bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 011: ACE2 Gene Transfer Ameliorates Dysfunctions in Hematopoietic Stem/Progenitor Cells of Diabetic Patients
Authors: Jarajapu Yagna P , Joshi Shrinidh , Quiroz-Olvera Julio C , Duran-Mendez Miguel , Cantu-Delgado Wendy , Gomez Samuel C , Bartelmez Stephen H , Raizada Mohan K , Garcia Charles
Published: March 2022

Hematopoietic stem/progenitor cells (HS/PCs) have the propensity of ischemic vascular repair, and this innate vasoprotective function is impaired in diabetes. Angiotensin-converting enzyme (ACE) and ACE-2 are primary enzymes of the cardiovascular-detrimental and protective axes of the renin-angiotensin system, respectively. In this study, we tested the hypothesis that diabetic dysfunction in HS/PCs is due to ACE2/ACE-imbalance, and that increasing ACE2 expression will restore the vasoreparative potential. Lineage- (Lin
-
) or CD34
+
cells were isolated from the peripheral blood mononuclear cells (MNCs) of nondiabetic subjects (ND), and type 1 or type 2 diabetic (DB) patients (male or female, age 48-76 years, HbA1C 6.5-11.2). ACE and ACE2 activities were measured in lysates of MNCs, Lin
-
and CD34
+
cells by enzyme-selective fluorogenic substrates and inhibitors. Lentiviral ACE2 (LV-ACE2) gene transfer was carried out by spinoculation. Reparative function of Lin
-
cells was evaluated in Foxn1
nu
mice undergoing hind limb ischemia (HLI). Lin
-
cells with or without ACE2-overexpression were administered (i.m) in the peri-ischemic region, and the blood flow recovery was monitored. Circulating Lin
-
or CD34
+
cells are lower in DB (Lin
-
((2±0.2)х10
5
, P<0.04) and CD34
+
((0.6±0.1)х10
3
, P<0.02), n=8) compared to ND group (Lin
-
(25±4)х10
5
; CD34
+
(2±0.4)х10
3
per 10
6
MNCs, n=8). This was associated with decrease in ACE2 and increase in ACE activity, resulting in 4.5-fold decrease in ACE2/ACE ratio in DB-CD34
+
cells (0.4±0.07 vs ND 1.8±0.2, P<0.01, n=6). This was negatively correlated with HbA1C (r
2
=0.89, P<0.01). Administration of ND-Lin
-
cells has no effect on the blood flow recovery of mice following HLI. In contrast, administration of DB-Lin
-
cells decreased this recovery (48±6%, n=5, P<0.001 vs ND-Lin
-
105±7%). However, treatment with ACE2-overexpressing DB-Lin
-
cells robustly enhanced blood flow recovery (112±8%, n=4, P<0.001 vs DB). These observations suggest that ACE2/ACE imbalance is correlated with diabetic vasoreparative dysfunction in HS/PCs, and that increasing ACE2 expression reverses the dysfunction. ACE2 gene transfer is a promising approach for enhancing vascularization outcomes of cell-based therapies in diabetic individuals.
Abstract 012: Vascular Smooth Muscle ADAM17 Contributes to Angiotensin II-induced Abdominal Aortic Aneurysm Formation but Not Hypertension in Mice
Authors: Kawai Tatsuo , Takayanagi Takehiko , Preston Kyle J , Forrester Steven J , Scalia Rosario , Rizzo Victor , Eguchi Satoru
Published: March 2022

Over activation of the renin angiotensin II (AngII) system has been implicated in abdominal aortic aneurysm (AAA). However, the precise molecular mechanism(s) by which AngII promotes AAA remain insufficiently understood, which hinders pharmacological treatment. At a past AHA conference, we reported critical roles for the metalloprotease, ADAM17, and downstream EGFR transactivation, in the development of AngII-induced AAA in mice treated with a lysyl oxidase inhibitor beta-aminopropionitrile (BAPN). Specifically, we demonstrated that in the mouse AngII-induced AAA was attenuated by either deletion of ADAM17 in VSMC or treatment with an EGFR inhibitor erlotinib. To better understand the clinical relevance of these findings, we studied the effect of an ADAM17 inhibitory antibody (A9B8), which recognizes both human and mouse ADAM17. Eight-week-old male C57BL6 mice were given AngII 1000 ng/kg/min via osmotic minipumps for 4 consecutive weeks and BAPN 150 mg/kg/day in drinking water for the initial 2 weeks. Additionally, mice were given 10 mg/kg/day A9B8 or control human IgG2 i.p. injection at day 1, 7, 14 and 21. As an index for AAA formation, abdominal aortic internal diameter was measured by ultrasound at day 0, 14, 21 and 28. Aortic external diameter was also measurement at day 28. AngII/BAPN treated mice given control IgG2 have a mortality rate of 46.2% due to aortic rupture/dissection. Mortality rate in mice given A9B8 was reduced to 23.1% (n=13). Surviving IgG2 treated mice developed AAA with max external/internal diameter (mm) of 2.55±0.43/1.79±0.34 (age matched control mice values were 1.10±0.13/1.01±0.09; p<0.01; n=6). Following A9B8 treatment, aortic maximal external/internal diameter (mm) were reduced to 1.84±0.32/1.45±0.32 (p<0.05 vs IgG2; n=6). Pathologically, less extravascular fibrosis, medial layer disruption, and matrix deposition were observed. Interestingly, both groups treated with AII/BAPN/A9B8 or AII/BAPN/IgG2 developed hypertension as assessed by telemetry (MAP mmHg: 181±5 vs 174±7; n=5). In conclusion, immunomodulation of ADAM17 function appears to be a potential therapeutic target to slow AAA development and rupture.
Abstract 014: B1 Integrin is Essential for Kidney Structure, Function and Vascular Development
Authors: Mohamed Tahagod , Kaur Rajwinderjit , Sequeira-Lopez Maria Luisa S.
Published: March 2022

Integrins are the largest family of cell adhesion molecules. β1-Integrin (Itgb1) is the most abundantly expressed β subunit and is present in almost every cell type. Previous studies showed that Itgb1 is required for normal development of the ureteric bud and podocytes and for the function of the proximal tubule. However, its role in the kidney vasculature has not been explored. Renin cells are crucial for blood pressure homeostasis and for normal nephrovascular development. The mechanisms involved in their morphogenetic functions are not well understood. We found that Itgb1 is highly expressed in renin expressing cells throughout development. Therefore, to study the role of Itgb1 in renin cells we generated a conditional deletion (cKO) of Itgb1 in cells of the renin lineage by crossing floxed Itgb1 mice with mice expressing
cre recombinase
driven by the
renin
locus. Itgb1 cKO mice were smaller in size (20.32 ± 4.35 g
vs
29.55 ± 7.39 g,
p=0.016
), had smaller kidney to body weight ratio (0.92 ± 0.30
vs
1.31 ± 0.30,
p=0.017
), hypotension (MABP 82.33 ± 4.00 mmHg
vs
92.55 ± 7.72 mmHg,
p=0.02
), anemia (hemoglobin 11.26 ± 1.48 g/dL
vs
15.07 ± 1.31 d/dL,
p=0.003
; hematocrit 40.39 ± 5.48%
vs
53.8 ± 4.21%,
p=0.002
), renal failure (BUN 71.44 ± 32.81 mg/dL
vs
29.4 ± 7.67mg/dL,
p=0.004),
and lower plasma renin levels (6664.58 ± 3251.92
vs
43357.09 ± 17032.63 pg/ml,
p
=0.001
).
Mutants also developed hyposthenuria (urine osmolality 452 ± 138.98 mOsm/kg
vs
1460.5 ± 482.09 mOsm/kg,
p<0.02
). Histological analysis revealed excessive collagen deposition in the interstitium and peri-glomerular areas; fibrocystic glomeruli; tubular dilatation and protein casts in the tubules. Immunostaining for renin and α-smooth muscle actin showed a marked decrease in renin protein expression and abundant α-smooth muscle actin expression in the interstitium. Microdissection of the renal arterial tree combined with renin immunostaining confirmed the marked decrease in renin and evidenced the overall vascular abnormalities including fewer and shorter arterial and arteriolar branches. Overall, this study shows that β1-Integrin in cells of the renin lineage is crucial for renin expression, morphogenesis of the renal vasculature and maintenance of the normal kidney architecture and function.
Abstract 030: Angiotensin II-induced Hypertension and Cardiac Hypertrophy are Mediated Differentially by TLR3- and TLR4-dependent Pathways
Authors: Singh Madhu V , Cicha Michael Z , Chapleau Mark W , Abboud François M
Published: March 2022

The innate immune system plays a key role in onset and maintenance of hypertension. We showed that the toll-like receptor (TLR) adaptor protein TRIF (toll interleukin receptor domain-containing adaptor-inducing interferon-b), but not MyD88 (myeloid differentiation 88), is required for angiotensin II (Ang II) induced hypertension in mice. TRIF transduces signals from TLR3 and TLR4, to induce inflammatory gene expression. In this study, we sought to determine which TLR is responsible for TRIF-mediated hypertensive effects of Ang II. We used a TLR4 deficient mice (TLR4-del) that have TLR4 gene deleted and the wild type (WT) control strain (C57BL/10). We also used a TLR3-knockout mice (TLR3ko) that have the exon 1 of the
Tlr3
gene deleted. Saline or Ang II (1000 ng/kg/min) was infused subcutaneously for 3 weeks using mini-osmotic pumps and systolic blood pressure (SBP) was measured by tail cuff. Ang II increased peak SBP in WT (from 108 ± 1.3 mmHg to 136.0 ± 12.7 mmHg, n= 3) and TLR4-del (from 115.6 ± 2.7 mmHg to 154.4 ± 3.3 mmHg, n=3) mice. In contrast, peak SBP was not increased significantly with Ang II infusion in TLR3ko mice (from 111.3 ± 4.5 to 122.2 ± 18.6 mmHg, n=6) nor was it increased in WT mice after selective inhibition of TLR3 signaling with CU CPT 4a. Thus, the TLR3/TRIF, but not TLR4, pathway is essential for Ang II hypertension. In parallel with the pressure responses to Ang II, renal expression of
Nox4
was significantly decreased in TLR3ko mice but was unchanged in TLR4-del and WT mice.

In contrast to Ang II-induced hypertension, AngII-induced cardiac hypertrophy, measured as heart weight to body weight ratio, after 3 weeks of Ang II infusion was reduced in both TLR4-del (5.38 ± 0.19 mg/g) and TLR3ko (4.99 ± 0.15 mg/g) compared to WT (7.14 ± 0.49 mg/g). Thus, cardiac hypertrophy is abrogated in TLR4-del despite a robust pressor response to Ang II. The cardiac pro-inflammatory gene expression of tumor necrosis factor alpha (
Tnfa
), NADPH oxidase 4 (
Nox4
), and matrix metalloproteinase 9 (
Mmp9
) was increased in WT heart but attenuated in both TLR4-del and TLR3ko hearts. The results indicate a selective dependence of Ang II hypertension on TLR3/TRIF pathway whereas Ang II-induced cardiac hypertrophy depends on both TLR3 and TLR4, likely through the common TRIF adaptor protein.
Abstract 034: Remote Patient Monitoring for Postpartum Hypertension: A Pilot Study
Authors: Hoppe Kara K , Zella Julia B , Thomas Nicole A , Johnson Heather M
Published: March 2022

Background:
Postpartum hypertension is a leading indication for hospital readmission and maternal mortality.

Objective:
To conduct a pilot intervention to establish the feasibility of telehealth monitoring/treatment after hospital discharge for women with or at risk of developing severe postpartum hypertension (SBP
>
150 or DBP
>
105 mmHg).

Methods:
This prospective intervention at a Midwestern academic group practice included adult women with a hypertension-related diagnosis in the antenatal and/or postpartum period. Prior to discharge, patients received a tablet computer and blue tooth equipment (scale, blood pressure, oxygen saturation and heart rate monitor) to transmit home vital signs daily to a nurse. Patients had a nurse telehealth visit 48 hours and 7 days post-discharge. A nurse-driven outpatient treatment algorithm was developed and utilized for initiation and/or cessation of antihypertensive medications. Study follow-up was 6 weeks postpartum, followed by transfer to routine clinical care.

Results:
Among the 121 women with a hypertension-related disorder of pregnancy; 32 of the intended 55 have been enrolled to date (26%). [HJ2] Among the study patients, 6/32 (19%) were discharged on antihypertensive medication, of which 4/6 (67%) required an increase in the dose after discharge. After discharge, 10/32 (31%) required antihypertensive initiation after discharge due to development of severe hypertension. Overall, postpartum blood pressures became severe on day 4.9 (mean SBP was 158mmHg and DBP was 96mmHg). Among enrolled participants, there were two emergency room visits, however no hospital readmissions; 3/32 (9%) discontinued the study prior to study completion due to social situations.

Conclusions:
The preliminary results of our pilot intervention demonstrate feasibility and patient acceptability with telehealth monitoring for postpartum hypertension-related disorders. Furthermore, we demonstrated important temporal trends in the natural history of postpartum hypertension from discharge through 6 weeks postpartum which will guide larger clinical trials. Telehealth monitoring is a promising outpatient treatment strategy for postpartum hypertension to reduce readmissions and decrease maternal morbidity.
Abstract 040: Low Soluble Fms-like Tyrosine Kinase-1, Endoglin, and Endothelin-1 Levels in Women With Confirmed or Suspected Preeclampsia Using Proton Pump Inhibitors
Authors: Danser Alexander H , Saleh Langeza , Visser Willy , van den Meiracker Anton H
Published: March 2022

Preeclamptic patients display elevated placenta-derived soluble Fms-like tyrosine kinase-1 (sFlt-1) and endoglin levels, and decreased placental growth factor (PlGF) levels. Proton pump inhibitors (PPIs) decrease trophoblast sFlt-1 and endoglin secretion in vitro. PPIs are used during pregnancy, to combat reflux disease. Here we investigated whether PPIs affect sFlt-1 in women with confirmed/suspected preeclampsia, making use of a prospective cohort study involving 430 women. Of these women, 40 took PPIs (6 esomeprazole, 32 omeprazole and 2 pantoprazole) for 8-45 (median 29) days before sFlt-1 measurement. Measurements were only made once, at study entry between weeks 20-41 (median 33 weeks). PPI use associated with lower sFlt-1 levels, with no change in PlGF levels, both when compared to all non-PPI users, and to 80 gestational age-matched controls selected from the non-PPI users. No sFlt-1/PlGF alterations were observed in women using ferrous fumarate or macrogol, while, as expected, women using antihypertensive medication displayed higher sFlt-1 levels and/or lower PlGF levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with preexisting proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Finally, their plasma endoglin and endothelin-1 levels were lower, while sFlt-1 levels correlated positively with both. In conclusion, PPI use associates with low sFlt-1, endoglin, and endothelin-1 levels, warranting prospective trials to investigate the therapeutic potential of PPIs in preeclampsia.
Abstract 047: Clinical Outcomes by Race and Ethnicity in the Systolic Blood Pressure Intervention Trials (SPRINT): A Randomized Control Trial
Authors: Still Carolyn H , Rodriguez Carlos J , Wright Jackson T , Craven Timothy E , Bress Adam P , Chertow Glenn M , Whelton Paul K , Whittle Jeffrey C , Freeman Barry I , Johnson Karen C , Foy Capri G , He Jiang , Kostis John B , Lash Jame P , Pedley Carolyn F , Pisoni Roberto , Powell James R , Wall Barry M
Published: March 2022

Background:
Lowering systolic blood pressure (SBP) reduces cardiovascular disease morbidity and mortality; however, appropriate SBP targets, especially by race/ethnicity remain uncertain.

Methods and Results:
We examined the effects of an intensive SBP goal (<120 mm Hg) compared to the current recommendation (< 140 mmHg) on cardiovascular disease (CVD) outcomes in racial-ethnic groups in SPRINT (Systolic Blood Pressure Intervention Trial). High-risk non-diabetic patients with hypertension (N = 9,361; 30% Black; 11% Hispanic), 50 years and older were enrolled at 102 clinical sites across the U.S. and Puerto Rico. Primary outcome was a composite of the first occurrence of a myocardial infarction, acute coronary syndrome, stroke, decompensated heart failure, or CVD death. Average ± SD post-baseline SBP across race/ethnic groups ranged from 134.7±0.1 to 135.5±0.2 mmHg in the standard arm compared to 119.9±0.4 to 122.6±0.2 in the intensive arm. Intensive vs. standard arm hazard ratios [HRs] (95% CI) for the primary outcome were 0.70 (0.57-0.86), 0.71 (0.51-0.98), 0.62 (0.33-1.15) in Non-Hispanic Whites, Non-Hispanic Blacks, and Hispanics respectively. CVD mortality HRs were 0.49 (0.29-0.81), 0.77 (0.37-1.57), and 0.17 (0.01-1.08) with all-cause mortality HRs 0.61 (0.47-0.80), 0.92 (0.63-1.35), and 1.58 (0.73-3.62). Tests for interaction were not statistically significant after adjustment for multiple comparisons.

Conclusion:
Regardless of racial/ethnic origin, there are cardiovascular benefits from treating to a SBP target of < 120 mmHg compared to <140 mmHg.
Abstract 049: Prevention of Glomerular Hyperfiltration by Enhancement of Tubuloglomerular Feedback Response Induces Hypertension and Exacerbates Diabetic Kidney Injury
Authors: Zhang Jie , Wei Jin , Jiang Shan , Wang Lei , Wang Shaohui , Liu Ruisheng
Published: March 2022

The mechanism underlying the higher prevalence of hypertension in diabetes remains unclear. We hypothesized that blunted tubuloglomerular feedback (TGF) mediated by the neuronal nitric oxide synthesis (NOS1) β in the macula densa promotes glomerular hyperfiltration in diabetes, whereas inadequate NOS1β in the macula densa restricts glomerular hyperfiltration, induces hypertension and exacerbates diabetic kidney injury. First, we measured the protein levels of NOS1β in the renal cortex, which was 6.5±1.2 fold higher in db/db mice than in db/+ mice (n=5, p<0.01). Then, in isolated and perfused juxtaglomerular apparatus, we measured TGF-induced NO generation by the macula densa, which was 115.4±9.8 Units/min in db/+ mice and 161.5±12.7 Units/min in db/db mice (n=5, p<0.01). We next measured TGF
in vivo
using micropuncture, which was 3.7±0.4 mmHg in db/db mice and 5.3±0.3 mmHg in db/+ mice (n=5, p<0.05). Then we developed a macula densa specific NOS1 knockout db/db mouse line (KO) (Lepr
db/db
; NKCC2
cre
; NOS1
flox/flox
). Littermate db/db (Lepr
db/db
; NOS1
flox/flox
) and db/+ (Lepr
db/+
; NOS1
flox/flox
) mice serve as diabetic and non-diabetic controls. Glomerular filtration rate (GFR) was 236±18 μl/min in db/+ mice, and significantly increased to 375±12 and 284±11 μl/min in the db/db and KO mice (n=4-5, p<0.01). Telemetric mean arterial pressure (MAP) was 97.1±3.5 and 103.6±5.2 mmHg in db/+ and db/db mice, and significantly raised to 124.4±8.1 mmHg in the KO mice (n=4-5, p<0.01). Proteinuria increased by 70 and 120 folds in the db/db and KO mice compared with db/+ mice (n=4, p<0.01). The kidney histology was assessed with light and transmission electron microscopy in the mice at age of 24 weeks. The diabetic kidney injury score was 0.37±0.16 in the db/+ mice, and significantly increased to 1.14±0.2 and 2.37±0.67 in the db/db and KO mice (n=5, p<0.01). In conclusion, upregulation of the macula densa NOS1 blunts TGF response and promotes elevation of GFR in diabetes. Contrary to popular belief about glomerular hyperfiltration in diabetes, our data suggest that directly limiting the increase in GFR by enhancement of TGF response is detrimental, which induces hypertension and exacerbates diabetic kidney injury.
Abstract 059: miR-29 is Required for Normal Endothelium-dependent Vasodilation and Protects Against Hypertension
Authors: Jensen David M , Widlansky Michael E , Liang Mingyu , Wang Jingli , Liu Yong , Geurts Aaron , Kriegel Alison , Liu Pengyuan , Ying Rong , Malik Mobin , Branum Amberly , Tanner Michael J , Usa Kristie , Casati Marc , Zhang Guangyuan , Chu Chen
Published: March 2022

MicroRNA miR-29 is down-regulated in Dahl salt-sensitive (SS) rats compared to salt-insensitive SS-13
BN
rats. We investigated the role of miR-29 in endothelial function and the development of hypertension. Using TALENs (Transcriptional Activator-Like Effector Nucleases) we deleted 4 nucleotides from
Mir29b-1
gene in SS-13
BN
rats. The targeted mutation resulted in reduced abundance of miR-29b-3p and the co-transcribed miR-29a-3p in arteriolar endothelial cells. When stimulated with acetylcholine to induce endothelium-dependent vasodilation (EDVD), gluteal arterioles from

Mir29b-1
-/-

rats were only able to dilate to an average 47% of maximum diameter while wild-type littermates dilated to 77% (N=7 and 9, respectively, p<0.05). The development of hypertension was significantly exacerbated in

Mir29b-1
-/-

compared to

Mir29b-1
+/+

littermates. Mean arterial blood pressure was 129 ± 2 mmHg in

Mir29b-1
+/+

rats after 2 weeks of 4% NaCl diet and 140 ± 5 mmHg in

Mir29b-1
-/-

rats (N=6, 10, respectively, p<0.05). Gluteal arterioles from

Mir29b-1
-/-

rats exhibited significantly reduced nitric oxide (NO) levels compared to

Mir29b-1
+/+

littermates as measured by DAF2-DA intensity (N=6, 11, respectively). Mutation of the
Mir29b-1
gene resulted in preferential differential expression of genes in arterioles related to the regulation of NO levels including Lypla1. Lypla1 is a direct target of miR-29 and could abrogate the effect of miR-29 in promoting NO production. Reduction of LYPLA1 by transfection of pre-miR-29b or a Lypla1 siRNA resulted in a significant increase in NO as measured by DAF2-DA in cultured human dermal microvascular endothelial cells. Taken together, we have shown that targeted mutation of
Mir29b-1
reduces EDVD and exacerbates the development of hypertension. We have identified a mechanism by which miR-29 affects NO production. These findings indicate miR-29 is required for normal endothelial function in rats and has therapeutic potential for hypertension.
Abstract 068: Impact of Renal Outer Medullary Potassium Channel Inhibition on Afferent Arteriolar Tone in Rats With Type 1 Diabetes
Authors: Carmines Pamela K , Zhou Xiaoyan , Dajee Maya , Sullivan Kathleen A , Walsh Shawn P , Pasternak Alexander
Published: March 2022

The bee venom toxin tertiapin Q (TPQ) evokes tubuloglomerular feedback-independent afferent arteriolar constriction in kidneys from rats with streptozotocin-induced type 1 diabetes (STZ rats). Because TPQ inhibits both Kir1.1 and Kir3.x channels, the contribution of Kir1.1 (renal outer medullary potassium channel; ROMK) to afferent arteriolar tone in diabetes remains uncertain. To test the hypothesis that Kir1.1 exerts a tonic dilator influence on the afferent arteriole during diabetes, we compared afferent arteriolar responses to the novel, small molecule Kir1.1-selective inhibitor Compound C (CmpdC) to those evoked by TPQ. The
ex vivo
blood-perfused juxtamedullary nephron technique was used to monitor afferent arteriolar lumen diameter before and during exposure to TPQ (1-100 nM) or CmpdC (10 nM-10 μM). Neither agent altered afferent arteriolar diameter in kidneys from normal rats. In kidneys from STZ rats (blood glucose concentration = 465 ± 12 mg/dl), baseline afferent arteriolar diameter averaged 22.9 ± 0.6 μm (
n
= 30). Both TPQ and CmpdC evoked concentration-dependent arteriolar constriction, with 100 nM TPQ decreasing diameter by 2.5 ± 0.6 μm (
n
= 6;
P
< 0.001 vs baseline) and 100 nM CmpdC reducing diameter by 1.7 ± 0.6 μm (
n
= 10;
P
= 0.004 vs baseline;
P
= 0.42 vs 100 nM TPQ). During subsequent exposure to 10 μM CmpdC, arteriolar diameter was 2.1 ± 0.8 μm below baseline. The similar effects of the Kir1.1/3.x inhibitor TPQ and the Kir1.1-selective inhibitor CmpdC on arteriolar diameter in kidneys from STZ rats support the contention that Kir1.1 exerts a tonic afferent arteriolar dilator influence during type 1 diabetes. In follow-up studies, the NKCC inhibitor furosemide (30-300 μM) administered via the bath did not alter afferent arteriolar diameter in kidneys from STZ rats; however, prior exposure to furosemide prevented the vasoconstrictor response to 100 nM CmpdC (Δ diameter = -0.4 ± 0.3 μm;
n
= 8) although the response to 100 nM TPQ remained intact (Δ diameter = -2.6 ± 1.3 μm;
n
= 6). The differential impact of furosemide pretreatment on arteriolar responses to TPQ and CmpdC suggests a complex interplay between the furosemide-sensitive vascular NKCC1 and tubular NKCC2, and the TPQ- and CmpdC-sensitive Kir1.1 expressed in both the vasculature and tubule.
Abstract 080: Endothelin-1 Exaggerates Type-1 Diabetes-Accelerated Atherosclerosis Through NADPH Oxidase 1
Authors: Paradis Pierre , Ouerd Sofiane , Idris-Khodja Noureddine , Trindade Michelle , Coelho Suellen C , Neves Mario F , Jandeleit-Dahm Karin A , Schiffrin Ernesto L
Published: March 2022

Introduction:
NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (

Apoe
-/-

) mice exaggerated high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We hypothesized that ET-1 overexpression in the endothelium would exaggerate diabetes-accelerated atherosclerosis through a mechanism involving NOX1 but not NOX4.

Methods:
Six-week-old male

Apoe
-/-

mice, eET-1/

Apoe
-/-

and eET-1/

Apoe
-/-

mice deficient in
Nox1
(eET-1/

Apoe
-/-

/

Nox1
y/-

) or
Nox4
(eET-1/

Apoe
-/-

/

Nox4
-/-

) were rendered diabetic with 55 mg/kg/day streptozotocin (STZ) IP for 5 days and studied 14 weeks later. Aortic atherosclerotic lesions were quantified using Oil Red O staining. Monocyte/macrophage infiltration and alpha-smooth muscle actin area were determined by immunofluorescence in aortic atherosclerotic lesions. Plasma cholesterol, HDL and triglycerides were measured.

Results:
ET-1 overexpression exaggerated 2.5-fold the atherosclerotic lesion area of the aortic sinus in diabetic

Apoe
-/-

mice (plaque area [x10
5
μm
2
]: 5.3±0.2 vs 2.1±0.4,
P
<0.05), which was reduced ~35% by
Nox1
(3.5±0.4 x10
5
μm
2
,
P
<0.05) but not
Nox4
knockout (5.0±0.7 x10
5
μm
2
). Monocyte/macrophage infiltration was reduced ~30% in diabetic eET-1/

Apoe
-/-

and eET-1/

Apoe
-/-

/

Nox4
-/-

mice (31±1 and 35±2 vs 48±5% of lesion area,
P
<0.05) but not eET-1/

Apoe
-/-

/

Nox1
y/-

mice (35±2%). ET-1 overexpression decreased alpha-smooth muscle actin content by ~35% (9±1 vs 14±2% of lesion area,
P
<0.05), which was blunted by
Nox1
(15±2%,
P
<0.05) but not
Nox4
knockout (9±1%). Plasma triglycerides were unaffected by ET-1 overexpression (3.4±0.3 vs 3.6±0.5 mmol/L) but reduced by
Nox1
and
Nox4
knockout (2.2±0.4 and 1.8±0.4 mmol/L,
P
<0.05). Plasma HDL and cholesterol were similar between groups.

Conclusions:
Endothelium ET-1 overexpression exaggerates diabetes-accelerated atherosclerosis and reduces plaque stability through NOX1.
Abstract 084: Neurons in the Nodose Ganglion that Express Angiotensin Type 1a Receptors Function as Primary Baroreceptor Afferents: An
in vitro
and
in vivo
Optogenetic Study
Authors: Bruce Erin B , Domingos-Souza Gean , Smeltzer Michael D , Tan Yalun , Cahill Karlena , Harden Scott W , Frazier Charles J , Sumners Colin , Raizada Mohan K , Krause Eric G , de Kloet Annette D
Published: March 2022

The baroreflex is an essential regulator of blood pressure (BP); whereby, baroreceptors sense acute changes in BP and convey this information, via the nodose ganglia (NG), to the nucleus of the solitary tract (NTS). Manipulation of the baroreflex may provide a novel strategy in the treatment of hypertension. To that end, our neuroanatomical studies revealed a dense localization of angiotensin type 1a receptor (AT1a)-containing neuronal cell bodies in the NG and terminals in the NTS, thereby positioning them to play a role in the baroreflex. We, therefore, hypothesized that AT1a neurons residing in the NG potently influence cardiovascular function. Male and female mice expressing channelrhodopsin-2 (ChR2) and yellow fluorescent protein (eYFP) specifically in AT1a-expressing neurons (AT1aR-ChR2-eYFP) were used to determine the function of these neurons.
In vitro
patch clamp electrophysiological recordings from neurons in the NTS receiving axons expressing ChR2-eYFP revealed that optogenetic stimulation (473nm) reliably evoked excitatory postsynaptic currents (EPSCs). In concurrence with studies demonstrating that baroreceptor afferents utilize glutamate in the NTS, these EPSCs were eliminated by the presence of glutamate receptor antagonists. Next, the NG of anesthetized mice were subjected to optogenetic stimulation of varying frequencies (1, 15, 30Hz) for 1 min, and BP and HR responses were assessed. Optogenetic stimulation of these AT1a-expressing neurons led to significant decreases in mean arterial pressure (ΔMAP= -16±3*, -36±4*, -44±7* mmHg) and HR (ΔHR= -13±7, -104±44*, -163±59* bpm) in AT1a-ChR2-eYFP mice (n=6), but there was no effect on control mice harboring only the stop-FLOX-ChR2-eYFP gene (n=5; ΔMAP= 0±2, -2±1, 5±5 mmHg; ΔHR= 4±4, 3±4, -13±21 bpm). Additionally, AT1a-ChR2-eYFP mice rendered hypertensive via DOCA-salt (n=7) exhibited a dampened response to optogenetic stimulation (ΔMAP= -7±1#, -14±3*#, -30±6*# mmHg; ΔHR= -29±34, -71±37*, -178±50* bpm). Collectively, these data suggest that AT1a neurons in the NG are key regulators of the baroreflex, and may serve as a target for antihypertensive therapeutics. (p<0.05, *significantly different from control, #significantly different from normotensive AT1a-ChR2-eYFP)
Abstract 087: Deletion of Brain-specific Isoform of Renin (renin-b) Increases Resting Metabolic Rate by Stimulating Thermogenic Sympathetic Nerve Activity
Authors: Gomez Javier , Nakagawa Pablo , Shinohara Keisuke , Morgan Donald A , Weidemann Benjamin J , Folchert Matthew D , Rahmouni Kamal , Grobe Justin L , Sigmund Curt D
Published: March 2022

The brain specific isoform of renin, Renin-b (Ren-b), has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We generated mice with a selective deletion of Ren-b (Ren-b KO) while preserving expression of the classical Renin-a isoform. Deletion of Ren-b induced central RAS activation and hypertension through increases in brain Renin-a. However the metabolic effects of Ren-b deletion have yet to be described. Under basal conditions, Ren-b KO mice do not show differences in body weight, food consumption or physical activity. On a high fat diet, Ren-b KO male mice gained significantly less weight than the control mice (Ren-b KO: 36.8g ± 1.2 vs control: 41.9g ± 1.4; p<0.03, mean ± SEM). All subsequent experiments were performed on male mice. The analysis of the area under the curve (AUC) in a glucose tolerance test revealed a mild but significant glucose intolerance in Ren-b KO mice (Ren-b KO: 152.5 mg/dL*hr ± 20.9 vs control: 93.0 mg/dL*hr ± 14.3; p<0.03). However, there were no significant differences in the AUC in the insulin tolerance test (Ren-b KO: 174.3 mg/dL*hr ± 12.8 vs control: 207.0 mg/dL*hr ± 12.8; p=0.077). Ren-b KO mice exhibited increased resting metabolic rate (Ren-b KO: 0.156 ± 0.005 kcal/h vs control: 0.145 ± 0.003 kcal/h; p<0.015). Ren-b KO mice also exhibited an increase in sympathetic nerve activity (SNA) to the interscapular brown adipose tissue (BAT) (Ren-b KO: 40.8 ± 3.1 spikes/sec vs control: 27.2 ± 3.1 spikes/sec; p<0.003). This was associated with an increase in BAT uncoupled protein 1 (UCP1) protein expression (Ren-b KO: 2.1 ± 0.5 fold increase vs control, p<0.05). Altogether, these data indicate that the brain RAS regulates energy homeostasis. The changes noted in Ren-b KO mice may be due to activation of the brain RAS. The activation of BAT SNA and the subsequent increase in UCP1 levels likely contributes to the metabolic phenotype observed in Ren-b KO mice. Dysregulation of Ren-b may be an important pathophysiological mechanism involved not only in the development of neurogenic hypertension, but also in obesity and other metabolic diseases.
Abstract 090: Nocturia as an Unrecognized Symptom of Uncontrolled Hypertension in Middle-age Black Men
Authors: Victor Ronald G , Li Ning , Mason O’Neil , Lynch Kathleen , Rashid Mohamad , Elashoff Robert
Published: March 2022

Hypertension (HTN) is assumed to be asymptomatic (“the silent killer”). Yet nocturia - awakening at night to urinate - is bothersome if occurring
>
2 times/night and constitutes a putative but understudied symptom of HTN. Hypertensive black men may be especially prone to nocturia due to high sodium diet, blunted nocturnal blood pressure (BP) dipping (driving pressure-natriuresis), diuretic BP drugs, and common comorbid determinants of nocturia (prostate disease, diabetes, sleep apnea). To test if uncontrolled HTN is an independent, common, and potentially reversible determinant of nocturia in black men, we conducted in-person structured interviews and measured BP with a highly-rated automated monitor (that took 5 readings and averaged the last 3) in a large community-based sample of black men in their barbershops, a uniquely relaxed social setting to obtain high participation and accurate out-of-office BP. As nocturia is steeply age-dependent, we studied younger men ages 35 to 49 Y in whom nocturia would be unexpected. Among 1,748 black men, mean age 43±4 (SD) years, 45% (782 of 1748) had HTN; of these, HTN was: controlled with drugs (barbershop BP < 135/85 mmHg) in only 16% (123 of 782). Nocturia prevalence ranged from 24% (232 of 966) of normotensive men to 50% (96 of 191) of men whose HTN was drug-treated but still uncontrolled. Using normotensive men (BP 120±9/71±7) as the reference group and adjusting for all known nocturia determinants, the odds of having nocturia (
>
2 episodes/night vs. 0-1) was: (1) 34% higher in men with untreated HTN (BP 143±11/87±10): adjusted odds ratio (aOR) 1.34 (95% confidence intervals [CI]: 1.04-1.71, p=.02); (2) 174% higher in men with treated but uncontrolled HTN (BP 148±14/91±11): aOR 2.74 (95% CI:1.97-3.82, p<.001); but (3) not increased in men whose HTN was both treated and controlled (BP 123±8/74±7): aOR 1.24 (95% CI: 0.81-1.89, p=.32). Thus, in the largest study of nocturia in black men to date and the only one to measure BP, the data show that nocturia—a bothersome symptom—often signifies uncontrolled HTN in black men ages 35 to 49 Y. Because nocturia is far more likely when HTN is inadequately treated than when untreated, the data also suggest that nocturia may be a side-effect of BP drugs unless strict BP control is achieved.
Abstract 092: Global SYMPLICITY Registry: 3 Year Safety and Efficacy Data
Authors: Böhm Michael , Mancia Giuseppe , Schmieder Roland , Schlaich Markus , Mahfoud Felix
Published: March 2022

The objective of the Global SYMPLICITY Registry (GSR) is to collect and analyze real-world data on the safety and efficacy of renal denervation (RDN) using either the original Symplicity Flex
TM
renal denervation catheter or the newer-generation Symplicity Spyral
TM
catheter, which simultaneously applies energy to each renal artery quadrant.

GSR is a prospective, multi-center, non-randomized international RDN registry for patients with uncontrolled hypertension. In-office and ambulatory blood pressure measurements, clinical assessment and blood tests are among the data collected. To date, there are 2237 patients treated with the Symplicity Flex
TM
catheter with 6 month follow up and 1199 patients with 36 month follow up. Baseline demographics for this cohort included a mean age of 60.8 ± 11.9 years, 58.0% male and baseline eGFR of 76.3 ± 25.0 mL/min/1.73 m
2
. At 36 months, reduction in office systolic blood pressure (OSBP) was -16.5 mm Hg (N=872). A smaller subset of patients was treated with the Symplicity Spyral
TM
catheter, and 174 of these patients had blood pressure measurements at 12 months, with a reduction in OSBP of -16.3 mm Hg. Reductions in ambulatory blood pressure measurements (ABPM) were sustained for both cohorts as shown in Figure 1. Rate of renal artery re-intervention at 36 months was 0.8% (10/1199) for Symplicity Flex
TM
and 0.0% (0/211) for Symplicity Spyral
TM
.

Reductions in OSBP and ABPM were sustained to 36 months for patients who had RDN treatment with the Flex catheter. A subset of patients that received treatment with the Spyral catheter also saw reductions in blood pressure measurements. Rate of renal artery re-intervention was low for both groups.
Abstract 095: Digital Solution Assisted Retail Pharmacists in Community Hypertension Control in China: A Real World Study of Large Samples
Authors: Qu Wenhao , Wang Zhen , Chen Ying , Li Yingjie , Liu Kai
Published: March 2022

Objective:
To identify the effects of a digital healthcare solution for hypertension management at retail pharmacies by pharmacists.

Methods:
We developed a digital healthcare solution that includes BP telemonitor, an App, and a cloud database with algorithms to assist: 1) CVD risk screening, 2) personalized meal planning, 3) personalized health coaching, and 4) medication guidance and compliance during the pharmacy consultation service. This solution has been implemented in 5,067 retail pharmacies in 141 cities in China as a decision support system to help pharmacists manage their hypertensive members. During Jan 1
st
2015 to Dec 31
st
2016, a total of 1,817,594 patients received in-store hypertension care and 23,024 of them were selected in this analysis following 4 inclusion criteria: 1) baseline BP was hypertensive (≥ 140/90 mm Hg), 2) the frequency of in-store hypertensive care was ≥ 1 time per month, 3) the intervention duration between the first- and last-time hypertensive care was ≥ 1 month, and 4) baseline characteristics were complete. Dynamic changes of SBP, DBP, disease staging, and population distribution over time were the major end points in this real-world, retrospective analysis.

Results:
SBP and DBP of the study population (n=23,024) were reduced on average by 11.2 mm Hg (baseline: 151.7 ± 14.8 mm Hg, last time: 140.5 ± 18.8 mm Hg, P< 0.001) and 6.3 mm Hg (baseline: 91.2 ± 11.9 mm Hg, last time: 84.9 ± 12.7 mm Hg, P<0.001), respectively. A total of 13,001 (56.5%) patients demonstrated improved hypertension stages by the last time BP measures with 9,625 (41.8%) of them returning to the normal range. The principal BP control effect took place after the first-time intervention, followed by gradual BP reduction over time. Simulation analysis revealed linear descending relationship of both SBP and DBP to time, and the concentration distributions were moving towards the normal BP level. The linear fitting functions were: SBP, Y = -0.103x + 140.278; DBP, Y = -0.060x + 84.799.

Conclusion:
Digital healthcare solution is effective in assisting retail pharmacists to deliver community hypertension care in real world.
Abstract 106: Probenecid Downregulates Kidney Pendrin and AQP-2 and Potentiates Hydrochlorothiazide-induced Diuresis
Authors: Soleimani Manoocher , Barone Sharon , Zahedi Kamyar , Xu Jie
Published: March 2022

Background:
Concurrent inactivation of the kidney Na-Cl co-transporter NCC and the Cl
-
/HCO
3
-
exchanger pendrin leads to significant salt wasting, whereas single deletion of NCC does not cause any significant salt wasting, indicating that pendrin mitigates the salt excretion caused by NCC inactivation. Probenecid is a uricosuric agent that, in addition, exhibits positive ionotropic effect in the heart, downregulates/inactivates pendrin (in mammary gland cells) and blocks the ATP transporter Pannexin 1 in the proximal tubule and colleting duct.

Hypothesis:
Pretreatment with probenecid downregulates pendrin; therefore, leaving NCC as the main salt absorbing transporter in the distal nephron, and hence enhancing the hydrochlorothiazide (HCTZ) diuresis.

Results:
Male Sprague Dawley rats were treated with probenecid intraperitoneally (i.p.) at 250 or 100 mg/kg for 6 days and then received HCTZ while being maintained on probenecid for 4 more days. Urine output increased from 9.8 at baseline to 15.9 ml/24 hrs after 10 days of Probenecid at 250 mg/kg (p<0.02, n=5). Treatment with HCTZ alone for 4 days caused a mild diuresis, with urine output increasing to 13.8 ml/24 hrs (p>0.05, vs. baseline, n=5) However, rats pretreated with Probenecid for 6 days exhibited a profound diuresis when HCTZ was added for 4 additional days, with urine output increasing to 42.9 ml/day, a more than 300% increase vs. rats treated with either Probenecid or HCTZ (p<0.003 vs. both groups, n = 5). In the absence of pretreatment with Probenecid, the diuresis caused by concurrent Probencid plus HCTZ treatment was similar to HCTZ alone (p>0.05). Immunofluorescent, Northern and/or Western hybridization studies demonstrated a significant reduction in the expression of pendrin and AQP2 in the kidney cortical collecting duct/cortex of probenecid treated rats. At 100 mg/kg, Probenecid alone had no significant effect on urine output but caused a robust diuresis when HCTZ was added, with the urine output increasing from 9.93 baseline to 24.23 (p<0.001, n=7).

Conclusion:
Probenecid pretreatment downregulates pendrin and AQP2 and robustly enhances diuresis by HCTZ-mediated NCC inhibition in the distal nephron.
Abstract 115: Primary Hyperadrenergic Postural Tachycardia Syndrome. Evidence From Sympathetic Nerve Recordings
Authors: Okamoto Luis E , Garland Emily M , Sato Kyoko , Diedrich Laura , Furlan Raffaello , Jacob Giris , Robertson David , Biaggioni Italo , Diedrich André
Published: March 2022

Postural tachycardia syndrome (POTS) is a chronic disabling condition with excessive upright tachycardia and symptoms due to enhanced sympathetic activity in otherwise healthy young individuals. Because it is not clear if sympathetic activation is a primary phenomenon, or an appropriate compensatory response to hypovolemia, deconditioning or partial neuropathy, we analyzed resting supine muscle sympathetic nerve activity (MSNA) in 38 female POTS patients (mean±SD, age 32.1±9.1, BMI 22.7±5.4). MSNA showed a wide range of burst rate (19.7±12.1 bursts/min, range 1.2 to 54, 95% CI: 15.7 to 23.6). We compared the 1
st
and 4
th
Quartiles of 28 MSNA records (MSNA_Q1: < 7.3; MSNA_Q4: > 23.4 bursts/min) to determine if resting MSNA is related to heart rate (HR) or blood pressure (BP) responses to orthostatic challenge and the Valsalva maneuver (2-way ANOVA with post-hoc tests).

Upright HR was inappropriately high in both groups (MSNA_Q1: 120±19 vs. MSNA_Q4: 110±20 bpm, NS), but the MSNA_Q4 group had higher upright diastolic BP than MSNA_Q1 (81±12 vs. 62±8 mmHg, P<0.01). Similarly, there were no differences in HR response to the Valsalva maneuver between groups, but systolic and diastolic BP were higher during late phase 2 in MSNA_Q4 (p<0.05), and this was preceded by higher MSNA spike rate (44.3±16.3 vs. 81.2 ±25 maximal spikes/secs per beat, p<0.01) during early phase 2 of Valsalva maneuver.

The greater BP responses, but comparable HR responses, to posture and Valsalva challenges provide evidence that the subset of POTS patients with higher resting MSNA have a primary sympathetic activation. These patients might benefit from sympatholytic therapy in contrast to other POTS patients with low or absent resting MSNA.
Abstract 117: Renal Nerves Mediate Renal Inflammatory Signaling Independent of Hypertension in the DOCA-salt Rat
Authors: Banek Christopher T , Osborn John W
Published: March 2022

Preclinical and clinical studies demonstrate renal denervation (RDx) may be an effective treatment for hypertension (HTN); however, the mechanisms of this effect remain unknown. We recently reported (RDx) mitigates HTN, and prevents renal inflammation in the deoxycorticosterone acetate (DOCA)-salt rat model of HTN. Although these findings suggest renal nerves directly mediate renal inflammatory signaling, this effect may also be secondary to lowering arterial pressure (AP). In this study, we aimed to elucidate the specific role of renal nerves on renal inflammatory signaling using a unilateral RDx approach to control for lowered AP. We tested the hypothesis that RDx will ameliorate the renal inflammation independent of HTN in the DOCA-salt rat. To test this hypothesis, 8 male Sprague Dawley (SD) rats were implanted with radiotelemeters to measure AP and subjected to unilateral RDx. Rats were then administered DOCA (100mg, s.c.) and 0.9% saline for 21 days. Rats were then anesthetized, and renal tissue and urine were collected from both RDx and contralateral control (CON) kidneys. Renal inflammation was assessed by assay for pro-inflammatory cytokines (IL-1β, IL-2, IL-6, GRO/KC, MCP-1) in both urine and renal tissue. Data presented as mean ± SEM, *p<0.05. Mean AP increased from 99±3 to 135±4mmHg over DOCA-salt treatment. Renal GRO/KC content was markedly reduced in RDx kidneys compared to CON (14±5* vs. 467±96pg/mg total protein), and this was mirrored in the urinary excretion of GRO/KC in RDx vs. CON (51±11* vs. 3717±500pg/mg creatinine). Similarly, renal MCP-1 content was lower in RDx (13±2*) compared to CON (292±51). Urinary excretion of MCP-1 was also decreased by RDx (67±31* vs. 1758±721). Finally, urinary protein:creatinine was abated by RDx (13±3* vs. 19±3au). Notably, there was no effect of RDx on renal or urinary content of IL-1β, IL-2, nor IL-6. From this data, we conclude that renal nerves mediate renal inflammation associated with chemokines GRO/KC and MCP-1 release, independent of HTN. However, RDx had no effect on IL-1β, IL-2, IL-6, which suggests a chemokine specificity of renal nerve contribution to inflammatory signaling. Studies are currently underway to establish the effect of RDx on renal infiltration of specific immune cell populations.
Abstract 118: Barorreflex Hypofunction is Due to Increased Arterial Stiffness in Chronic Hypertension
Authors: Duarte Mariano , Milei Jose , Savio Galimberti Eleonora , Reyes Toso Carlos , Bellido Claudio
Published: March 2022

The autonomic nervous system (ANS) plays a central role in blood pressure (BP) homeostasis. BP changes can activate barorreflex response, which is one of the main mechanisms through which ANS rapidly regulates BP. This regulatory mechanism is compromised in chronic arterial hypertension (HT). We hypothesize that barorreflex activity is diminished in patients with high BP due to increased arterial stiffness (AS), which decreases the barorreceptors’ sensitivity to mechanical deformation, and that the decreased barorreflex activity might contribute to the maintenance and progression of HT. To test this hypothesis, we studied the chronotropic response of patients (>65 years of age, n=101 patients, 75 % with HT) after Valsalva’s maneuver (pressor maneuver) by measuring BP, heart rate (HR), and ECG (DII). Chronotropic response after the test was defined as the smallest R-R interval up to 5 s. post-test, normal response being considered 10-30 beats/min. of increment in HR and decreased response was defined as <10 beats/min of HR increment. We also assessed AS by measuring carotid-femoral pulse wave velocity (PWV-CF), which has a predictive value for cardiovascular events. We observed a significant increase in systolic BP in the HT group respect to control (147.2±15.7 mm Hg vs. 130.2±10.8 mm Hg). We also observed altered barorreflex function in 60 out of 76 HT patients (~79 %) but only 3 out of 25 controls (12 %). Median of increased HR was significantly decreased in the HT group respect to control response (6 beats/min. vs. 12 beats/min., P<0.001). PWV-CF significantly increased in the HT group compared to control ((10,54 m/s vs. 8,58 m/s, p<0.001). Also, changes in PWV-CF were inversely correlated to cronotropic response post-Valsalva. These results suggest that HT patients > 65 years of age are particularly prone to hypofunction of the barorreflex mechanism. Valsalva’s maneuver in combination with ECG might represent a quick, non-invasive method to assess chronotropic response and evaluate barorreflex function. Barorreflex hypofunction might contribute to the maintenance and even progression of HT in these patients. The increased AS revealed by increased PWV-CF may be the nexus between HT and barorreflex hypofunction.