Marked Blood Pressure Research Articles

Abstract P195: Vascular MAPK/ERK Activation in sFTL-1-Induced Preeclampsia In Vivo

Vascular endothelial growth factor (VEGF) inhibition is linked to the development of hypertension and proteinuria in preeclampsia. This occurs as anti-angiogenic factors from the placenta contribute to pregnancy-related hypertension disorder. Soluble VEGF receptor fms-like tyrosine kinase-1 (sFLT-1) is an anti-angiogenic factor that counteracts VEGF. Levels of sFLT-1 are three times higher in preeclamptic placentas compared to those from normotensive pregnancies, and plasma sFLT-1 levels increase with the severity of preeclampsia. Infusing sFLT-1 in rodents induces hypertension, proteinuria, and glomerular endotheliosis, resembling the human condition of preeclampsia. Currently, there is no effective pharmacological treatment of preeclampsia, and in severe cases, early delivery is often the only effective treatment. In this study, we aim to determine how sFLT-1 exposure affects the activation of the vascular MAPK/ERK pathway and the contractility of the aorta ex-vivo using wire myography, to assess if the MAPK/ERK pathway can be a therapeutic target in preeclampsia. To this end, we treated pregnant female C57BL/6 mice from embryonic day E7.5 to E18.5 with either sFLT-1 (3.7mg/kg/day) or vehicle (phosphate-buffered saline) delivered by osmotic minipumps (intraperitoneal) and carried out non-invasive tail-cuff blood pressure measurements. After sacrifice, we isolated descending thoracic aorta for isometric tension measurements in a wire myograph. Infusion of sFLT-1 resulted in marked systolic blood pressure (SBP) elevation (D increase of 14 mmHg, P=0.0003) and augmented aortic phosphorylated-ERK activation (2-fold increase, P=0.040) by western blot and displayed impaired acetylcholine-induced endothelial relaxation in thoracic aortic segments (P<0.05), providing in vivo evidence of increased vascular p-ERK activation, accompanied by higher SBP and endothelial dysfunction in sFLT-1 - indued mouse model of preeclampsia. Future experiments are aimed to test the effect of pharmacological ERK inhibition in sFLT-1 infusion in vivo . We hypothesize that sFLT-1-induced rise in SBP and vascular p-ERK could be prevented in vivo by treatment with the pharmacological ERK inhibitor.

Abstract P438: Is aprocitentan also sympatholytic in patients with resistant hypertension?

Background: Aprocitentan is an endothelin ET A /ET B receptor antagonist (ERA) approved for the treatment of hypertension not adequately controlled on other drugs. Resistant hypertension is associated with sympathetic activation. The insufficient blood pressure (BP) lowering of many patients at night (non-dipping) and an often-increased heart rate are signs of sympathetic activation. Because ET A and ET B receptors participate in adrenaline and noradrenaline release and dual ERAs have been shown to decrease catecholamines, we hypothesized that aprocitentan might, among the various effects of dual blockade, behave as a sympathetic inhibitor. To assess this hypothesis, we investigated the effect of aprocitentan on nighttime BP and heart rate, both influenced by the sympathetic system. Methods: In the PRECISION study, where enrolled subjects were still hypertensive despite being on a standard fixed-dose background combination therapy composed of amlodipine, valsartan and hydrochlorothiazide, 730 patients were randomized to receive aprocitentan 12.5 mg, 25 mg or placebo for the first 4 weeks (double-blind placebo-controlled phase). 24-hour ambulatory BP monitoring (ABPM) was recorded in all randomized patients at baseline and Week 4. Results: At baseline, 60% of patients were non-dippers at night . Among those, 25%, 39% and 37% were reverted to dippers in the placebo, aprocitentan 12.5 and 25 mg groups, respectively, at Week 4. Accordingly, aprocitentan 12.5 mg and 25 mg decreased nighttime BP by -8.1 and -11 mmHg, respectively, vs -2.6 mmHg on placebo at Week 4. This reduction in nighttime BP by aprocitentan was larger than the reduction in daytime BP (-6.2 and -7.8 mmHg decrease at 12.5 and 25 mg, respectively, vs -2.3 mmHg on placebo). At baseline, mean heart rate, measured by office BP measurement at trough, was 74 beats/min. At Week 4, aprocitentan 12.5 mg and 25 mg, despite the respective 15.3 and 15.5 mmHg reduction of office BP from baseline, did not increase heart rate (-3.3 and -2.6 beats/min at 12.5 and 25 mg, respectively, versus -2.7 beats/min on placebo). Conclusion: We conclude that, by blocking ET A and ET B receptors, aprocitentan may have downstream sympatholytic effects, which may help its efficacy on nighttime BP – a prognostic factor for CV events in hypertension – and allow marked BP lowering without any reactive tachycardia.

Atrioventricular Interval Modulation (AVIM) therapy for ambulatory systolic blood pressure (aSBP) reduction with a dual chamber pacemaker: comparison of conduction system vs. right ventricular pacing

Abstract Background AVIM is a pacing algorithm incorporated into dual-chamber pacemakers to treat hypertension. AVIM delivers repeating sequences of short and longer atrioventricular delays leading to reduced preload and afterload. The therapy lowers blood pressure while simultaneously modulating the autonomic nervous system. The marked blood pressure reducing capability of AVIM has been already confirmed by a previous randomized clinical trial using conventional right ventricular (RV) pacing. Nevertheless, whether a similar blood pressure reduction could be also achieved by AVIM when conduction system pacing (CSP) is applied instead of RV pacing has not been investigated yet. Considering the facts that CSP using Left Bundle Branch Area Pacing (LBBAP) has been found to elicit more synchronous ventricular contraction and improved hemodynamics compared to RV pacing and AVIM is associated with a signficant burden of ventricular pacing, it is tempting to hypothesize that AVIM with CSP could be particularly beneficial. Purpose To compare the effects of AVIM therapy when delivered via an LBBAP location with the effects when delivered using a traditional RV lead location. Methods This single-center study evaluated subjects indicated for a dual chamber pacemaker who also had uncontrolled hypertension despite a stable dose of ³ 1 antihypertensive drug. Leads were placed in the RV or the LBBAP position. Subjects entered a run-in period of 4 weeks in which baseline office (oSBP)and 24-hour aSBP were measured. Subjects with baseline aSBP >130 mmHg and oSBP>140 mmHg at week 4 were included in the study. AVIM therapy was activated and a 24-hour aSBP was performed immediately after activation. Results Using a dedicated CSP pacemaker lab setup, CSP was performed in 5 patients with the Select Secure electrode (model 3830-69 cm) delivered via a fixed curve sheath (C315HIS). During the run in phase, in 3 out of the 5 CSP-AVIM patients, high blood pressure did not reach the level of inclusion and therefore these patients were not used for further analysis. In the remaining two patients, AVIM was activated. These two patients had a V6 stimulus-peak time of 69 ms and 61 ms, while V1 stimulus peak time was: 121ms and 109ms respectively. The effect of AVIM on 24-hour aSBP in the activated CSP-AVIM patients was compared to the average effect seen in patients from the same center enrolled in the prior randomized study with leads in the RV. Table 1 shows individual aSBP values for the two patient groups. Results suggest that delivery of AVIM therapy through leads in either position generates a significant reduction in blood pressure: -24.1 mmHg vs. -15.4 mmHg when the lead is placed in LBBAP or RV positions respectively. Conclusion These results demonstrate a significant reduction in aSBP in both lead locations. Additional studies evaluating larger sample sizes are required to assess if specific lead positions are preferable.Table 1

Neonatal blood pressure by birth weight, gestational age, and postnatal age: a systematic review.

Blood pressure is a vital hemodynamic marker during the neonatal period. However, normative values are often derived from small observational studies. Understanding the normative range would help to identify ideal thresholds for intervention to treat hypotension or hypertension. Therefore, the aim of this study was to assess observed blood pressure values in neonates who have not received any blood-pressure modifying treatments from birth to three months postnatal age and whether these vary according to birth weight, gestational age and postnatal age. This was a systematic review. A literature search was conducted in MEDLINE, PubMed, Embase, Cochrane Library, and CINAHL from 1946 to 2017 on blood pressure in neonates from birth to 3months of age (PROSPERO ID CRD42018092886). Unpublished data were included where appropriate. Of 3,587 non-duplicate publications identified, 30 were included (one unpublished study). Twelve studies contained data grouped by birth weight, while 23 contained data grouped by gestational age. Study and clinical heterogeneity precluded meta-analyses thus results are presented by subgroup. A consistent blood pressure rise was associated with increasing birth weight, gestational age, and postnatal age. In addition, blood pressure seemed to rise more rapidly in the most preterm and low birth weight neonates. Despite blood pressure increasing with birth weight, gestational age, and postnatal age, there was marked blood pressure variability observed throughout. To better define hypotension and hypertension, future studies should develop consistent approaches for factors related to blood pressure variability, including the method and timing of measurement as well as statistical control of relevant patient characteristics.

Antihypertensive drug treatment in white-coat hypertension: data from the Plaque HYpertension Lipid-Lowering Italian Study.

Little evidence is available on whether antihypertensive treatment lowers cardiovascular risk in white-coat hypertension (WCH). Protection might be indirectly inferred, however, from the blood pressure (BP) effects of treatment as in trials BP reduction is linearly related to outcome reduction. We analyzed the effect of antihypertensive treatment on office and ambulatory BP in WCH using data from the Plaque HYpertension Lipid-Lowering Italian Study (PHYLLIS). : Office and ambulatory blood pressure were measured in 470 hypertensive patients randomized to fosinopril or hydrochlorothiazide alone or combined with a statin before treatment and at 6 month or yearly intervals during 2.6 years of follow-up. Patients were divided into two groups according to whether before randomization to treatment office and 24-h mean BP were elevated (sustained hypertension) or office BP was elevated but 24-h BP values were normal (WCH). : In both sustained hypertension and WCH antihypertensive treatment was associated with an early marked office BP reduction, which persisted virtually unchanged throughout the treatment period. In contrast, 24-h (and day and night) BP showed a marked and persistent treatment-related fall in sustained hypertension but no change in WCH. The results were similar when data were separately analyzed in patients under fosinopril or diuretic, with or without statin treatment. : In WCH, antihypertensive treatment can effectively and durably reduce office BP. This reduction is accompanied by the inability to lower ambulatory BP from the normal values characterizing this condition at baseline. This appears to be unrelated to the type of treatment employed.

Central volume shift in acute heart failure revealed by blood volume monitoring during haemodialysis

ABSTRACTCentral volume shift is one of the major pathophysiological mechanisms of acute pulmonary oedema in acute heart failure (AHF). Pathological vasoconstriction results in central volume shift; however, its onset and course have been rarely detected or recorded in clinical practice. We report an exceptional case of AHF developing during haemodialysis, with marked blood pressure (BP) elevation and paradoxical repeated reduction in blood volume (BV) detected by real-time BV monitoring, accompanied by worsening dyspnoea. This inverse correlation of BV and BP during haemodialysis indicates that the theoretical central volume shift was captured in real-world AHF.

POSSIBLE ROLE OF THE INVASIVE ARTERIAL BLOOD PRESSURE MEASUREMENT IN SEVERE RESISTANT HYPERTENSION AND GENERALISED ATHEROSCLEROSIS

Objective: In severe resistant hypertension, a generalised atherosclerosis with high arterial stiffness present significant challenge for clinicians to obtain the realistic non-invasive blood pressure measurements and adjust antihypertensive treatment successfully. Design and method: Several patients with generalised atherosclerosis and severe resistant hypertension of the renovascular and renoparenchymal aetiology were referred to our Excellence centre. After performing ambulatory blood pressure monitoring (ABPM) and testing for non-compliance, often we still don’t reach target blood pressure. Due to generally expressed atherosclerosis, daily oscillometer technique could not be reliable in these set of patients. Invasive arterial blood pressure measurements via intra-arterial radial line were recorded for 24-hours and the consecutive non-invasive blood pressure was measured on the ipsilateral arm by oscillatory method. Results: In 3 patients, hypertension was renovascular and renoparenchymal (serum creatinine 134–219 micromol/l, oGF CDK-EPI 47 ml/min). The blood pressure values obtained by oscillatory method ranged from 170/100 mmHg to 230/120 mmHg. Generalised atherosclerosis with obstructive coronary and carotid artery disease, stenosis of iliac arteries, a hemodynamically important renal artery stenosis and subclavian artery stenosis was present in all 3 patients; one had comorbid periaortitis. Two patients were treated with six and one with five antihypertensives in maximum doses, at least one being a diuretic, and with at least one antihypertensive drug exceeding maximum dose. The difference in blood pressure measurements by the invasive vs. non-invasive method ranged from -20/10 mmHg to -50/30 mmHg. In 2 patients, marked blood pressure elevations (+40/20 mmHg) were triggered by elevated sympathycotonus. At discharge, doses of antihypertensive drugs could be lowered or stayed in the same range and a short-acting anxiolytic was added. Conclusions: In patients with severe resistant hypertension and generalised atherosclerosis, after excluding non-adherence, invasive blood pressure technique could be helpful in determining the relative difference to non-invasive measurements and safely adjusting antihypertensive therapy.

Abstract MP36: Blood Pressure Reductions in the Hyperacute Phase of Large Vessel Occlusion Ischemic Stroke Are Associated With Infarct Progression and Poor Functional Outcome

Introduction: Decreases in blood pressure (BP) during endovascular therapy (EVT) have been associated with infarct progression and worse outcome after large vessel occlusion (LVO) stroke. However, BP trajectories in the hyperacute phase prior to EVT have not been well characterized. We used high-frequency BP and hemodynamic monitoring to study the timing of BP reductions during the hyperacute period of stroke and evaluated their relation to infarct progression and functional outcome. Methods: We prospectively enrolled patients with anterior circulation LVO stroke undergoing EVT. BP and cardiac hemodynamic variables were recorded every 20 seconds from ER admission until the end of EVT using non-invasive finger plethysmography. Patients underwent initial CT perfusion imaging and a follow-up MRI at 24 hours to calculate infarct growth. The following hemodynamic parameters were defined as exposure variables: the difference between admission MAP and lowest MAP (ΔMAP), MAP drop> 20% from admission, MAP<70 mmHg, and SBP<140 mmHg. Functional outcome was measured with the modified Rankin Scale (mRS) at 90 days. Core associations between BP reductions and outcomes were studied using linear regression and logistic regression models. Results: 45 patients underwent continuous BP monitoring (age 72±17; 58% female; NIHSS 13±6). Aggregated time series data revealed a marked BP reduction around the time of imaging from which patients recovered (mean SBP 33 mmHg, duration 18 min). A sustained decrease in BP was observed after groin puncture without return to baseline BP levels. A linear regression analysis revealed a 13ml infarct growth for every 10 mmHg reduction in ΔMAP (p=0.054). Patients were divided into two groups based on median ΔMAP = 29. Those with ΔMAP ≤29 had better functional outcome at 90 days (34.78% vs. 9.09%, p = 0.038). Conclusion: Marked and frequently iatrogenic BP reductions occur around the time of initial imaging and may present a potential target for therapeutic intervention. Decrease in blood pressure before reperfusion may increase the risk of infarct progression and poor functional outcome. Changes in cardiac hemodynamic variables throughout the acute stroke period suggest a potential role for fluid resuscitation for hemodynamic optimization.

Association of lower nighttime diastolic blood pressure and hypoxia with silent myocardial injury: The Japan Morning Surge-Home Blood Pressure study.

Whether marked nocturnal blood pressure (BP) reduction is associated with cardiovascular disease (CVD) is still controversial. In addition, no report has yet discussed the relationship between lower nocturnal BP and CVD, involving modification by nighttime hypoxia. We evaluated 840 patients who had one or more cardiovascular risk factors by measuring their high‐sensitivity cardiac troponin T (Hs‐cTnT), N‐terminal pro‐B‐type natriuretic peptide (NT‐pro BNP), and nighttime saturation levels and performing ambulatory BP monitoring. The lowest tertile in nighttime diastolic BP (DBP) (≤66 mmHg) had increased likelihood of the presence of ≥0.014 ng/ml of Hs‐cTnT compared with the second tertile (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.01–3.63), and the lowest tertile of minimum blood oxygen saturation (≤81%) had increased likelihood of the presence of ≥0.014 ng/ml of Hs‐cTnT compared with the third tertile (OR 2.15, 95% CI 1.13–4.10). Additionally, the patients with both lowest tertile of nighttime DBP and minimum SpO2 showed increased likelihood of the presence of ≥0.014 ng/ml of Hs‐cTnT compared with those without this combination (OR 2.93, 95% CI 1.40–6.16). On the other hand, these associations were not found in the presence of ≥125 pg/ml of NT‐pro BNP. In the clinical population, each of lower nocturnal DBP and nighttime hypoxia was associated with asymptomatic myocardial injury, which was represented as higher Hs‐cTnT, and coexisting lower nocturnal DBP and nighttime hypoxia had an additive effect on the risk of myocardial injury.

Sex differences in blood pressure of aged Ren-2 transgenic rats.

Sex-related differences were observed not only in human but also in experimental hypertension. The aim of our study was to compare blood pressure (BP) of aged male and female heterozygous transgenic rats (TGR) harboring Ren-2 mouse gene, with their normotensive Hannover Sprague-Dawley (HanSD) controls. At the age of 9 months, systolic (SBP) and diastolic blood pressure (DBP) were measured by a direct puncture of carotid artery in rats awaking from isoflurane anesthesia. Thiobarbituric acid-reactive species (TBARS) formation was monitored as indicator of lipid peroxidation damage in heart, kidney and liver, whereas intracellular content of reduced glutathione was determined in the same organs as the main intracellular antioxidant. Furthermore, plasma triglycerides and total cholesterol as well as high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions of cholesterol were measured. As compared to HanSD rats, we found significantly elevated BP only in male TGR (MAP: 123±1 vs. 171±5, SBP: 150±2 vs. 208±7, and DBP: 99±3 vs. 140±4 mm Hg), but not between TGR and HanSD females, which were both normotensive. We also did not find any significant differences in TBARS and reduced glutathione in the three above mentioned organs as well as in plasma cholesterol or its HDL and LDL fractions between transgene-negative HanSD and TGR animals of either sex. However, we found significant sex differences in TBARS, glutathione and plasma lipids in both rat strains. Our results confirmed that aged TGR exhibit a marked sexual BP dimorphism, which does not seem to be dependent on oxidative stress or abnormal cholesterol metabolism.

Abstract WP374: High Frequency Blood Pressure Monitoring in the Acute Phase of Large Vessel Occlusion Ischemic Stroke

Introduction: Decreases in blood pressure (BP) during endovascular therapy (EVT) have been associated with infarct progression and worse outcome after large vessel occlusion (LVO) stroke. However, BP trajectories in the acute phase prior to EVT have not been well characterized. We thus used high-frequency BP and hemodynamic monitoring to create a continuous BP time trend and to determine timing of BP reductions. Methods: We prospectively enrolled patients with LVO stroke undergoing EVT. BP and cardiac hemodynamic variables were recorded every 20 seconds from emergency room admission until end of EVT using non-invasive finger plethysmography. Time trends of BP recordings were categorized into 4 windows: admission to imaging; imaging to EVT; EVT to groin puncture and groin puncture to recanalization. Episodes of hypotension (mean arterial pressure ≤ 70 mmHg) were correlated with administered medications and other potentially related interventions. Time trends in hemodynamic variables were analyzed using generalized estimating equations. Results: 25 patients underwent continuous BP monitoring (age 74±18; 68% female; mean NIHSS 12, monitoring time 8.34±2 hrs). Aggregated time series data revealed a marked BP reduction around time of imaging from which patients recovered (mean SBP 33 mmHg, duration 18 min, Fig A). A sustained decrease in BP was observed after groin puncture without return to baseline BP levels. In 62% of cases, reductions in BP were associated with BP lowering medications. A significant reduction in cardiac output (p=0.003) and increase in stroke volume variation (p=0.022) was seen across predetermined time points (Fig B & C). Conclusion: In patients with LVO, marked and frequently iatrogenic BP reductions occur around time of initial imaging and may present a potential target for intervention. Changes in cardiac hemodynamic variables throughout acute stroke period suggest a potential role for fluid resuscitation for hemodynamic optimization.

Lower serum calcium and pre-onset blood pressure elevation in cerebral hemorrhage patients undergoing hemodialysis.

Asymptomatic blood pressure (BP) elevation may be associated with cerebral hemorrhage (CH); however, few studies have investigated this association. We aimed to evaluate BP elevation before CH in hemodialysis (HD) patients and elucidate its associated factors. We reviewed HD patients treated for CH at our hospital between 2008 and 2019 (CH group). The control group comprised HD patients treated at Nagasaki Renal Center between 2011 and 2012. Data were obtained from medical records and three consecutive HD charts, made immediately before CH. HD1 was the session closest to onset, followed by HD2 and HD3. Systolic and mean BP were evaluated at the beginning of HD, and factors associated with BP elevation were investigated. The CH and control groups included 105 and 339 patients, respectively. Systolic and mean BP at HD1 were significantly higher than those at baseline (HD2 + HD3) in the CH group by 5 and 3mmHg, respectively (P < 0.001). Multiple linear regression analysis showed that lower calcium levels were significantly associated with BP elevation in the CH group (P < 0.05). The CH group was sub-divided by June 2013; the latter group had lower calcium levels (9.2mg/dL) and a marked systolic BP difference from baseline (+ 10mmHg) compared with the former (9.5mg/dL and -4mmHg). Asymptomatic BP elevation was observed in HD patients before CH; this elevation was associated with lower serum calcium levels and observed more frequently in the recent era. The precise mechanism underlying this effect remains unknown.

Extreme dipping

: Extreme dipping (i.e. a marked blood pressure fall during night-time period) is an alteration of circadian blood pressure (BP) rhythm frequently observed in the setting of systemic hypertension as well as in the general population. Some reports have suggested that cardiovascular prognosis in extreme dippers (ED) is similar as in dippers, whereas other studies have documented either a better or worse prognosis in ED. Available information on clinical and prognostic implications of ED is scanty and data provided by studies are controversial. Furthermore, a comprehensive report summarizing the key features of this BP pattern is lacking. The present review focuses on a number of issues concerning ED pattern such as the prevalence and clinical correlates, mechanisms underlying this BP phenotype association with hypertension mediated organ damage (HMOD) and prognostic value in predicting cardiovascular events and all-cause mortality. The reported prevalence of this BP rhythm alteration ranges from 5% to 30%, depending on diagnostic criteria, clinical and demographic characteristics of subjects. Most studies targeting the association of this condition with HMOD failed to find consistent findings in support of an adverse impact of ED on vascular, renal of cardiac structure and function. Available data on ED as compared to low risk reference group (i.e. dippers) do not allow to conclude that high BP variability resulting from a marked BP fall at night adversely affects cardiovascular prognosis at the community level and in the general hypertensive population. Thus, further studies aimed to assess the prognostic significance of ED as well as the impact of therapeutic interventions aimed to normalize this circadian BP pattern, are highly needed.

Expert panel consensus recommendations for ambulatory blood pressure monitoring in Asia: The HOPE Asia Network.

Hypertension is an important public health issue because of its association with a number of significant diseases and adverse outcomes. However, there are important ethnic differences in the pathogenesis and cardio-/cerebrovascular consequences of hypertension. Given the large populations and rapidly aging demographic in Asian regions, optimal strategies to diagnose and manage hypertension are of high importance. Ambulatory blood pressure monitoring (ABPM) is an important out-of-office blood pressure (BP) measurement tool that should play a central role in hypertension detection and management. The use of ABPM is particularly important in Asia due to the specific features of hypertension in Asian patients, including a high prevalence of masked hypertension, disrupted BP variability with marked morning BP surge, and nocturnal hypertension. This HOPE Asia Network document summarizes region-specific literature on the relationship between ABPM parameters and cardiovascular risk and target organ damage, providing a rationale for consensus-based recommendations on the use of ABPM in Asia. The aim of these recommendations is to guide and improve clinical practice to facilitate optimal BP monitoring with the goal of optimizing patient management and expediting the efficient allocation of treatment and health care resources. This should contribute to the HOPE Asia Network mission of improving the management of hypertension and organ protection toward achieving "zero" cardiovascular events in Asia.

Regulator of G protein Signaling 2 and 5 Coordinate Their Activity to Control Cardiac Contractility

Fine‐tuning of signaling via heterotrimeric G proteins by regulators of G protein signaling (RGS) proteins is critical to maintaining physiological homeostasis. Abnormal G protein signaling due to the loss of G protein regulation by RGS proteins is implicated in several diseases including cardiovascular disorders such as hypertension, cardiac hypertrophy, and heart failure. RGS proteins act as GTPase activating proteins (GAPs) to control the kinetics and amplitude of G protein signaling. Multiple RGS proteins are prominently expressed in the cardiovascular system; however, whether their activities/functions are coordinated to control G protein signaling and cardiovascular function is unknown. Here, we generated mice concurrently lacking RGS2 and 5 (Rgs2/5 dbKO) to determine how the dual absence of potent GAPs for Gq/11 and Gi/oclass G proteins affects cardiovascular function. Blood pressure and heart rate were monitored in conscious, freely moving mice via radiotelemetry. Surgical implantation of the radiotelemetry device induced marked systolic blood pressure increase in Rgs2/5 dbKO mice (WT: 140 ± 6 vs. dbKO: 170 ± 2 mmHg; p&lt;0.01) at baseline, which gradually declined but remained elevated in Rgs2/5 dbKO relative to wild type (WT) mice, several days later. Whereas all WT mice survived the surgery, ~70–80% of male Rgs2/5 dbKO mice surprisingly died 72–96 hr post‐surgery. When subjected to cardiac stress test using acute dobutamine infusion and echocardiography or the invasive pressure‐volume loop analysis of cardiac function, male Rgs2/5 dbKO mice showed hypocontractile response and decreased ejection fraction relative to WT mice. Freshly isolated ventricular cardiomyocytes from male Rgs2/5 dbKO mice showed decreased fractional shortening (WT: 16.1 ± 4.3 vs. dbKO: 7.4 ± 1.1 %; p&lt;0.01) but high calcium transients (WT: 117 ± 20 vs. dbKO: 198 ± 50 au; p=0.07) at baseline, and application of electrical field stimulation or low concentration of the non‐selective β‐adrenergic receptor agonist, isoproterenol (ISO), triggered premature calcium transients, tachyarrhythmia and death of cells from Rgs2/5 dbKO mice. Interestingly, cells from mice harboring just one copy of Rgs2 (Rgs2+/−, Rgs5−/−) but not Rgs5 (Rgs2−/−, Rgs5+/−) were resistant to low‐dose ISO‐induced arrhythmia. These results together suggest that RGS2 and 5 coordinate their activity to control cardiomyocyte excitation‐contraction coupling and normal cardiac rhythm.Support or Funding InformationNIH – NHLBI (1R01 HL139754‐01) and AHA Scientist Development Grant (16SDG27260276)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Anti-hypertensive mechanisms of cyclic depsipeptide inhibitor ligands for Gq/11 class G proteins

Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper-stimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting Gq/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it’s synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K+-induced Ca2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FRt1/2 ≅ 12 h vs. YMt1/2 ≅ 4 h). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support the hypothesis that increased LTCC and Gq/11 activity is involved in the pathogenesis of hypertension, and that dual targeting of both proteins can reverse hypertension and associated cardiovascular disorders.

Abstract P184: Coordinated Control of Cardiac Contractility By Multiple RGS Proteins

Signaling via heterotrimeric G proteins is critical to maintaining cardiovascular homeostasis. Abnormal G protein signaling due to the loss of G protein regulation by proteins such as regulators of G protein signaling (RGS) proteins is implicated in several cardiovascular disorders such as hypertension, cardiac hypertrophy, and heart failure. RGS act as GTPase activating proteins (GAPs) to control the kinetics and amplitude of G protein signaling. Multiple RGS proteins are prominently expressed in the cardiovascular system; however, it is unknown whether their activities/functions are coordinated to control G protein signaling and cardiovascular function. This study used mice concurrently lacking RGS2 and 5 ( Rgs2/5 dbKO) to determine how the dual loss of potent GAPs for Gq/11 and Gi/o class G proteins affects cardiovascular function. Blood pressure and heart rate in conscious, freely moving mice were monitored via radiotelemetry. Surgical implantation of the radiotelemetry device induced marked systolic blood pressure increase in Rgs2/5 dbKO mice (WT: 140 ± 6 vs. dbKO: 170 ± 2 mmHg; p &lt;0.01) at baseline, which gradually declined but remained elevated above wild type (WT) control level several days later. Whereas all WT mice survived the surgery, ~70-80% of male Rgs2/5 dbKO mice died 72-96 hr post-surgery. When subjected to cardiac stress test using acute dobutamine infusion and echocardiography, male Rgs2/5 dbko mice showed hypocontractile response relative to WT mice. Freshly isolated ventricular cardiomyocytes from male Rgs2/5 dbKO mice showed decreased fractional shortening (WT: 16.1 ± 4.3 vs. dbKO: 7.4 ± 1.1 %; p &lt;0.01) but high calcium transients (WT: 117 ± 20 vs. dbKO: 198 ± 50 au; p =0.07) at baseline, and application of electrical field stimulation or the non-selective β-adrenergic receptor agonist, isoproterenol (ISO), triggered premature calcium transients, tachyarrhythmia and death of cells from Rgs2/5 dbKO mice. Interestingly, cells from mice harboring just one copy of Rgs2 ( Rgs2+/-,Rgs5-/- ) but not Rgs5 ( Rgs2-/-,Rgs5+/- ) were resistant to low-dose ISO-induced arrhythmia. These results together suggest that RGS2 and 5 coordinate their activity to control cardiomyocyte excitation-contraction coupling and normal cardiac rhythm.

Use of Antihypertensive Drugs in Neoplastic Patients.

The introduction of Vascular Endothelial Growth Factor (VEGF) signaling pathway inhibitor treatment has highlighted the role of the baseline activity of the VEFG system for blood pressure regulation. VEGF signaling pathway is associated with hypertension and proteinuria. Activation of the endothelin system, endothelial dysfunction and capillary rarefaction are among the underlying mechanisms possibly explaining the rise in blood pressure and, to some extent, also the renal injury. The hypertension induced by VEGF signaling pathway inhibition is, usually, responsive to treatment. Recommendations about the management of cardiovascular toxicity in patients receiving VEGF signaling pathway inhibitors include a formal cardiovascular risk assessment before initiation of VEGF signaling pathway inhibitor treatment, active monitoring of blood pressure and cardiac toxicity throughout treatment, with more frequent monitoring during the first cycles of therapy, given that marked and unpredictable blood pressure rises can occur early after treatment with a VEGF signaling pathway inhibitor, and aggressive management of blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications. In patients with preexisting hypertension, the blood pressure target for initiating VEGF signaling pathway inhibitor treatment should be <140/90mmHg. Blockers of the renin-angiotensin system and calcium channel antagonists are among the drugs to be preferably used in these clinical conditions.

Masked Hypertension and Morning Blood Pressure Surge in Patients with Obstructive Sleep Apnea Syndrome

Objective: Frequent hypoxic episodes and arousal during sleep in obstructive sleep apnea syndrome (OSAS) result in increased nocturnal blood pressure, which in turn may lead to sustained hypertension. Patients with severe OSAS exhibit attenuated nocturnal blood pressure (BP) dipping, as well as marked and rapid BP elevation in the morning shortly after waking. We examined the prevalence of masked hypertension and morning BP surge in patients with OSAS, and the relationship between the severity of OSAS and abnormal circadian BP patterns. Methods: We performed 24-hour ambulatory BP monitoring in the absence of antihypertensive medication on 26 patients with OSAS (49.3 ± 8.4 yrs) to investigate masked hypertension and morning BP surge. Results: Results of the 26 patients, three (11.7%) were normotensive, six (23.0%) exhibited masked hypertension, and 17 (65.3%) were hypertensive. The apnea/hypopnea index was significantly correlated with 24-hour mean, daytime, and night time systolic and diastolic BP. 24-hour mean, daytime, and night time BPs in the severe OSAS group were significantly higher than in the mild to moderate OSAS group. We observed morning BP surge in 16 patients (61.5%). There were no significant differences in the prevalence of morning BP surge and masked hypertension between the mild to moderate and the severe OSAS groups. Conclusion: Mild to moderate OSAS may play an important role in masked hypertension and morning BP surge.

Effect of high salt diet on blood pressure and renal damage during vascular endothelial growth factor inhibition with sunitinib.

Antiangiogenic treatment with the multitargeted vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib associates with a blood pressure (BP) rise and glomerular renal injury. Recent evidence indicates that VEGF derived from tubular cells is required for maintenance of the peritubular vasculature. In the present study, we focussed on tubular and glomerular pathology induced by sunitinib and explored whether a high salt (HS) diet augments the BP rise and renal abnormalities. Normotensive Wistar Kyoto (WKY) rats were exposed to a normal salt (NS) or HS diet for 2 weeks and subsequently for 8 days to sunitinib or vehicle administration after which the rats were euthanized and kidneys excised. Mean arterial pressure (MAP) was telemetrically measured. Urine was sampled for proteinuria and endothelinuria, and blood for measurement of endothelin-1, creatinine and cystatin C. Compared with the NS diet, MAP rapidly rose by 27 ± 3 mmHg with the HS diet. On sunitinib, MAP rose further by 15 ± 1 with the NS and by 23 ± 4 mmHg with the HS diet (P < 0.05). The HS diet itself had no effect on proteinuria, endothelinuria or the plasma levels of endothelin-1, creatinine and cystatin C. Only with the HS diet, sunitinib administration massively increased proteinuria and endothelinuria and these two parameters were related (r = 0.50, P < 0.01). Likewise, renal glomerular pathology was enhanced during sunitinib with the HS diet, whereas tubulointerstitial injury or reduced peritubular capillary density did not occur. An HS diet induces a marked BP rise in WKY rats and exacerbates both the magnitude of the BP rise and glomerular injury induced by sunitinib.