Hypertensive End-organ Damage Research Articles

A Role of T-Lymphocyte β-Arrestins in Hypertension

The adaptive immune system and T-cells play a central role in the development of essential hypertension. The renin-angiotensin system regulates blood pressure (BP) through multiple mechanisms including effects on the immune system. Among several G-protein coupled receptors (GPCR) that regulate T-cell function, it has been hypothesized that specific T-cell populations use the angiotensin receptor (AT1R) to modulate immune responses in hypertension. Selective ablation of AT1R in T-cells paradoxically increases hypertensive end-organ damage (EOD). While AT1R typically induces the classical G protein signaling, recent studies have uncovered an alternative protective signaling-cascade at this receptor via β-Arrestin ( ARRB) proteins. Thus, we hypothesized that ARRB in T-lymphocytes mediates an anti-hypertensive and anti-inflammatory role in response to angiotensin II (ANG II) thereby decreasing EOD in hypertension. Transgenic mice with T-lymphocyte-specific knock outs of the Arrb1 gene were developed using a CD4-Cre x Arrb1-Flox system. Hypertensive conditions were modeled with a 3-pronged approach designed to induce kidney damage consisting of unilateral nephrectomy (UNX), maintenance on a 4% salt diet, and a continuous infusion of ANG II (1,000 ng/kg/min). Age and sex-matched Cre negative x Arrb1-Flox littermates were used as controls. BP was measured at baseline before and after UNX, and for the following three weeks using radiotelemetry. Inflammation was assessed using quantitative PCR (q-PCR). Preliminary data suggest that loss of T-cell specific Arrb1 is protective against ANG II-induced hypertension. At baseline CD4Arrb1-null and CD4Arrb1-WT mice had similar systolic BP (123.0±2.9 mmHg and 119.6±2.3 mmHg, respectively, n=5-7). However, CD4Arrb1-null mice exhibited an attenuated response to ANG II infusion after three weeks (162.5±11.8 mmHg vs 187.0±5.9 mmHg n=3-5; p = 0.03). After 15 days of ANG II, mice were placed in metabolic cages and urine was collected. In a 24-hour period, CD4Arrb1-null mice excreted significantly more sodium (1.98±0.07 mg/24hrs vs 1.66±0.03 mg/24hrs, n=3-4; p = 0.01). Tissue collected from the renal cortex following three weeks of ANG II infusion was analyzed for inflammatory cytokines using q-PCR. Gene expression was normalized to 18s expression in CD4Arrb1-WT mice under sham experimental conditions. Expression of tumor necrosis factor α (TNF-α) transcripts was attenuated in CD4Arrb1-null mice when compared to CD4Arrb1-WT (1.62±0.24-fold increase vs 0.67±0.07-fold decrease, respectively, n=3-4; p=0.006). Contrary to our hypothesis, these preliminary data suggest that T-cell Arrb1 does not protect against hypertensive or inflammatory responses to ANG II. However, these studies highlight the role of β-arrestin-1 proteins endogenous to T-lymphocytes in the modulation of the hypertensive response to ANG II. Supported by grants from the AHA and NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dietary Fructose and Sodium Consumed during Early Mid-Life Are Associated with Hypertensive End-Organ Damage by Late Mid-Life in the CARDIA Cohort.

We aimed to investigate how dietary fructose and sodium impact blood pressure and risk of hypertensive target organ damage 10 years later. Data from n = 3116 individuals were obtained from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Four groups were identified based on the four possible combinations of the lower and upper 50th percentile for sodium (in mg) and fructose (expressed as percent of total daily calories). Differences among groups were ascertained and logistic regression analyses were used to assess the risk of hypertensive target organ damage (diastolic dysfunction, coronary calcification and albuminuria). Individuals in the low-fructose + low-sodium group were found to have lower SBP compared to those in the low-fructose + high-sodium and high-fructose + high-sodium groups (p < 0.05). The highest risk for hypertensive target organ damage was found for albuminuria only in the high-fructose + high-sodium group (OR = 3.328, p = 0.006) while female sex was protective across all groups against coronary calcification. Our findings highlight that sodium alone may not be the culprit for hypertension and hypertensive target organ damage, but rather when combined with an increased intake of dietary fructose, especially in middle-aged individuals.

Abstract WP161: Characterizing the Underlying Microangiopathy of Deep Cerebellar Intracerebral Hemorrhage

Introduction: Superficial (gray matter, vermis) cerebellar intracerebral hemorrhage (cICH) is associated with strictly lobar supratentorial cerebral microbleeds—a strong marker for cerebral amyloid angiopathy. However, for deep (white matter, deep nuclei, cerebellar peduncle) cICH, it is unclear whether hypertensive cerebral small vessel disease (HTN-cSVD) is the underlying microangiopathy. Hypothesis: We hypothesized that left ventricular hypertrophy (LVH), a marker for hypertensive end-organ damage, and non-hemorrhagic imaging markers of HTN-cSVD such as peri-basal ganglia (BG) white matter hyperintensity (WMH) pattern, deep lacunes, and severe BG enlarged perivascular spaces (EPVS) would be associated with deep vs. superficial cICH. Methods: Brain MRI scans from a prospective database of consecutive non-traumatic ICH patients admitted to a single referral center (2003 to 2019) were analyzed for the presence of cerebral microbleeds (CMBs) and non-hemorrhagic neuroimaging markers. The presence of clinical risk factors, LVH, and neuroimaging markers were compared between patients with deep and superficial cICH in univariate and multivariable models. Results: Of 1,791 patients with spontaneous ICH, 129 (7%) were found to have cICH (mean age 73±12 years, 46% female). Of these, 83 (64%) patients had deep cICH and 46 (36%) patients had superficial cICH. Hypertension (94% vs. 67%, p &lt; 0.01) and LVH (60% vs. 28%, p &lt; 0.01) were more common among patients with deep vs. superficial cICH. Among those who received a brain MRI (74%), the frequency of peri-BG WMH pattern (24% vs. 5%, p = 0.02), deep lacunes (59% vs. 14%, p &lt; 0.01), severe BG EPVS (27% vs. 3%, p &lt; 0.01), deep CMBs (51% vs. 16%, p &lt; 0.01), and mixed location CMBs (37% vs. 11%, p &lt; 0.01) was greater among patients with deep cICH compared to superficial cICH. When these variables were entered into a multivariable regression model, LVH (OR 3.10, 95% CI [1.07-8.97], p = 0.04) and deep lacunes (OR 4.38, 95% CI [1.25-15.31], p = 0.02) remained significantly associated with deep cICH. Conclusions: Because supratentorial HTN-cSVD imaging markers are common in deep cICH, and deep lacunes and LVH are independently associated with deep cICH, it is likely that HTN-cSVD is the underlying microangiopathy of deep cICH.

Deficiency of Complement C3a and C5a receptors Does Not Prevent Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage.

Complement may drive the pathology of hypertension through effects on innate and adaptive immune responses. Recently an injurious role for the anaphylatoxin receptors C3aR (complement component 3a receptor) and C5aR1 (complement component 5a receptor) in the development of hypertension was shown through downregulation of Foxp3+ (forkhead box protein 3) regulatory T cells. Here, we deepen our understanding of the therapeutic potential of targeting both receptors in hypertension. Data from the European Renal cDNA Bank, single cell sequencing and immunohistochemistry were examined in hypertensive patients. The effect of C3aR or C3aR/C5aR1 double deficiency was assessed in two models of Ang II (angiotensin II)-induced hypertension in knockout mice. We found increased expression of C3aR, C5aR1 and Foxp3 cells in kidney biopsies of patients with hypertensive nephropathy. Expression of both receptors was mainly found in myeloid cells. No differences in blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation) or cardiac injury (cardiac fibrosis, heart weight, gene expression) between control and mutant mice was discerned in C3aR-/- as well as C3aR/C5aR1-/- double knockout mice. The number of renal Tregs was not decreased in Ang II as well as in DOCA salt induced hypertension. Hypertensive nephropathy in mice and men is characterized by an increase of renal regulatory T cells and enhanced expression of anaphylatoxin receptors. Our investigations do not corroborate a role for C3aR/C5aR1 axis in Ang II-induced hypertension hence challenging the concept of anaphylatoxin receptor targeting in the treatment of hypertensive disease.

End-Organ Damage in Hypertension: An Insight on a Differentiated Outpatient Consultation.

The objective of this study was to determine the prevalence of end-organ damage in hypertensive patients attending an outpatient consultation. Patients were selected from an outpatient consultation at a tertiary hospital care center. All patients who consulted between July 2022 and March 2023 were included. Data on demographic characteristics, blood pressure records, hypertension etiology, medication use, and the presence of target organ damage were collected. A total of 73 patients were included in the study, with 34 patients being male (46.6%) and 39 patients being female (53.4%). The mean age of the patients was 49.8 years. Among the cases of hypertension, 14 (19.2%) were classified as secondary arterial hypertension (AH). The most common cause of secondary AH was obstructive sleep apnea (OSA) (42.9%). Approximately 23.2% of patients had documented end-organ damage potentially related to hypertension, with kidney disease being the most frequent (n = 10, 13.7%). The most commonly prescribed pharmacological classes were angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists (n = 46, 63%). Despite numerous studies and trials on arterial hypertension, it remains a significant contributor to morbidity and mortality, necessitating the continued awareness of its long-term implications.

Prevalence of anemia and associated factors among adult hypertensive patients in Referral Hospitals, Amhara Regional State

Anemia is a risk factor for adverse cardiovascular disease outcomes in hypertensive patients. Chronic anemia increases preload, reduces afterload, and leads to increased cardiac output in hypertension patients. In the long term, this may result in maladaptive left ventricular hypertrophy, which in turn is a well-recognized risk factor for cardiovascular disease outcomes and all-cause mortality in hypertension. Low hemoglobin and hematocrit levels might be strongly indicate hypertensive end-organ damage, specifically kidney failure. Therefore, this study determined the prevalence of anemia and associated factors among hypertensive patients in Referral Hospitals, Amhara Regional State, Ethiopia, in 2020. An institution-based cross-sectional study was conducted in Amhara Regional Referral Hospitals from February 20 to April 30, 2020. Random and systemic sampling techniques were used to select 428 study participants. Data were entered and coded in to Epi data version 3.0 and then exported into STATA 14 for analysis. In bivariable logistic regression, variables with a p-value of < 0.25 were included in multivariable logistic regression. Using a 95% confidence interval, variables having a p-value ≤ 0.05 in multivariable logistic regression were declared as statistically significant variables. In this study, a total of 428 study participants were involved with 99.5% response rate. The prevalence of anemia among hypertensive patients was 17.6%, with a 95% CI (14.3–21.5%). Estimated glomerular filtration rate (eGFR) < 90 ml/min (AOR = 2.77, 95% CI 1.56- 4.92)], duration of hypertension (HTN) ≥ 5 years (AOR = 2.37, 95% CI 1.36–4.15), uncontrolled blood pressure (AOR = 1.91, 95% CI 1.08–3.35), and higher pulse pressure (AOR = 1.05 (95% CI 1.02–1.08) were significantly associated with anemia. Nearly one out of five hypertensive patients had anemia. Impaired estimated glomerular filtration rate, duration of HTN, blood pressure status, and pulse pressure were the independent predictors of anemia among hypertensive patients. Screening hemoglobin level at a regular interval is recommended for the hypertensive patients to take an appropriate intervention.

Mechanistic Implications of Cortical Superficial Siderosis in Patients With Mixed Location Intracerebral Hemorrhage and Cerebral Microbleeds.

Hypertensive cerebral small vessel disease (HTN-cSVD) is the predominant microangiopathy in patients with a combination of lobar and deep cerebral microbleeds (CMBs) and intracerebral hemorrhage (mixed ICH). We tested the hypothesis that cerebral amyloid angiopathy (CAA) is also a contributing microangiopathy in patients with mixed ICH with cortical superficial siderosis (cSS), a marker strongly associated with CAA. Brain MRIs from a prospective database of consecutive patients with nontraumatic ICH admitted to a referral center were reviewed for the presence of CMBs, cSS, and nonhemorrhagic CAA markers (lobar lacunes, centrum semiovale enlarged perivascular spaces [CSO-EPVS], and multispot white matter hyperintensity [WMH] pattern). The frequencies of CAA markers and left ventricular hypertrophy (LVH), a marker for hypertensive end-organ damage, were compared between patients with mixed ICH with cSS (mixed ICH/cSS[+]) and without cSS (mixed ICH/cSS[-]) in univariate and multivariable models. Of 1,791 patients with ICH, 40 had mixed ICH/cSS(+) and 256 had mixed ICH/cSS(-). LVH was less common in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-) (34% vs 59%, p = 0.01). The frequencies of CAA imaging markers, namely multispot pattern (18% vs 4%, p < 0.01) and severe CSO-EPVS (33% vs 11%, p < 0.01), were higher in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-). In a logistic regression model, older age (adjusted odds ratio [aOR] 1.04 per year, 95% CI 1.00-1.07, p = 0.04), lack of LVH (aOR 0.41, 95% CI 0.19-0.89, p = 0.02), multispot WMH pattern (aOR 5.25, 95% CI 1.63-16.94, p = 0.01), and severe CSO-EPVS (aOR 4.24, 95% CI 1.78-10.13, p < 0.01) were independently associated with mixed ICH/cSS(+) after further adjustment for hypertension and coronary artery disease. Among ICH survivors, the adjusted hazard ratio of ICH recurrence in patients with mixed ICH/cSS(+) was 4.65 (95% CI 1.38-11.38, p < 0.01) compared with that in patients with mixed ICH/cSS(-). The underlying microangiopathy of mixed ICH/cSS(+) likely includes both HTN-cSVD and CAA, whereas mixed ICH/cSS(-) is likely driven by HTN-cSVD. These imaging-based classifications can be important to stratify ICH risk but warrant confirmation in studies incorporating advanced imaging/pathology.

DEFICIENCY OF COMPLEMENT C3A AND C5A RECEPTORS DOES NOT PREVENT ANGIOTENSIN II–INDUCED HYPERTENSION AND HYPERTENSIVE END ORGAN DAMAGE

Objective: Complement activation may play an important role in pathophysiology of hypertension and associated end organ damage through its effect on tissue integrity and immune responses. The anaphylatoxins C3a and C5a are highly active effectors of the complement system operating through binding to their receptors C3a3R and C5aR1. Recently it was suggested that regulatory T cells (Tregs) are downregulated in hypertension and that combined deficiency of C3aR and C5aR1 in lymphocytes upregulates Tregs and heals hypertension (Circ Res 122: 970-983, 2018). Design and method: To further address the role of C3aR, C5aR1 and Tregs in human and murine hypertension we used data from the European Renal cDNA Bank, renal single cell sequencing and renal immunohistochemistry of hypertensive patients. Results: Expression of C3aR and C5aR1 was mainly found in myeloid cells and almost absent in lymphocytes and resident renal cells. An increased expression of C3aR, C5aR1 as well as forkhead box protein 3 (FoxP3), a known marker for Tregs, was found in the kidney in hypertension. Next we determined whether C3aR deficiency or C3aR/C5aR1 double deficiency decreases blood pressure and hypertensive injury in angiotensin (Ang) II infused mice. No difference was found for blood pressure, renal injury (glomerular filtration rate, albuminuria, glomerular and tubulointerstitial injury, inflammation) and cardiac injury (cardiac fibrosis, heart weight, gene expression) between C3aR knockout and wildtype mice as well as C3aR/C5aR1 double knockout respectively. Ang II as well as DOCA salt induced hypertension resulted in an increased number of Tregs in the kidney. Isolation of a very pure (&gt;99%) Treg population from a RORC x FIR double fluorescence reporter mouse revealed low abundance of C3aR and absence of C5aR1 in murine Tregs. Conclusions: In summary, hypertensive nephropathy in patients and mice is characterized by an increased expression of anaphylatoxin receptors and Tregs. However, deficiency of C3aR alone or C3aR and C5aR1 combined does not influence blood pressure or hypertensive end organ damage. Targeting the anaphylatoxin receptors C3aR alone or in combination with C5aR1 is not useful to treat cardiovascular disease in hypertension.

Influence of Cortical Superficial Siderosis in Patients with Mixed Location Cerebral Microbleeds and Intracerebral Hemorrhage (S36.006)

Influence of Cortical Superficial Siderosis in Patients with Mixed Location Cerebral Microbleeds and Intracerebral Hemorrhage (S36.006)

Abstract WP118: Mechanistic Implications Of Cortical Superficial Siderosis In Patients With Mixed Location Intracerebral Hemorrhage And Cerebral Microbleeds

Introduction: Hypertensive cerebral small vessel disease (HTN-cSVD) is the predominant microangiopathy in patients with a combination of lobar and deep cerebral microbleeds (CMBs) and intracerebral hemorrhage (mixed ICH/CMB). We tested the hypothesis that cerebral amyloid angiopathy (CAA) is also a contributing microangiopathy in mixed ICH/CMB patients with cortical superficial siderosis (cSS), a marker that is strongly associated with CAA. Methods: Brain MRIs from a prospective database of consecutive non-traumatic ICH patients admitted to a single referral center (2003 to 2019) were reviewed for the presence of CMBs, cSS, and non-hemorrhagic CAA markers (lobar lacunes, centrum semiovale enlarged perivascular spaces (CSO-EPVS), and multispot pattern of leukoaraiosis). The frequency of CAA markers and left ventricular hypertrophy (LVH), a marker for hypertensive end-organ damage, were compared between mixed ICH/CMB patients with cSS (mixed +cSS ) and without cSS (mixed -cSS ) in univariate and multivariate models. Results: Of the 1824 ICH patients, 40 had mixed +cSS and 256 had mixed -cSS . LVH was less common in patients with mixed +cSS compared to those with mixed -cSS (34% vs. 59%, p = 0.01). The frequency of multispot pattern (18% vs. 4%, p &lt; 0.01) and severe CSO-EPVS (33% vs. 11%, p &lt; 0.01) were higher in patients with mixed +cSS compared to mixed -cSS , whereas lobar lacune frequency was similar (23% vs. 20%, p = 0.67). In a logistic regression model, older age (aOR 1.04 per year, 95% CI [1.01-1.08], p = 0.01), presence of multispot pattern (aOR 5.82, 95% CI [1.82-18.60], p &lt; 0.03), severe CSO-EPVS (aOR 4.08, 95% CI [1.73-9.61], p &lt; 0.01), and LVH (aOR 0.43, 95% CI [0.20-0.94], p = 0.03) were independently associated with mixed +cSS after further adjustment for sex and hypertension (Table). Conclusions: CAA and HTN-cSVD appear to confer injury in patients with mixed ICH/CMB and cSS, a finding that warrants confirmation in studies incorporating advanced imaging/pathology.

The relationship between renal renal resistive index and hypertensive end-organ damage

Background/Aim: The prevalence of hypertension increases with age and one out of every three adults over the age of 40 has hypertension. Hypertensive end-organ damage is an important predictive factor for patient morbidity and mortality. This study aimed to investigate the role of the renal resistive index (RI) in predicting retinopathy and nephropathy in hypertensive patients. Methods: This study was cross-sectional in design. Sixty hypertensive patients who were followed in Samsun Research and Training Hospital Internal Medicine outpatient clinic were included in the study. In all patients, a routine ophthalmological examination, including visual acuity, anterior segment examination, and dilated ocular fundus examination, was performed. Urinary albumin to creatinine ratio (mg/g) was measured in spot urine samples, and a level ≥30 mg/g was accepted as the presence of proteinuria. Renal Doppler ultrasonography was performed using Esaote mylab x 9 model sonography device vovex probe (C1-8) 3.5 MHz. RI values were measured using Xflow Doppler at the level of interlobular or arcuate arteries of both kidneys. First, the patients were divided into two groups (with or without retinopathy). The patients who had retinopathy were then divided into two groups according to their retinopathy degree. Hypertensive retinopathy was graded according to the Scheie classification. The patients were also divided into two groups according to their proteinuria status (with or without proteinuria). Results: The mean of renal RI was 0.59 (0.04) in patients without retinopathy (n=15), 0.63 (0.05) in patients with grade 1 hypertensive retinopathy (n=29), and 0.66 (0.04) in patients with grade 2 hypertensive retinopathy (n=15). The difference between groups was statistically significant (overall P=0.001). It has been shown that proteinuria develops more frequently in cases in which the renal value is above 0.7, and these results were statistically significant (P=0.034). Conclusion: This study indicates that renal RI increase is a valuable tool for estimating retinopathy and proteinuria in hypertensive patients.

PS-B08-11: SALT DIRECTLY REGULATES UMOD TRAFFICKING IN A NORMOTENSIVE BACKGROUND

Objective: Uromodulin (UMOD) is the most abundant protein secreted into urine of healthy individuals and is primarily produced by the renal thick ascending limb cells (TAL) of the loop of Henle. Genetic studies have demonstrated an association between UMOD risk variants, kidney diseases, and hypertension. We have previously demonstrated that salt induces a reduction in urinary UMOD excretion in normotensive rats after three weeks, which was exacerbated in a chronic hypertensive rat model. Our next objective was to determine the influence of salt on UMOD secretion independent of blood pressure effects. Here we investigate the underlying molecular differences in the effects of intermittent and chronic salt-loading on UMOD trafficking dynamics in the TAL. Design and Methods: Wistar-Kyoto (WKY) normotensive rats were maintained on 1% NaCl for three weeks in an intermittent pattern (one week on, one week off, one week on) or continuously (chronic) over three months. Urine was collected over a 24-hour period every experimental week. Total kidneys were harvested for lysate extraction, subcellular fractionation, and immunofluorescence analyses. UMOD levels were measured using ELISAs, qPCR, and Western blotting. Results: No abnormal changes in blood pressure, body weight, or renal parameters including albumin-creatinine-ratio and injury markers KIM-1 and NGAL were observed in either animal study group. During intermittent salt-loading, there was no significant difference in UMOD mRNA expression or total kidney UMOD protein levels. However, UMOD excretion significantly decreased after one week and remained lower than control levels even after salt removal. Similarly, chronic salt-loading did not alter UMOD mRNA levels, however total kidney UMOD protein levels were increased after three months. More specifically, analysis of subcellular fractions of the medulla from these salt-loaded animals showed higher levels of cytosolic UMOD compared to membrane-bound UMOD. Immunofluorescence analyses revealed a trend towards increased localisation of UMOD with endoplasmic reticulum (ER) marker calnexin. Conclusions: Our findings underline the effect of salt in molecular trafficking of UMOD in the kidney independent of blood pressure effects. Long-term salt exposure of TAL cells leads to intracellular accumulation of this abundant renal protein. The relationship between salt, UMOD accumulation, and renal end-organ damage in hypertension requires further research.

JS-NG-10: A RARE CAUSE OF TREATMENT-RESISTANT HYPERTENSION

Objective: To present an educational case report. Design and method: In a 22-year old female arterial hypertension was diagnosed and she was treated to blood pressure target values with a combination of candesartan and lercanidipine. At the age of 27 years she planned a pregnancy, therefore antihypertensive treatment was switched to alpha-methyl-dopa and metoprolol. Blood pressure control was no longer achieved, the patient was symptomatic, mostly headaches. A diagnostic work-up for secondary causes of hypertension was performed. Results: There were no signs of kidney disease, renal artery stenosis was ruled out by color-coded duplex-ultrasound, plasma metanephrines were normal, sleep apnea syndrome and hypercortisolism were clinically very unlikely and not formally ruled out. No signs of hypertensive end-organ damage (left ventricular hypertrophy, microalbuminuria, carotid artery alterations) were detected. The only pathologic finding confirmed was a marked secondary hyperaldosteronism. Plasma renin concentration was 230 pg/ml, plasma aldosterone concentration 508 pg/ml, along with low normal serum potassium (3.5 to 4 mmol/l). Addition of nifedipine and low-dose HCT did not achieve blood pressure control, daytime ABPM mean was 144/102 mmHg, nighttime ABPM mean 127/86 mmHg. Because of suspected missed renal artery stenosis (fibromuscular dysplasia) an MR-angiography of the renal arteries was performed revealing normal renal arteries and normal adrenal glands but a left kidney tumor - not observed in the previous ultrasound examination but confirmed with contrast-enhanced ultrasound. Surgical removal of the tumor was performed. The histology was suggestive for a juxtaglomerular cell tumor (reninoma). After surgery, plasma aldosterone normalized to 57 pg/ml and plasma renin concentrations were low (3.4 pg/ml). Within 3 months after surgery, all antihypertensive medication could be discontinued and home blood pressure measurements averaged 119/78 mmHg. Soon thereafter the patient became pregnant and delivered a healthy girl. There were no pregnancy related complications and the patient remained normotensive. A juxtaglomerular cell tumor represents a rare curable cause of hypertension. The first report dates for 1967, until 2019 only about 100 cases were reported in the literature. It may be suspected that the diagnosis juxtaglomerular cell tumors is missed in many cases since these tumors are not easy to detect in standard diagnostic workup of hypertension and many antihypertensive drugs interfere with plasma renin concentrations.

The New Era of Retinal Imaging in Hypertensive Patients.

Structural and functional alterations in the microcirculation by systemic hypertension can cause significant organ damage at the eye, heart, brain, and kidneys. As the retina is the only tissue in the body that allows direct imaging of small vessels, the relationship of hypertensive retinopathy signs with development of disease states in other organs have been extensively studied; large-scale epidemiological studies using fundus photography and advanced semi-automated analysis software have reported the association of retinopathy signs with hypertensive end-organ damage includes the following: stroke, dementia, and coronary heart disease. Although yielding much useful information, the vessels assessed from fundus photographs remain limited to the larger retinal arterioles and venules, and abnormalities observed may not be that of the earliest changes. Newer imaging modalities such as optical coherence tomography angiography and adaptive optics technology, which allow a greater precision in the structural quantification of retinal vessels, including capillaries, may facilitate the assessment and management of these patients. The advent of deep learning technology has also augmented the utility of fundus photographs to help create diagnostic and risk stratification systems. Particularly, deep learning systems have been shown in several large studies to be able to predict multiple cardiovascular risk factors, major adverse cardiovascular events within 5 years, and presence of coronary artery calcium, from fundus photographs alone. In the future, combining deep learning systems with the imaging precision offered by optical coherence tomography angiography and adaptive optics could pave way for systems that are able to predict adverse clinical outcomes even more accurately.

Duration of hypertension and prevalence of end-organ damage in hypertensive patients

The objective of this study is to determine the prevalence of end-organ damage in hypertensive patients in a tertiary care hospital in Azad Kashmir. The study was conducted in a public sector teaching hospital of AJK-Medical College between March 2019 and Feb 2020. Adult hypertensive patients above the age of 27 years were included in the study from out-patient and in-patient departments. A standard Performa was used to collect and document the demographic information, medical history and physical examination of patients. The age, sex, residential area, marital status, education, profession, presenting complaints, smoking, addictions, functional status, and physical activity were recorded. The measurement of Blood Pressure (BP) was performed with a mercury sphygmomanometer and end-organs damage (Retinopathy, Nephropathy, Cardiovascular and cerebrovascular disease) was assessed by clinical evaluation and relevant investigations. A total of 100, hypertensive patients were enrolled in the study between the ages of 27 to 96 years. The mean age of the participants was 57 years (Std. deviation 17.8). 55% of patients were male while 45% of patients were female. 23% had good control of hypertension while 77% had poor control. 7% of participants were monitoring their BP on daily basis, 32% weekly, 39% once a month while 22% never had any schedule of monitoring their Blood Pressure. A family history of hypertension was present in 61%. Overall, 91% of the participants had retinopathy, 48% had nephropathy, 48% had cardiovascular disease and 19% had evidence of stroke. In conclusion, there is a high prevalence of End-Organ damage in middle age and elderly hypertensive patients. Keywords: Hypertension, hypertensive end-organ damage.

Growth Arrest Specific-6 and Axl Coordinate Inflammation and Hypertension.

[Figure: see text].

Potential therapeutic efficacy via avB3-integrin dependent interaction of developmental endothelial locus-1 (Del-1) after established angiotensin-II dependent hypertension

Abstract Introduction Cardiovascular diseases (CVDs) contribute to about 31% of global death. Hypertension is a major risk factor and also increases the risk of CVDs. An important regulator of systemic blood pressure in the body, the Renin Angiotensin Aldosterone system becomes overactivated during hypertension releasing a critical product, angiotensin-II (ANG-II), a known vasoconstrictor, activating the immune system leading to inflammation and as such mediating the effects of hypertension and subsequent end-organ damage due to the critical role of the innate and adaptive cells in producing pro-inflammatory cytokines such interleukin-17. Del-1, an extracellular matrix protein expressed mostly by endothelial cells is a known potent inhibitor of leukocyte recruitment. Aim We tested the hypothesis that, Del-1 via αvβ3-integrin dependent interaction protects against ANG-II induced cardiovascular remodeling after established hypertension. Methods Wild type (WT) mice were infused with 2 mg/kg/day of ANG-II for 14 days. Soluble Del-1 (Del-1-Fc) and a point mutant unable to bind to αvβ3-integrin (Del-1-RGE-Fc) was injected (50 μg/per injection) daily after 6 days of ANG-II infusion. SBP was measured using tail-cuff. Endothelial function was assessed using Mulvany myograph and quantification of inflammatory cells and IL-17 by flow cytometry. Histological staining for fibrosis, myocardial/medial hypertrophy and elastin degradation was used to evaluate both aortic and cardiac remodeling. Results After 6 days, mice infused with ANG-II showed significantly higher SBP of 140 mmHg as compared to control mice (110 mmHg). However, further progression of SBP after 6 days was blunted in infused mice treated with soluble Del-1 (ANGII+Del-1-Fc) as compared to similar increase in SBP in both infused mice treated with the point mutant (ANGII+Del-1-RGE-Fc) and non-treated infused mice (ANGII+Fc) leading to a difference of ∼20 mmHg. This effect was due to, the well protected endothelium dependent relaxation and reduced wall tension of the aorta in ANGII+Del-1-Fc mice. Further infiltration of CD45+ leukocytes, CD45+/IL-17A+ and TCRβ+T cells was significantly reduced in the aorta and heart of ANGII+Del-1-Fc mice as compared to both ANGII+Del-1-RGE-Fc and ANGII+Fc mice. However, the aorta and heart of ANGII+Del-1-Fc mice showed increased levels of anti-inflammatory regulatory T-cells (CD25+FOXP3+Treg). Also, aortic medial thickness, adventitial collagen and elastin degradation was decreased significantly in ANGII+Del-1-Fc mice. Additionally, in comparison to both ANGII+Del-1-RGE-Fc and ANGII+Fc mice, the hearts of ANGII+Del-1-Fc mice had significantly less interstitial and pericoronary collagen, smaller cardiomyocyte area and subsequently higher lumen-to-wall ratio. Conclusion Our study reveals the cardiovascular protective effects of Del-1 mediated via its association with αvβ3-integrin after established hypertension which could serve as potential therapeutic target. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): German Research Foundation (DFG)National Institutes of Health (NIH)

Abstract MP01: Deacetylation Of Mitochondrial Cyclophilin D K166 Inhibits Cytokine-induced Oxidative Stress And Attenuates Hypertension

We have previously reported that depletion Cyclophilin D (CypD), a regulatory subunit of mitochondrial permeability transition pore, improves vascular function and attenuates hypertension, however, specific regulation of CypD in hypertension is not clear. Analysis of human arterioles from hypertensive patients did not reveal alterations in CypD levels but showed 3-fold increase in CypD acetylation. We hypothesized that CypD-K166 acetylation promotes vascular oxidative stress and hypertension, and measures to reduce CypD acetylation can improve vascular function and reduce hypertension. Essential hypertension and animal models of hypertension are linked to inactivation of mitochondrial deacetylase Sirt3 by highly reactive lipid oxidation products, isolevuglandins (isoLGs), and supplementation of mice with mitochondria targeted scavenger of isoLGs, mito2HOBA, improves CypD deacetylation. To test the specific role of CypD-K166 acetylation, we developed CypD-K166R deacetylation mimic mutant mice. Mitochondrial respiration, vascular function and systolic blood pressure in CypD-K166R mice was similar to wild-type C57Bl/6J mice. Meanwhile, angiotensin II-induced hypertension was substantially attenuated in CypD-K166R mice (144 mmHg) compared with wild-type mice (161 mmHg). Angiotensin II infusion in wild-type mice significantly increased mitochondrial superoxide, impaired endothelial dependent relaxation, and reduced the level of endothelial nitric oxide which was prevented in angiotensin II-infused CypD-K166R mice. Hypertension is linked to increased levels of inflammatory cytokines TNFα and IL-17A promoting vascular oxidative stress and end-organ damage. We have tested if CypD-K166R mice are protected from cytokine-induced oxidative stress. Indeed, ex vivo incubation of aorta with the mixture of angiotensin II, TNFα and IL-17A (24 hours) increased mitochondrial superoxide by 2-fold in wild-type aortas which was abrogated in CypD-K166R mice. These data support the pathophysiological role of CypD acetylation in inflammation, oxidative stress and hypertensive end-organ damage. We propose that targeting CypD acetylation may have therapeutic potential in treatment of vascular dysfunction and hypertension.

Renal denervation in hypertension patients: Proceedings from an expert consensus roundtable cosponsored by SCAI and NKF.

Renal denervation in hypertension patients: Proceedings from an expert consensus roundtable cosponsored by SCAI and NKF.

Deacetylation mimetic of mitochondrial cyclophilin D CypD‐K166R mutant mice are protected from inflammation, oxidative stress, endothelial dysfunction and hypertension

Despite treatment with multiple drugs, a third of hypertensive patients remain hypertensive, therefore, new treatments may improve treatment of hypertension. Hypertension is a multifactorial disorder associated with inflammation, mitochondrial oxidative stress and vascular dysfunction. We have previously reported that depletion or inhibition of Cyclophilin D (CypD), a regulatory subunit of mitochondrial permeability transition pore, improves vascular function and attenuates hypertension. Analysis of human arterioles showed 3-fold increase in CypD acetylation in hypertensive subjects. We hypothesized that hyperacetylation of CypD promotes vascular oxidative stress and hypertension, and deacetylation mimetic CypD-K166R mutation prevents vascular oxidative stress and attenuates hypertension. To test this hypothesis, we used CypD-K166R mutant mice developed in our lab, angiotensin II model of hypertension and ex vivo treatment of aortic tissue with inflammatory cytokines. It was found that angiotensin II-induced hypertension was substantially attenuated in CypD-K166R mice (144 mmHg) compared with wild-type C57B/6J mice (161 mmHg). Furthermore, MitoSOX/HPLC analysis of mitochondrial superoxide in aortas isolated from angiotensin II-infused mice showed 2-fold increase in wild-type mice which was abrogated in CypD-K166R mice. Angiotensin II infusion in wild-type mice significantly impaired endothelial dependent relaxation and reduced the level of endothelial nitric oxide measured by electron spin resonance and NO spin trap. Meanwhile, endothelial dependent relaxation and vascular nitric oxide production were preserved in angiotensin II-infused CypD-K166R mice. Hypertension is linked to inflammation, increased levels of TNFα and IL-17A which promote vascular oxidative stress and end-organ damage. We have tested if CypD-K166R mice are protected from cytokine-induced oxidative stress. Indeed, ex vivo incubation of aorta with the mixture of angiotensin II, TNFα and IL-17A (24 hours) increased mitochondrial superoxide by 2-fold in wild-type tissue which was abolished in CypD-K166R mice. To define molecular mechanisms of mitochondrial protection in CypD-K166R mice we have investigated respiration and calcium-induced swelling in isolated kidney mitochondria. It was found that mitochondria isolated from deacetylation mimetic CypD-K166R mice have improved respiration and diminished swelling with pyruvate and palmitoyl-carnitine as a substrates which promote CypD acetylation in wild-type animals. These data support the pathophysiological role of CypD acetylation in inflammation, oxidative stress and hypertensive end-organ damage. We conclude that targeting CypD acetylation may have therapeutic potential in treatment of vascular dysfunction and hypertension.