase 1, thus revealing several potential pathways for exercise training to mitigate the effects of placental ischemia-induced hypertension. Lastly, the present study demonstrates that exercise training may be a useful approach to attenuate the development of placental ischemia-induced hypertension during pregnancy.

Description: Preeclampsia is a pregnancy-specific condition characterized by an imbalance of circulating angiogenic factors and new-onset hypertension. Although current treatment options are limited, recent studies suggest that pravastatin may improve angiogenic profile and reduce blood pressure in preeclampsia. We hypothesized pravastatin would restore angiogenic balance and reduce mean arterial pressure (MAP) in rats with reduced utero-placental perfusion pressure (RUPP)-induced hypertension. Pravastatin was administered intraperitoneally (1 mg/kg per day) in RUPP (RUPP+P) and normal pregnant rats (NP+P) from day 14 to 19 of pregnancy. On day 19, MAP was measured via catheter, conceptus data were recorded, and tissues collected. MAP was increased ( P 〈0.05) in RUPP compared with NP dams, and pravastatin ameliorated this difference. Pravastatin attenuated decreased fetal weight and plasma vascular endothelial growth factor and the RUPP-induced increased soluble fms-like tyrosine kinase-1 when compared with NP dams. Pravastatin treatment did not improve angiogenic potential in RUPP serum and decreased ( P 〈0.05) endothelial tube formation in NP rats. RUPP rats presented with indices of oxidative stress, such as increased placental catalase activity and plasma thiobarbituric acid reactive substances along with decreased plasma total antioxidant capacity compared with NP controls, and pravastatin attenuated these effects. MAP, fetal weight, plasma vascular endothelial growth factor, and plasma soluble fms-like tyrosine kinase-1 were unchanged in NP+P compared with NP controls. The present data indicate that treatment with pravastatin attenuates oxidative stress and lowers MAP in placental ischemia-induced hypertension, but may have negative effects on circulating angiogenic potential during pregnancy. Further studies are needed to determine whether there are long-term deleterious effects on maternal or fetal health after pravastatin treatment during pregnancy-induced hypertension or preeclampsia.