Hypertensive Response Research Articles

Unsupervised machine learning identifies distinct phenotypes in cardiac complications of pediatric patients treated with anthracyclines

BackgroundAnthracyclines are essential in pediatric cancer treatment, but patients are at risk cancer therapy-related cardiac dysfunction (CTRCD). Standardized definitions by the International Cardio-Oncology Society (IC-OS) aim to enhance precision in risk assessment.ObjectivesCategorize distinct phenotypes among pediatric patients undergoing anthracycline chemotherapy using unsupervised machine learning.MethodsPediatric cancer patients undergoing anthracycline chemotherapy at our institution were retrospectively included. Clinical and echocardiographic data at baseline, along with follow-up data, were collected from patient records. Unsupervised machine learning was performed, involving dimensionality reduction using principal component analysis and K-means clustering to identify different phenotypic clusters. Identified phenogroups were analyzed for associations with CTRCD, defined following contemporary IC-OS definitions, and hypertensive response.ResultsA total of 187 patients (63.1% male, median age 15.5 years [10.4–18.7]) were included and received anthracycline chemotherapy with a median treatment duration of 0.66 years [0.35–1.92]. Median follow-up duration was 2.78 years [1.31–4.21]. Four phenogroups were identified with following distribution: Cluster 0 (32.6%, n = 61), Cluster 1 (13.9%, n = 26), Cluster 2 (24.6%, n = 46), and Cluster 3 (28.9%, n = 54). Cluster 0 showed the highest risk of moderate CTRCD (HR: 3.10 [95% CI: 1.18–8.16], P = 0.022) compared to other clusters. Cluster 3 demonstrated a protective effect against hypertensive response (HR: 0.30 [95% CI: 0.13– 0.67], P = 0.003) after excluding baseline hypertensive patients. Longitudinal assessments revealed differences in global longitudinal strain and systolic blood pressure among phenogroups.ConclusionsUnsupervised machine learning identified distinct phenogroups among pediatric cancer patients undergoing anthracycline chemotherapy, offering potential for personalized risk assessment.

Global deficiency in the inflammatory chemokine receptors 1,2,3 and 5 prevents vascular dysfunction in angiotensin II-induced hypertension and selectively modulates aortic myeloid cell phenotype

Abstract Background Leukocyte migration to the vasculature and the heart plays a critical role in hypertensive immune responses and is a carefully orchestrated process, regulated by the interactions of inflammatory chemokines with their receptors, notably CCR1, CCR2, CCR3, and CCR5 (collectively termed inflammatory chemokine receptors (iCCRs)). However, the inflammatory chemokine/receptor system is characterised by redundancy, ligand sharing and overlapping expression patterns. Consequently, our understanding of the specific and combinatory roles of chemokine receptors in cardiovascular inflammation remains incomplete, thus hindering the development of targeted therapies. To address this challenge, we have utilised two novel mouse models: iREP mice, carrying fluorescent reporters of inflammatory chemokine receptor expression, and TACKO mice, in which the entire iCcr locus containing Ccr1, Ccr2, Ccr3, and Ccr5 has been deleted. Purpose To evaluate the expression pattern of iCCRs in experimental hypertension and understand how the global deletion of iCCRs impacts disease progression. Methods We induced hypertension in mice by subcutaneously implanting osmotic minipumps administering angiotensin II (Ang II) for a duration of 14 days. Single-cell RNA sequencing was utilised for investigating iCCR expression in aortas during hypertension. Additionally, we employed flow cytometry and confocal microscopy to track iCCR expression and localization in aortas and hearts obtained from iREP mice. TACKO mice were utilised to assess the effect of global iCCr deficiency on hypertensive phenotypes. Blood pressure was measured via telemetry and vascular function was assessed using myography. Vascular and heart remodelling were evaluated through histology. Molecular mechanisms were analysed using Western Blotting and RT-qPCR, while immune cell changes in the aorta were evaluated through cytometry of time-of-flight (CyTOF). Results Ang II infusion induced higher iCCRs expression levels in both the aorta and the heart in comparison with sham treatment, particularly in fibrotic areas. After Ang II-treatment, global deletion of iCCRs in TACKO mice resulted in the prevention of endothelial dysfunction (n=5/group, P<0.05) and perivascular fibrosis (n=6-9, P<0.01), and a reduction in cardiomyocyte size (n=12-16, P<0.01) compared to wild type mice. However, no significant improvements were observed in other hypertensive phenotypes, including blood pressure, heart fibrosis, vascular NO synthase, and oxidative stress. CyTOF analysis revealed reductions in inflammatory monocytes and conventional type 2 dendritic cells in TACKO aorta, accompanied by a phenotypic switch in macrophages towards a less inflammatory phenotype. Conclusion Deficiency in iCCRs confers protective effects against vascular dysfunction in experimental hypertension, primarily by selectively reducing inflammatory myeloid cell homing to the aorta.

Treadmill exercise test as a screening tool in the development of hypertension

Abstract Background Guidelines promote screening people with high normal BP for the presence of end-organ damage because their presence is associated with a 2- to 3-fold increase in the risk of CVD. Purpose Office blood pressure measurements may be unable to detect early subclinical cardiac damage of adverse prognostic significance in subjects with high normal blood pressure. Methods 100 consecutive subjects with high normal BP [systolic BP=130-139mmHg and/or diastolic BP=85-89mmHg] were examined for early signs of hypertension-mediated organ damage (HMOD). They underwent an echocardiographic study, a negative for ischemia treadmill exercise test (Bruce protocol) where the index SBP/MET-slope [(peak SBP—resting SBP)/(peakMET-1)] was used. Arterial stiffness was evaluated based on carotid-femoral pulse wave velocity (PWV). The sympathetic drive was assessed by MSNA. Follow-up was scheduled every 6 months for 3 consecutive years, where BP measurements were assessed in the office and with ambulatory BP monitoring (ABPM). All participants offered lifestyle advice to lower their BP. The endpoint was the development of HTN either with Office BP or ABPM. Results Of 100 subjects (54±8 years, 42 males, baseline office BP: 132/82 mmHg, 24-hour BP: 122/76 mmHg), 40 developed HTN in 3 years. 34 subjects developed Hypertensive Response to Exercise (HRE) (BP >210mmHg in men and >190mmHg in women) and all of them developed HTN. The SBP/MET-slope in future hypertensives was increased in all stages till peak exercise independently of sex type (stage1: 6.7vs4.9 p=0.049, stage2: 8.4vs4.8 p=0.001, peak: 6.7vs4.9, p=0.001). Their exercise capacity was reduced (10vs11.3METs, p=0.002) as well as their maximum exercise heart rate (156vs164, p=<0.0001). Those with HRE had higher 24hSBP (124vs121mmHg, p=0.009), Night SBP (117vs111mmHg, p<0.001), Day SBP (127vs124mmHg, p=0.012) Office Pulse Pressure (51vs47mmHg, p=0.01). Additionally, they had increased PWV (8.3vs7.5m/sec, p=<0.0001), MSNA levels (36vs28 bursts, p=<0.0001), LVMI (38vs34 gr/m2.7, p=0.02), and a statistically significant deterioration of 2021 CKD-EPI eGFR (90 vs 97 mL/min/1.73 m², p=0.02). All of them correlated with development of hypertension (p=0.002), while they did not differ regarding their metabolic profile at the follow-up. Conclusion Detecting exaggerated blood pressure response and specifically an increased SBP/MET-slope in the end of second stage of Bruce protocol at treadmill exercise test is associated with increased systemic vascular resistance and early subclinical HMOD which may upgrade an individual’s cardiovascular disease (CVD) risk as they progress to HTN indicating a need for instituting a BP-lowering strategy.

Gradual hypertensive response in aortic alterations and myocardial inflammatory activation in progressing HFpEF in mice

Abstract Introduction Hypertension is the most common comorbidity in patients affected by heart failure with preserved ejection fraction (HFpEF). Early effects of pressure overload and its contribution to the gradual development of cardiac and vascular pathology leading to HFpEF are not well recognized, as patients are diagnosed when the disease has already advanced and show symptoms. Several hypertensive HFpEF mouse models possessing the hallmarks of the clinical-like phenotype are available. Nonetheless, initial and gradual pathological manifestations of hypertensive HFpEF have not been comprehensively described. Purpose This study aimed to investigate the gradual progression of HFpEF phenotype development in mice from the early manifestation of cardiac and vascular pathology to global cardiac dysfunction to multiorgan syndrome in response to hypertension. Methods Hypertensive HFpEF was induced by angiotensin II infusion in C57BL/6JOlaHsd 18-20-week-old male mice that were given low, moderate and high doses (0.5mg/kg/day - 1.5 mg/kg/day) subcutaneously for 4 weeks. Cardiac physiology and alterations in haemodynamics were assessed with echocardiography of heart and aorta, weekly ECG monitoring, and blood pressure measurements from the mouse tail. Extensive histology and immunohistochemistry analyses of cardiac tissue, microvasculature, lungs and kidneys were performed. Results In the low dose group, loss of aortic wall flexibility and presence of aortic root dilatation were detected. This group also demonstrated initiation of concentric remodelling process with the upsurge in macrophage infiltration in myocardium, but the signs of diastolic dysfunction were not yet present. The high dose group exhibited characteristic HFpEF features with diastolic dysfunction, left ventricular hypertrophy and fibrosis. Pathology in cardiac conduction system was noticed in all groups, with prominent ECG waveform abnormalities already on week one. However, only the high dose group experienced non-recovery in impulse propagation, accompanied by significant prolongation of ventricular depolarization. Conclusion This study demonstrates that change in aortic root dimensions and aortic wall dynamics are the first hypertension-sensitive alterations together with myocardial inflammatory cell infiltration that may contribute to myocardial remodelling and subsequent development of HFpEF and systemic effects. Hypertensive angiotensin II-induced HFpEF is a relevant mouse model, recapitulating not only hallmarks of cardiac pathology but also an extensive range of vascular and multiorgan alterations, demonstrating similarities with the clinical phenotype.

Increased TRPV4 Channel Expression Enhances and Impairs Blood Vessel Function in Hypertension.

Endothelial cell TRPV4 (transient receptor potential vanilloid 4) channels provide a control point that is pivotal in regulating blood vessel diameter by mediating the Ca2+-dependent release of endothelial-derived vasoactive factors. In hypertension, TRPV4-mediated control of vascular function is disrupted, but the underlying mechanisms and precise physiological consequences remain controversial. Here, using a comprehensive array of methodologies, endothelial TRPV4 channel function was examined in intact mesenteric resistance arteries from normotensive Wistar-Kyoto and spontaneously hypertensive rats. Our results show there is a notable shift in vascular reactivity in hypertension characterized by enhanced endothelium-dependent vasodilation at low levels of TRPV4 channel activation. However, at higher levels of TRPV4 activity, this vasodilatory response is reversed, contributing to the aberrant vascular tone observed in hypertension. The change in response, from dilation to constriction, was accompanied by a shift in intracellular Ca2+ signaling modalities arising from TRPV4 activity. Oscillatory TRPV4-evoked IP3 (inositol triphosphate)-mediated Ca2+ release, which underlies dilation, decreased, while the contraction inducing sustained Ca2+ rise, arising from TRPV4-mediated Ca2+ influx, increased. Our findings also reveal that while the sensitivity of endothelial cell TRPV4 to activation was unchanged, expression of the channel is upregulated and IP3 receptors are downregulated in hypertension. These data highlight the intricate interplay between endothelial TRPV4 channel expression, intracellular Ca2+ signaling dynamics, and vascular reactivity. Moreover, the data support a new unifying hypothesis for the vascular impairment that accompanies hypertension. Specifically, endothelial cell TRPV4 channels play a dual role in modulating blood vessel function in hypertension.

7706 Racial Disparities in Thyroid-Related Procedure Reoperation Rates: Insights from NSQIP Database

Abstract Disclosure: H.A. Erol: None. A. Liu: None. K. Wardwell: None. S. Woodruff: None. Background: Racial disparities in health outcomes are well-documented, with specific conditions affecting racial groups differently. However, the influence of race on endocrine surgery outcomes remains an evolving field of study. This research seeks to evaluate the effect of race on unplanned reoperations using the National Surgical Quality Improvement Program(NSQIP)-database and to investigate additional risk factors for reoperations in this cohort. Methods: We analyzed the NSQIP-database for thyroid-related procedures from 2012-2021 using CPT codes. Patient demographics, including age, sex, height/weight, ASA classification, and comorbid conditions, were assessed for unplanned reoperations. Univariate, multivariable logistic regression, and adjusted residual analyses were conducted assessing individual variables, adjusted odds ratios(ORs), and for post-hoc analyses. Results: Over the 10-year period, 169,251 patients were identified, with an overall reoperation incidence of 1.32%. Univariate analysis revealed that race correlated with increased reoperation rates, with the highest incidence observed among American Indian/Alaska Native (2.13%) patients, followed by Native Hawaiian/Pacific Islander (1.93%), Black/African American(1.84%), White (1.22%), and Asian(1.08%) patients. In multivariate logistic regression analysis, Black/African American (OR 1.452, 95% CI 1.293-1.630, p < 0.001) and American Indian/Alaska Native (OR 1.775, 95% CI 1.039-3.031, p = 0.036) patients had a higher risk of reoperation compared to White patients. Other factors associated with increased reoperation risk included male gender, higher ASA class, smoking, partially dependent functional status, ventilator dependency, hypertension, dialysis, disseminated cancer, bleeding disorders, and systemic inflammatory response syndrome or sepsis. Most reoperations were hematoma related(63.02%), with statistical significance noted among different ethnicities and types of reoperations. White patients had lower rates of hematoma-related procedures, fewer tracheostomies, and more additional thyroid procedures. Black/African American patients had more tracheostomies and fewer lymphatic-related or additional thyroid procedures. Conclusions: Using the NSQIP-database, Black/African American and American Indian/Alaska Native patients were at a greater risk of reoperation following thyroid surgeries, even after accounting for multiple variables. Black/African American patients also had disparate types of reoperations. These findings highlight the impact of race on thyroidectomy-related outcomes. Further research is imperative to comprehensively understand the role of race in surgical outcomes and to address healthcare disparities and inequities. Presentation: 6/2/2024

The relationship between exercise-related hypertension and carotid artery intima media thickness and brachial artery endothelial function

Aims: Hypertension is one of the most common chronic diseases in the world. There are some non-invasive tests which are used to assess end organ damages in patients with hypertension. The purpose of this study is to show relationship between carotid artery intima media thickness (CIMT) and flow mediated dilatation (FMD) in patients with exercise induced hypertension (EIH). Methods: 73 healthy normotensive men and women, who are between 18 and 65 years of age, participated in this study. All patients underwent electrocardiography, echocardiography, 24-hour ambulatory blood pressure monitoring and symptom-limited treadmill testing before CIMT and FMD were measured with Doppler ultrasonography. CIMT and FMD values of both groups were statistically compared with each other. Results: Of a total of 73 individuals, 56 were evaluated as the patient group and 17 as the control group. Age, smoking rate, body mass index, resting and maximum blood pressure values, and ascending aorta diameter were significantly higher in the patient group (p=0.02 for smoking, p<0.01 for the rest). Right/left main CIMT, right/left bulbus IMT, and left ventricular diastolic dysfunction was significantly higher in the patient group (p<0.05 for all). In addition, the mean CIMT and mean FMD (%) values were significantly higher and lower, respectively, in the patient group compared to the control group. No difference was observed between the two groups in terms of right/left internal CIMT and passive smoking exposure. In addition, the mean values of CIMT and FMD (%) did not show a statistically significant difference according to hypertensive response stages and gender. Conclusion: CIMT and FMD are significantly associated with EIH. EIH should be evaluated as important risk factor for future hypertension and may cause asymptomatic end-organ damage. It can be easily assessed using CIMT and FMD.

The P2Y6 receptor as a potential keystone in essential hypertension.

Essential hypertension (HT) is a highly prevalent cardiovascular disease of unclear physiopathology. Pharmacological studies suggest that purinergic P2Y6 receptors (P2ry6) play important roles in cardiovascular function and may contribute to angiotensin II (AgtII) pathophysiological effects. Here, we tested the hypothesis that functional coupling between P2ry6 and AgtII receptors mediates altered vascular reactivity in HT. For this, a multipronged approach was implemented using mesenteric vascular smooth muscle cells (VSMCs) and arteries from BPN (Blood Pressure Normal) and BPH (Blood Pressure High) mice. Differential transcriptome profiling of mesenteric artery VSMCs identified P2ry6 purinergic receptor mRNA as one of the top upregulated transcripts in BPH. P2Y receptor activation elicited distinct vascular responses in mesenteric arteries from BPN and BPH mice. Accordingly, 10 µM UTP produced a contraction close to half-maximal activation in BPH arteries but no response in BPN vessels. AgtII-induced contraction was also higher in BPH mice despite having lower AgtII receptor type-1 (Agtr1) expression and was sensitive to P2ry6 modulators. Proximity Ligation Assay (PLA) and super-resolution microscopy (SRM) showed closer localization of Agtr1 and P2ry6 at/near the membrane of BPH mice. This proximal association was reduced in BPN mice, suggesting a functional role for Agtr1-P2ry6 complexes in the hypertensive phenotype. Intriguingly, BPN mice were resistant to AgtII-induced HT and showed reduced P2ry6 expression in VSMCs. Altogether, results suggest that increased functional coupling between P2ry6 and Agtr1 may contribute to enhanced vascular reactivity during HT. In this regard, blocking P2ry6 could be a potential pharmacological strategy to treat HT.

Abstract P447: Impact of Altered Receptor Expression On the Cardiovascular Response to Estrogen

Premenopausal women benefit from estrogen's protective effects, including lower arterial stiffness than men of the same age. Despite estrogen's protective role, menopausal hormone therapy showed no cardiovascular benefits in the Women's Health Initiative. One theory is that the response to menopausal hormone therapy is modulated by the presence of pre-existing cardiovascular disease. Estrogen signals through nuclear estrogen receptors ERα and ERβ, and the membrane-bound G protein-coupled estrogen receptor (GPER). Our lab has shown that GPER induces protective cardiovascular effects including decreased blood pressure, protection from renal damage, and attenuation of arterial remodeling. In this study, we hypothesized that GPER deletion would attenuate the protective vascular effects of estrogen after menopause. Female C57Bl/6J wildtype (wt) and global GPER knockout (ko) mice underwent ovariectomy (OVX) at 46 weeks of age and concurrently administered estrogen (E) or vehicle (Veh). Angiotensin II (Ang II; 700 ng/kg/day) infusion was used to induce hypertension either four weeks prior (Ang-E) or at the time of OVX (E-Ang) to evaluate the impact of cardiovascular diseases preceding or coinciding with menopause. Blood pressure was measured by tail-cuff plethysmography and arterial stiffness was assessed by pulse wave velocity (PWV). Statistical analysis was performed using one-way ANOVA. Ang II induced a similar level of hypertension in wt and ko mice and was not impacted by E or timing. In wt mice, PWV was significantly higher in Veh-treated compared with E-treated hypertensive animals, independent of timing (P<0.001). In contrast, PWV was not impacted by E in GPER ko mice (P=0.99). In conclusion, we found that E did not affect the hypertensive response to Ang II in both wt and GPER ko mice. GPER deletion reduced estrogen’s protection from arterial stiffening. Whether Ang II preceded or coincided with menopause did not alter the effects of E. These studies are important for determining whether cardiovascular status should be a factor when considering menopausal hormone therapy.

Abstract 36: Ablation of T-Lymphocyte β-Arrestins Reduces Inflammation and Increases Salt Retention in the Absence of Blood Pressure Changes Following Angiotensin II Infusion

Introduction: T-cells contribute to hypertension (HT) development. Among several G-protein coupled receptors regulating T-cell function, it has been hypothesized that some subpopulations use the angiotensin II (ANG II) type 1 receptor (AT 1 R) to modulate immune responses in HT. Selective ablation of AT 1 Rs in T-cells paradoxically increases hypertensive end-organ damage (EOD). While AT 1 Rs typically induces classical G-protein signaling, recent studies have uncovered a protective signaling cascade via β-arrestin ( ARRB ) proteins. We hypothesize that T-cell ARRB s mediate an anti-hypertensive and anti-inflammatory role in response to ANG II, decreasing EOD in HT. Methods: Breeding CD4-Cre mice with Arrb1 -Flox or Arrb2 -Flox mice generated lines with T-cell-specific deficiency of Arrb1 or Arrb2 genes. Hypertensive conditions modeling kidney damage consisted of unilateral nephrectomy, 4% salt diet, and continuous infusion of 1 mg/kg/min ANG II (UNX/HSD/ANG). Age/sex-matched Cre - littermates were used as controls (WT). Blood pressure (BP) was measured at baseline and for the following three weeks using radiotelemetry. Results: At baseline, there were no significant differences in systolic BP between groups (WT:124.1±8.0 mmHg; CD4 Arrb1-null :125.4±8.1; CD4 Arrb2-null :128.7±3.1; p =0.37; n=12/10/8). Three weeks of UNX/HSD/ANG equally increased systolic BP in all groups (WT:178.0±14.0 mmHg; CD4 Arrb1-null :174.8±26.3; CD4 Arrb2-null :179.9±11.1; p =0.86; n=7/9/7). Despite similar BPs, CD4 Arrb2-null mice demonstrated less renal inflammation than WT after four weeks of UNX/HSD/ANG, with a reduction in interleukin-1α protein (3.8±3.2 vs. 8.3±2.8 p <0.05; n=4/6) and a trend towards decreased tumor necrosis factor-α transcript (0.63-fold change vs. 1.9, p =0.051; n=10/8). Furthermore, CD4 Arrb1-null mice increased 24-hour voluntary water intake compared to WT (15.7±3.4 mL vs. 12.2±1.6; p <0.05; n=12/7), and 24-hour urine output (10.0±3.7 mL/d vs. 6.8±1.5; p <0.05; n=11/8). However, there was no difference in sodium excretion during this period (1.9±0.5 eq/d vs. 1.7±0.1; p =0.14; n=11/7). Interestingly, 4 hours after intraperitoneal saline injection, CD4 Arrb1-null mice excreted significantly less sodium compared to WT (5.6±3.5% vs . 31.4±10.6%; p <0.05; n=4/5). Conclusion: Contrary to our hypothesis, these data suggest that T-cell Arrb s do not protect against the hypertensive response to ANG II, but instead play a complicated role in the modulation of hydromineral balance and inflammation.

O95 HYPERTENSIVE RESPONSE TO EXERCISE RELATIVE-TO-FITNESS AND LEFT VENTRICULAR HYPERTROPHY ARE ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR EVENTS: EVIDENCE FROM THE EXERCISE STRESS TEST COLLABORATION (EXERTION) STUDY

Background. A hypertensive response to exercise (HRE) is associated with a high prevalence of left ventricular hypertrophy (LVH), both being related to an increased risk of cardiovascular disease (CVD). However, these associations may be influenced by aerobic capacity (fitness). This study aimed to determine if an HRE considered relative-to-fitness and LVH are associated with increased risk for CVD events. Methods. Records for 4,307 individuals (aged 58.6±12.7 years, 52.0% male) who underwent exercise stress echocardiography were linked to administrative health datasets (hospital and emergency admissions) to ascertain CVD events (n=458, mean follow-up, 44.8±25.9 months). LVH presence/absence (LVH+/LVH-) was defined as LV mass index adjusted for body surface area around a cut point of ≥115 g/m2 for men and ≥95 g/m2 for women. HRE presence/absence (HRE+/HRE-) relative-to-fitness was defined as peak systolic blood pressure (SBP) divided by peak metabolic equivalents around a cut point of ≥90th percentile. Survival analysis using Cox-proportional hazard regression was used to compare CVD event rates across the four groups defined by the combinations of HRE+/HRE- with LVH+/LVH-, adjusted for age, sex, pre-exercise SBP, and CVD history. Results. Compared to the reference group (HRE-/LVH-), there was a stepwise increase in CVD event rate (Figure 1) across the following groups: HRE+/LVH- [Adjusted HR(95%CI), 1.34(1.02-1.76)], HRE-/LVH+ [Adjusted HR(95%CI), 2.1(1.6-3.76)], HRE+/LVH+ [Adjusted HR(95%CI), 2.55(1.64-3.97)]. Conclusion. Individuals with both HRE considered relative-to-fitness and LVH are at the highest risk of CVD events, greater than either clinical presentation alone. These results emphasise the need to address an HRE and low fitness in people with LVH to improve CVD risk management.

Abstract MP33: A20 in the Kidney Epithelium Attenuates Angiotensin II-induced Hypertension by Constraining Renal Tubular NHE3 Expression

Whereas the ubiquitin editor A20 limits NF-κB-mediated signaling in myeloid leukocytes, the functions of A20 in renal epithelial cells during hypertension have not been described. We recently found that A20 in the kidney tubule ameliorates hypertension and cardiac hypertrophy induced by chronic angiotensin (Ang) II infusion (500ng/kg/min) in mice. Here we report that following 3 weeks of hypertension, the kidneys of mice with tubular deletion of A20 in the kidney epithelium (“A20 iKKO” = A20 flox/flox Pax8-rtTA TetO-Cre + ) have augmented protein expression of the proximal tubular sodium transporter NHE3 (1.5±0.1 vs. 1.0±0.1; p <0.01) but similar levels of ENaC subunit expression in the collecting tubule ( p =NS for all 3 subunits) vs wild-type (WT) controls. Moreover, kidneys from A20 iKKO mice have upregulated mRNA levels for the T cell chemokine CCL5 (2.4±0.3 vs. 1.0±0.3; p <0.01) and higher proportions of effector memory CD8 + T cells (51.2±2.3 vs. 39.3±2.9 % of CD8 + ; p =0.013) compared to WTs despite similar numbers of effector memory T cells in the spleen ( p =NS). To examine whether A20 in the kidney attenuates hypertension by constraining tubular NHE3 expression, we bred A20 iKKO mice with an NHE3 flox/flox line, thereby generating mice with double A20 and NHE3 deletion in the kidney tubule (“Dual KKO”) mice. At baseline, kidneys from Dual KKO mice showed robust reductions in mRNA for A20 (0.5±0.1 vs. 1.0±0.1; p =0.022) and NHE3 (0.2±0.05 vs. 1.0±0.15; p =0.002) compared to WT littermates. During the first ten days of Ang II infusion, mean arterial pressures (MAPs) in the Dual KKO mice were lower than the MAPs previously recorded in our A20 iKKO cohort (129±3 vs. 152±4 mmHg; p <0.01). Moreover, during 3 weeks of Ang II infusion, Dual KKO and WT mice maintained similar MAPs (145±7 vs. 149±13 mmHg; p =0.78), and heart weight to body weight ratios (5.9±0.3 vs. 5.5±0.2 mg/g; p =0.37) in concomitant measurements. Thus, A20 in the kidney tubule blunts the chronic hypertensive response by curtailing NHE3 expression. Our data further suggest that A20 in the nephron can blunt renal inflammation without altering systemic T cell immunity. Stimulating the A20 signaling pathway in the kidney may thus attenuate NHE3-dependent hypertension without conferring attendant risks of global immunosuppression.

P135 FITNESS INFLUENCES THE RELATIONSHIP BETWEEN EXERCISE BLOOD PRESSURE AND LEFT VENTRICULAR STRUCTURE: EVIDENCE FROM THE EXERCISE STRESS TEST COLLABORATION (EXERTION) STUDY

Background. A hypertensive response to exercise is associated with left ventricular (LV) remodelling, a principal sign of hypertensive heart disease. Fitness may modify this relationship, making clinical interpretation of peak exercise systolic blood pressure (SBP) challenging. This study examines the influence of fitness on the relationship between peak exercise SBP and LV structure. Methods. Cardiovascular structure and function (LV mass index (LVMI), LV relative wall thickness (RWT), cardiac output (CO) and total peripheral resistance (TPR)) were assessed at rest by echocardiography on 4,309 individuals (aged 58.6±12.7 years,52.0% male). SBP was measured at peak treadmill exercise, and fitness (exercise duration (minutes)) was grouped into thirds. Multiple regression analysis was conducted with fitness as an interaction term with peak exercise SBP, adjusted for age, sex, pre-exercise SBP, and cardiovascular disease (CVD) history. Results. Peak exercise SBP was similar across low (180±26.5mmHg), moderate (181±26.3mmHg) and high (182±24.5mmHg) fitness groups. Fitness modified the relationship between exercise SBP and LVMI; each 5mmHg increase in exercise SBP was associated with LVMI in moderate [0.27(0.10–0.43) and high [0.25(0.06–0.43)] fitness groups, which was not observed among those with low fitness [-0.05(-0.22–0.12)]. RWT increased with higher peak exercise SBP at all fitness levels (all p<0.001), with higher values among those with low fitness. Prevalence of LV concentric remodelling was highest in those with low fitness (29.9%) and lowest in those with high fitness (10.8%). A lower CO and higher TPR were observed in the low fitness group (7.5±2.5L/min and 14.3±5.1mmHg min/L) compared to those with high fitness (10.9±3.1L/min and 9.2±2.09mmHg min/L). Conclusion. Whilst a small effect, fitness modified the peak exercise SBP-LV structure relationship, such that for similar peak exercise SBP, those with low fitness exhibit a more adverse LV remodelling, with lower CO and higher TPR, compared to those with higher fitness. Considering fitness when interpreting SBP and cardiac imaging results from exercise stress testing may be relevant in identifying CVD risk and optimal patient management.

Blood pressure behavior during exercise in patients with diastolic dysfunction and a hypertensive response to exercise.

A hypertensive response to exercise is a precursor leading to hypertension, which is a major risk factor for the development of heart failure and diastolic dysfunction. Herein, we aimed to assess blood pressure (BP) in patients with a hypertensive response to exercise and different degrees of diastolic dysfunction. Between January 2009 and December 2014, 373 patients with a hypertensive response to exercise (HRE) and echocardiographic data assessing diastolic function were enrolled at the University Hospital of Zurich. ANCOVA was used to assess the changes in BP response during exercise testing in individuals with different degrees of diastolic dysfunction. Normalization of systolic BP was blunted in patients with grade II and III diastolic dysfunction after 3 min of recovery in univariable [β (95%) - 9.2 (-13.8 to - 4.8) p<.001, -16.0 (-23.0 to 9.0) p<.001, respectively] and adjusted models. In fully adjusted models, when taking maximal effort into account, there were no differences with regard to systolic BP during exercise. Patients without diastolic dysfunction achieved higher heart rates (HRs) [both in absolute terms (p<.001) and as a percentage of the calculated maximum (p=.003)] and greater wattage (p<.001) at maximum exertion. The findings of this cross-sectional study suggest that exercise capacity is compromised in patients with diastolic dysfunction. A hypertensive response to exercise and the finding of a blunted BP recovery may help identify patients at risk of developing heart failure.

Hypertension and Ventilatory Responses During Exercise in the Fitness Registry and the Importance of Exercise National Database (FRIEND).

A high minute ventilation/rate of carbon dioxide production (V̇E/V̇co2) slope during exercise is prognostic for cardiovascular death. Recent data indicate that adults with either controlled or untreated primary hypertension, but not those with uncontrolled hypertension, exhibit a higher V̇E/V̇co2 slope during exercise. However, the sample sizes were modest. Therefore, we used the Fitness Registry and the Importance of Exercise National Database to determine whether adults with hypertension, particularly those with controlled or untreated hypertension, exhibit higher V̇E/V̇co2 slopes compared with adults without hypertension. Using the Fitness Registry and the Importance of Exercise National Database, we isolated primary hypertension by excluding those with any disease other than hypertension or taking any medications other than antihypertension medications. We also excluded current smokers and those with obesity. The V̇E/V̇co2 slope was determined during a peak cycling exercise test. All data are presented as median [interquartile range]. We compared groups using linear regression adjusted for age, male/female, and body mass index. The characteristics of the entire sample (n=4109) were age, 42 [18] years; 48% women; body mass index, 26 [4] kg/m2. The V̇E/V̇co2 slope did not differ between adults with hypertension (n=1940; 24.7 [3.7]) compared with those without hypertension (n=2169; 24.9 [3.8]) (hypertension versus no hypertension, P=0.31; overall model: R2=0.07, F4,4104=73.0; P<0.001). Further, the V̇E/V̇co2 slope did not differ between adults with medication-controlled hypertension (n=107; 24.4 [3.0]), untreated hypertension (n=1626; 24.8 [3.9]), uncontrolled hypertension (n=207; 24.8 [3.0]), or those without hypertension (n=2169; 24.9 [3.8]) (hypertension subgroup versus no hypertension, P≥0.06; overall model: R2=0.07, F6,4102=49.6, P<0.001). Primary hypertension is not associated with V̇E/V̇co2 slope in the Fitness Registry and the Importance of Exercise National Database.

Alfentanil versus fentanyl for emergency department rapid sequence induction with ketamine: A-FAKT, a pilot randomized trial

BackgroundFentanyl is often administered during rapid sequence induction of anesthesia (RSI) in the emergency department (ED) to ameliorate the hypertensive response that may occur. Due to its more rapid onset, the use of alfentanil may be more consistent with both the onset time of the sedative and the commencement of laryngoscopy. As such, we compared the effect of alfentanil and fentanyl on post-induction hemodynamic changes when administered as part of a standardized induction regimen including ketamine and rocuronium in ED RSI. MethodsThis was a double-blind pilot randomized controlled trial of adult patients requiring RSI in the ED of three urban Australian hospitals. Patients were randomized to receive either alfentanil or fentanyl in addition to ketamine and rocuronium for RSI. Non-invasive blood pressure and heart rate were measured immediately before and at two, four, and six minutes after induction. The primary outcome was the occurrence of at least one post-induction systolic blood pressure outside the pre-specified range of 100-160mmHg (with adjustment for patients with baseline hypertension). Secondary outcomes included hypertension, hypotension, hypoxia, first-pass intubation success, 30-day mortality, and the pattern of hemodynamic changes. ResultsA total of 61 patients were included in the final analysis (31 in the alfentanil group and 30 in the fentanyl group). The primary outcome was met in 58% of the alfentanil group and 50% of the fentanyl group (difference 8%, 95% confidence interval: -17% to 33%). The 30-day mortality rate, first-pass success rate, and incidences of hypertension, hypotension, and hypoxia were similar between the groups. There were no significant differences in systolic blood pressure or heart rate between the groups at any of the measured time-points. ConclusionAlfentanil and fentanyl produced comparable post-induction hemodynamic changes when used as adjuncts to ketamine in ED RSI. Future studies could consider comparing different dosages of these opioids.

Comparison of Lidocaine Versus Nifedipine for Attenuation the Cardiovascular Response to Direct Laryngoscopy and Intubation during General Anesthesia

Background: Laryngoscopy and Endo-tracheal intubation are gold standard for securing the airway and giving positive pressure ventilation. Drugs like Lidocaine, Fentanyl citrate and Nifedipine are used frequently to attenuate presser response to laryngoscopy and intubation, Single drug or technique is not satisfactory. Different methods of attenuation of response to laryngoscopy and intubation are still to be studied with new drugs tried every once a while. Aim: To compare the lidocaine and nifedipine effect on the cardiovascular response to direct laryngoscopy and intubation during general anesthesia Methods: Following the approval of the Institutional Review Board of AL jala Teaching hospital and written informed consent from patients undergoing elective surgery under general anesthesia, fifty patients between 18 and 60 years old, American Society of Anesthesiologist (ASA) Grades I and II, were randomized to one of the following groups, Group A: Lidocaine group 1.5 mg/kg IV bolus 3 minutes prior to laryngoscopy and intubation, Group B: Nifedipine group. 10 mg SL 15 minutes prior to induction. The induction protocol was standard for all patients. Intraoperative vitals were monitored using ECG, Pulse Oxymeter and NIBP. HR, SBP, DBP and MAP were recorded &amp; RPP was calculated in all patients inside the operation theater just before induction (baseline), immediate after laryngoscopy and intubation, every 2 minutes after intubation during which no stimulus was given to patient for the next 10 minutes after laryngoscopy and intubation. Results: Patients' characteristics of age, gender and were comparable in the two groups. There was no significant difference between the groups regarding the type of the surgery. Statistically there was no significant difference (p=0.66) in the two groups in terms of ASA grading. No significant difference was observed between Lignocaine group and Nifedipine group values (P&gt; 0.05), in any parameters at pre anaesthetic check-ups. the first significant change between the two groups , in which significant drop (p &lt;0.05 ) in MAP occurred 4 minutes after intubation in group received Nifedipine sublingually, Once again , 6 minutes after intubation we recorded significant drop in SBP and MAP in Nifedipine group compared to Lidocaine group, No significant changes in parameters between two groups , 8and 10 minutes after intubation. The HR reached its maximum value immediately after intubation, after that the recording of HR became fluctuant in both groups. The percentage of rise in HR was less significant in Lidocaine group immediately after intubation and after that except for the reading 2 minutes, which was less significant in Nifedipine group. Both drugs failed to bring the HR to pre-operative value even after 10 minutes; the highest SBP was recorded at the pre-anaesthetic check-up. After that the SBP started to decline in both groups, this decline reached its maximum 4 minutes after intubation. After that the SBP started to gradually rise until 10 minutes without reaching the pre-anaesthetic basal value. The percentage of decline was more pronounced in Lidocaine group immediately and after 2 minutes of intubation and more pronounced in Nifedipine group after that, The highest DBP was recorded at the pre-anaesthetic check-up. After that the DBP started to decline in both groups, this decline reached its maximum 4 minutes after intubation. After that the DBP started to gradually rise until 10 minutes without reaching the pre-anaesthetic basal value. The percentage of decline was more pronounced in Lidocaine group immediately after intubation and more pronounced in Nifedipine group after that, The highest MAP was recorded at the pre-anaesthetic check-up. After that the MAP started to decline in both groups, this decline reached its maximum 4 minutes after intubation. After that the MAP started to gradually rise until 10 minutes without reaching the pre-anaesthetic basal value. The percentage of decline was more pronounced in Lidocaine group immediately after intubation and more pronounced in Nifedipine group after that. The Pressure Rare Product reached its maximum value immediately after intubation, the highest decrease in Pressure Rare Product occurred 4 minutes after intubation in both groups Conclusion: Both drugs in our study ( Lidocaine and Nifedipine ) has been shown to be effective in attenuating and preventing the increase in haemodynamic stress response to direct laryngoscopy and intubation during general anaesthesia in our patients. However, Nifedipine is more effective than Lidocaine in preventing the hypertensive response and attenuating the increase in RPP, and Lidocaine is more effective in attenuating the tachycardia response than Nifedipine. Recommendation: Based on the results of this study, it is recommended to consider the use of iv Lidocaine and sublingual Nifedipine to reduce the presser effect of laryngoscopy and intubation.

Blood pressure response during exercise testing in individuals with and without hypertension: The value of the recovery phase.

Hypertension and exercise testing are essential for cardiovascular risk assessment. However, an exact description of blood pressure (BP) in patients with a hypertensive response during exercise (HRE), especially in the recovery phase is lacking. Herein, we aimed to analyse BP and heart rate during exercise testing and recovery in patients with an HRE. 800 patients aged 17-90 with an HRE during a standardized bicycle ergometry test were recruited. The BP behaviour during exercise testing was correlated with clinical data. Furthermore, data were analysed according to the presence of pre-existent hypertension. Of the 800 patients included in this study 497 (62%) were previously diagnosed with hypertension. Analysis of covariance showed a significantly faster systolic (β [95% CI] 8.0 [4.9-11.1]) and diastolic (2.4 [0.4-4.4]) BP recovery 3 min after maximal exercise in patients without hypertension in univariable models. These results remained robust in fully adjusted models taking into account age, sex, body mass index, cardiovascular disease, and antihypertensive treatment for systolic (5.3 [1.2-9.4]) and diastolic BP (4.5 [1.9-7.0]). Furthermore, patients with hypertension displayed higher systolic BP during maximal exercise in univariable (3.8 [0.1-7.5]) and fully adjusted (5.5 [1.1-10.0]) models. There was no difference in maximum diastolic BP between groups. In this large cohort study, patients without hypertension showed a faster systolic and diastolic BP recovery and lower maximal systolic BP compared to patients with hypertension. Overall, this study provides new insights into cardiovascular health during recovery phase.

Single nucleotide polymorphism of AGT rs699 in the pathogenesis of hypertension and ACE inhibitors response: a narrative review

Single nucleotide polymorphism of AGT rs699 in the pathogenesis of hypertension and ACE inhibitors response: a narrative review

Novel formylpeptide receptor 1/2 agonist limits hypertension-induced cardiovascular damage.

Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.e. hypertension-induced end-organ damage. The parallels between the murine and human hypertensive proteome were also investigated. The hypertensive response to angiotensin II (Ang II, 0.7 mg/kg/day, s.c.) was attenuated by Cmpd17b (50 mg/kg/day, i.p.). Impairments in cardiac and vascular function assessed via echocardiography were improved by Cmpd17b in hypertensive mice. This functional improvement was accompanied by reduced cardiac and aortic fibrosis and vascular calcification. Cmpd17b also attenuated Ang II-induced increased cardiac mitochondrial complex 2 respiration. Proteomic profiling of cardiac and aortic tissues and cells, using label-free nano-liquid chromatography with high-sensitivity mass spectrometry, detected and quantified ∼6000 proteins. We report hypertension-impacted protein clusters associated with dysregulation of inflammatory, mitochondrial, and calcium responses, as well as modified networks associated with cardiovascular remodelling, contractility, and structural/cytoskeletal organization. Cmpd17b attenuated hypertension-induced dysregulation of multiple proteins in mice, and of these, ∼110 proteins were identified as similarly dysregulated in humans suffering from adverse aortic remodelling and cardiac hypertrophy. We have demonstrated, for the first time, that the FPR agonist Cmpd17b powerfully limits hypertension-induced end-organ damage, consistent with proteome networks, supporting development of pro-resolution FPR-based therapeutics for treatment of systemic hypertension complications.