Arteriolar Resistance Research Articles

Postprandial renal haemodynamic effects of the dipeptidyl peptidase‐4 inhibitor linagliptin versus the sulphonylurea glimepiride in adults with type 2 diabetes (RENALIS): A predefined substudy of a randomized, double‐blind trial

AimTo determine the effect of the dipeptidyl peptidase‐4 inhibitor linagliptin on postprandial glomerular hyperfiltration compared with the sulphonylurea glimepiride in adults with type 2 diabetes (T2D).Materials and MethodsIn this predefined substudy within a randomized, double‐blind, parallel‐group, intervention trial, overweight people with T2D without renal impairment were treated with once‐daily linagliptin 5 mg (N = 10) or glimepiride 1 mg (N = 13) as an add‐on to metformin for 8 weeks. After a standardized liquid protein‐rich meal, the glomerular filtration rate (GFR) and effective renal plasma flow were determined by inulin and para‐aminohippuric acid clearance, respectively, based on timed urine sampling. Intrarenal haemodynamics were estimated using the Gomez equations. Glucoregulatory/vasoactive hormones, urinary pH and fractional excretions (FE) of sodium, potassium and urea were measured.ResultsCompared with glimepiride, linagliptin increased the postprandial filtration fraction (FF; mean difference 2.1%‐point; P = .016) and estimated glomerular hydraulic pressure (mean difference 3.0 mmHg; P = .050), and tended to increase GFR (P = .08) and estimated efferent renal arteriolar resistance (RE; P = .08) from baseline to week 8. No differences in FE were noted. Glimepiride reduced HbA1c more than linagliptin (mean difference −0.40%; P = .004), without between‐group differences in time‐averaged postprandial glucose levels. In the linagliptin group, change in FF correlated with change in mean arterial pressure (R = 0.807; P = .009) and time‐averaged mean glucagon (R = 0.782; P = .008), but not with changes in glucose, insulin, intact glucagon‐like peptide‐1, renin or FENa. Change in glucagon was associated with change in RE (R = 0.830; P = .003).ConclusionsIn contrast to our hypothesis, compared with glimepiride, linagliptin does not reduce postprandial hyperfiltration, yet appears to increase FF after meal ingestion by increasing blood pressure or RE.

Commentary on Intraglumerular dysfunction predicts kidney failure in the type 2 diabetes.

The key physiological parameters that determine glomerular filtration rate levels are renal plasma flow, filtration fraction, intraglomerular pressure, and balance between afferent and efferent glomerular arteriolar resistance. The evaluation of the balance between afferent and efferent glomerular arteriolar resistance might be useful for the classification of diabetic kidney disease.

Renal Hemodynamics and Renin-Angiotensin-Aldosterone System Profiles in Patients With Heart Failure

Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF. In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5). The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P < 0.01). In patients with HF, a greater ACE gradient was associated with greater renal vascular resistance (r = 0.42; P 0.007) and greater arteriolar resistances (RA: r = 0.39; P = 0.012; RE: r = 0.48; P = 0.002). Similarly, a greater aldosterone gradient was associated with lower GFR (r = -0.51; P = 0.0007) and renal blood flow (RBF), r = -0.32; P = 0.042) whereas greater PRA gradient with lower ERPF (r = -0.33; P = 0.040), GFR (r = -0.36; P = 0.024), and RBF (r = -0.33; P = 0.036). Dobutamine and nitroprusside treatment decreased the transrenal gradient of ACE (P = 0.012, P < 0.0001, respectively), aldosterone (P = 0.005, P = 0.030) and PRA (P = 0.014, P = 0.002) in patients with HF only. A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile.

Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine

BackgroundType 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail.MethodsPatients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model.ResultsTreatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups.ConclusionsIn patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects.Trial registration: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016

Myogenic Tone in Peripheral Resistance Arteries and Arterioles: The Pressure Is On!

Resistance arteries and downstream arterioles in the peripheral microcirculation contribute substantially to peripheral vascular resistance, control of blood pressure, the distribution of blood flow to and within tissues, capillary pressure, and microvascular fluid exchange. A hall-mark feature of these vessels is myogenic tone. This pressure-induced, steady-state level of vascular smooth muscle activity maintains arteriolar and resistance artery internal diameter at 50–80% of their maximum passive diameter providing these vessels with the ability to dilate, reducing vascular resistance, and increasing blood flow, or constrict to produce the opposite effect. Despite the central importance of resistance artery and arteriolar myogenic tone in cardiovascular physiology and pathophysiology, our understanding of signaling pathways underlying this key microvascular property remains incomplete. This brief review will present our current understanding of the multiple mechanisms that appear to underlie myogenic tone, including the roles played by G-protein-coupled receptors, a variety of ion channels, and several kinases that have been linked to pressure-induced, steady-state activity of vascular smooth muscle cells (VSMCs) in the wall of resistance arteries and arterioles. Emphasis will be placed on the portions of the signaling pathways underlying myogenic tone for which there is lack of consensus in the literature and areas where our understanding is clearly incomplete.

Intraglomerular Dysfunction Predicts Kidney Failure in Type 2 Diabetes.

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (RA) and efferent (RE) arteriolar resistance and intraglomerular pressure (PGLO) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the RA-to-RE ratio and PGLO with ESKD incidence in 237 Pima Indian individuals with T2D who underwent serial measures of GFR (iothalamate) and RPF (p-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants. Of the 237 participants (mean age 42 years, diabetes duration 11 years, and GFR 153 mL/min and median urine albumin-to-creatinine ratio 36 mg/g), 69 progressed to ESKD during a median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing RA-to-RE ratio (HR 4.60, 95% CI 2.55-8.31) or elevated PGLO followed by a rapid decline (HR 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. PGLO (R 2 = 21%, P < 0.0001) and RA-to-RE ratio (R 2 = 15%, P < 0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression. In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.

Association Between Vascular Overload Index and New-Onset Ischemic Stroke in Elderly Population with Hypertension

BackgroundVascular overload index (VOI) is a marker of arterial stiffness and arteriolar resistance, which predicts the increasing risks of cardiovascular and cerebrovascular disease. This study aimed to evaluate the association between VOI and new-onset ischemic stroke in an elderly population with hypertension.MethodsThis retrospective cohort study included 3315 hypertensive participants aged 60 years or more. Ischemic stroke was diagnosed according to cranial computed tomography, magnetic resonance imaging of the brain or cerebrovascular angiography. The calculation of VOI was based on systolic and diastolic blood pressure. VOI was divided by quartiles (<7.88 mmHg, 7.88–16.10 mmHg, 16.10–27.14 mmHg, ≥27.14 mmHg) and evaluated the association with new-onset ischemic stroke by multivariable Cox regression models.ResultsA total of 3315 participants (55.5% female) aged 71.4±7.20 years were included in the analysis. The median follow-up period was 5.5 years, and 206 participants reached the endpoint, new-onset ischemic stroke. With per standard deviation increment in VOI, the risks of new-onset ischemic stroke increased in non-adjusted model (Hazard ratio [HR], 1.11; 95% confidence interval [CI]: 1.03–1.22; p = 0.001), adjusted model (HR, 1.11; 95% CI: 1.04–1.22; p = 0.003) and fully-adjusted model (HR, 1.15; 95% CI: 1.08–1.26; p<0.001), respectively. In multivariate fully adjusted model, the risks of ischemic stroke increased in higher quartiles in comparison to the first quartiles (p for trend <0.001).ConclusionIn an elderly hypertensive population, VOI is significantly associated with the incidence of new-onset ischemic stroke. Elevated VOI is the cardiovascular risk factor and increases the probability of new-onset ischemic stroke.

Age corrected changes in intracranial hemodynamics after carotid endarterectomy.

Transcranial Doppler ultrasound (TCD) is a frequently used method to monitor brain perfusion during and following carotid endarterectomy (CEA). Our aim was to define the normally occurring changes of intracranial hemodynamics in patients undergoing CEA measuring recently developed TCD parameters. A retrospective, single-center cohort study was performed. Patients undergoing CEA were evaluated pre- and postoperatively from day 0 to day 3 measuring middle cerebral artery flow velocity (MCAFV). The following parameters were analyzed: the first systolic peak (Sys1), the second systolic peak (Sys2) and diastolic flow velocity at a fixed time after heartbeat onset (Dias@560). These parameters linearly decrease with age and were, therefore, transformed to Z-scores. Three hundred eighteen patients were included with a mean age of 70.8 years. Most patients were male (71%). Compared to preoperatively, the Z-scores of Sys1 and Sys2 were larger on postoperative day 3: +1.12 standard deviation (SD) or 16.0 cm/s (CI: 0.93 to 1.32; P<0.001) and +0.55 SD or 7.8 cm/s (CI: 0.35 to 0.74; P<0.001), respectively. The Z-score for Dias@560 was smaller than preoperatively: -0.23 SD or -1.9 cm/s (CI: -0.41 to -0.05, P=0.015). Under normal circumstances Sys1 profits more from CEA than Sys2, whilst diastolic flow velocity decreases. This indicates a return to normal arteriolar vascular resistance. Carefully describing normal changes in MCAFV, may in future enable discrimination of abnormalities, such as hyperperfusion syndrome.

Differential responses of resistance arterioles to elevated intraluminal pressure in blacks and whites.

Black Americans have an earlier onset, higher average blood pressure, and higher rates of hypertension-related mortality and morbidity, compared to whites. The racial difference may be related to microvasculature, the major regulatory site of blood pressure. The goal of this study was to compare the response of resistance vessels to high intraluminal pressure between black and white participants. A total of 38 vessels were obtained from human fat samples [21 black, 17 white; mean age 32 ± 12 yr and body mass index (BMI) 26.9 ± 4.9; between-group P ≥ 0.05] and included in this study. Internal diameter was measured in response to the flow induced by various pressure gradients (Δ10, Δ20, Δ40, Δ60, and Δ100 cmH2O), and flow-induced dilation (FID) was calculated before and after high intraluminal pressure (150 cmH2O). Before high intraluminal pressure, FID was not different between blacks and whites (P = 0.112). After exposure to high intraluminal pressure, FID was reduced at every pressure gradient in vessels from blacks (P < 0.001), whereas FID did not change in white participants except at Δ100 cmH2O. When incubated with the hydrogen peroxide (H2O2) scavenger polyethylene glycol-catalase (PEG-catalase), the FID response in vessels from black, but not white, individuals was significantly reduced and the magnitude was higher at normal pressure relative to high pressure. Our findings suggest that the vessels from self-identified black individuals are more susceptible to microvascular dysfunction following transient periods of high intraluminal pressure compared to whites and show greater dependence on H2O2 as a main contributor to FID at normal pressures.NEW & NOTEWORTHY Microvascular function regulates blood pressure and may contribute to racial differences in the incidence and prevalence of hypertension and other cardiovascular diseases. Here, we show that using an ex vivo model of resistance arterioles isolated from human gluteal fat tissue, flow-induced dilation is not different between black and white participants. However, when exposed to transient increases in intraluminal pressure, the flow-induced dilation in resistance arterioles from black participants demonstrated greater reductions relative to their white counterparts, indicating a higher sensitivity to pressure change in the microvasculature.

Impact of Nrf2 Deficiency on Potassium Channel Function in Rat Soleus Arterioles

Introduction Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its response element are essential in regulation of cellular oxidative stress. Nrf2 expression has also been linked to potassium (K+) channel function. We hypothesized that vasoactive responses that are enhanced by exercise training and also modulated by K+channel function would be impaired in arterioles from skeletal muscle of rats in which Nrf2 (Nrf2 KO) is deleted. Methods Exercise training was performed in male wildtype (WT) Sprague-Dawley rats, and their littermates lacking the Nrf2 gene (Nrf2 KO). Rats were exercise trained using a mixed moderate and high-intensity interval treadmill program for 10-12 weeks. After exercise training, soleus resistance arterioles were isolated and cannulated for the assessment of vascular reactivity. Vasodilatory responses to low concentrations of KCl [10 and 20mM} were assessed. Vasoconstrictor responses to higher concentrations of KCl [30–100mM] and myogenic responses to increasing intraluminal pressure (pressure 0cm H2O – 130cm H2O) were also assessed. The contribution of inward rectifying K+ channels (Kir) to vasodilation during low concentrations of KCl was assessed by treatment with barium chloride (BaCl2, 100mM). Results Myogenic responsiveness was reduced in resistance arterioles from soleus muscle of Nrf2 KO rats as compared to those from WT rats (p<0.01). Vasodilatory responses to low concentrations of KCl were also reduced in resistance arterioles from soleus muscle of Nrf2 KO rats as compared to those from WT rats (p<0.05); however, there were no differences in vasoconstrictor responses to higher concentrations of KCL between arterioles from WT and KO rats. Inhibition of Kir channels with BaCl2 eliminated the differences in vasodilatory responses to low concentrations KCl between genotypes. Conclusion These data indicate that vasodilatory responses to low concentrations of KCl and myogenic responsiveness, which may be modulated by Kir activity, are impaired in soleus muscle arterioles from Nrf2KO rats. The finding that blockade of Kir eliminated genotypic differences in vasodilatory responsiveness to low concentrations of KCl suggests that altered redox homeostasis and/or direct transcriptional regulation by Nrf2 impacts Kir function and related vascular tone.

Sequential Afferent‐Targeted and Total Renal Denervation and Impact on Regulation of Arterial Pressure, Glomerular Filtration, and Sodium Handling in Sprague Dawley Male Rats

Renal denervation (RDNx) is often reported to chronically decrease mean arterial pressure (MAP) in conscious, unchallenged Sprague Dawley (SD) rats, but has no effect of salt-sensitivity of MAP. Although these findings indicate an important role of renal nerves in long-term regulation of MAP under unchallenged conditions, the individual contributions of sympathetic and afferent renal nerves in MAP and renal homeostasis remain unclear. The present study was conducted to test the hypothesis that efferent (sympathetic) renal nerves are the primary contributors both MAP and renal function responses to RDNx in normotensive Sprague Dawley rats. To test this hypothesis, 12 adult male Sprague Dawley rats (300-325g) were subjected to sequential denervation procedures to ablate afferent and efferent nerves separately by subjecting rats to the following surgical sequence: Sham, then afferent-targeted RDNx (A-RDNx), then complete (T)-RDNx. A-RDNx was achieved by periaxonal application of 33mM capsaicin, and T-RDNx was achieved by surgical dissection followed by perivascular application of 10%(v/v) phenol in ethanol. One week was permitted for recovery from surgery before cardiovascular and renal measurements were collected. 24-hour mean arterial pressure (MAP) was recorded by implanted telemetry. Glomerular filtration rate (GFR) was assessed in unrestrained, conscious rats by acute FITC-sinistrin clearance. Renal excretory function was assessed by measuring the urinary sodium excretion response to an acute saline challenge (150mM PBS, 10% bodyweight, i.p.) over four hours. Data was analyzed by one-way repeated-measures ANOVA with Bonferroni post-hoc test (α=0.05). Data presented as mean±SEM. Sham surgery had no significant effect on MAP, GFR or Na Clearance. Following A-RDN treatment, MAP increased ∆5.4±0.9mmHg; (p<0.01); however, no significant changes in GFR or the excretory response to acute sodium load were detected. In contrast, following T-RDN, MAP was decreased 4.9±0.9mmHg (p<.01) following T-RDN vs. compared to A-RDN. Regarding renal function, GFR increased (1.20±0.05 vs. 1.06±0.04 mL/min/100gBWT; p<.01) as did the sodium excretory response to a saline load (28.2±2.3 vs. 18.6±1.0% Na load excreted per 4 hours; p<.01). Together, these data partly support our hypothesis and solidify the role for renal efferent (sympathetic) nerves contribute to long-term regulation of MAP, GFR, and sodium handling in the conscious SD rat. Contrary to our hypothesis, A-RDNx resulted in a small, yet significant, increase in MAP; however, no impact on renal function was observed. We speculate that the increased GFR and decrease in MAP are likely due to a decrease in renal vascular resistance and dilation of the renal afferent arterioles. Moreover, renal afferent nerves appear to contribute to maintenance of MAP in Sprague Dawley rats, which we speculate is through a tonic sympatho-inhibition due to the increase MAP following A-RDNx. These data highlight the important, yet differential roles of efferent and afferent renal nerves, and further studies are underway to further test this hypothesis.

Investigation of the Dual Functional Role of Ceramide in the Human Microcirculation

Increased plasma ceramide levels and microvascular dysfunction are both independent risk factors for major adverse cardiac events (MACE). We have previously shown that chronic exposure to exogenous ceramide promotes microvascular endothelial dysfunction, defined as hydrogen peroxide (H2O2)-mediated flow-induced dilation (FID) as opposed to dilation due to formation and release of endothelial nitric oxide (NO). Interestingly, ceramide and its metabolites (e.g. sphingosine-1-phosphate; S1P) have also been shown to stimulate production of NO. Our previous studies indicate that activation of the ceramide-producing enzyme neutral sphingomyelinase (NSmase) in necessary for NO-mediated FID. We therefore hypothesized that formation of S1P is responsible for cellular increases in NO from both acute exogenous administration as well as endogenous formation of ceramide from shear. Human resistance arterioles (100-200µm) were dissected from adipose tissue collected from healthy patients and were prepared for videomicroscopy. Increasing doses of exogenous C2 ceramide (10-9 to 10-5 M) were administered in the absence or presence of the NO scavenger c-PTIO (1µM) and a sphingosine kinase inhibitor (SpKi, 5µM). We observed a dose-response increase in arteriolar dilation from ceramide (46.9%±10.3 of maximal dilator capacity±SEM, n=3) that was impaired by c-PTIO (15%±6.0, n=3). Ceramide-induced dilation was also decreased in the presence of the SpKi (20.8%±4.0, n=3). To examine the role of S1P formation in NO-mediated FID, SpKi was administered to healthy arterioles (5µM, 30 min) prior to initiating flow (pressure gradient 5-100cm H2O) and a dramatic decrease in overall dilation was observed (7.7%±8.0, n=3). Together these findings suggest that NO generated from ceramide is primarily due to the formation of S1P, a process also critical to maintain FID in arterioles from healthy individuals.

Mechanisms of Increased Infarct Volume in a Rat Model of Ischemic Stroke: Implications for Leptomeningeal Collateral Artery Function and Beta Blocker Therapy

Beta blockers are associated with higher ischemic stroke risk than other anti-hypertensive medications, but the mechanisms of this increased risk remain unknown. We previously reported β1-adrenoceptor-mediated dilation of rat cerebral arteries that is inhibited by the clinical beta blocker metoprolol. The present study examines the effect of β1-adrenoceptor blockade on the leptomeningeal collateral arteries (LCAs). LCAs connect distal branches of middle cerebral arteries to those of posterior and anterior cerebral arteries and provide a path for protective retrograde blood flow to the ischemic tissue during stroke. Pre-treatment with metoprolol increased cerebral infarct volume in Sprague-Dawley rats after middle cerebral artery occlusion (MCAO). Recovery of cortical blood flow after acute MCAO estimated by laser speckle contrast imaging was significantly blunted by topical suffusion of CGP20712, a β1-adrenoceptor antagonist. Isolated LCAs constricted significantly to the mixed adrenoreceptor agonist norepinephrine after pre-treatment with CGP20712 during ex vivo pressure myography. The in vivo diameter response of LCAs or small pial resistance arterioles following MCAO, however, was not significantly altered by topical suffusion of CGP20712. More research is required to fully characterize the effects of beta blockers on cerebral arteries during ischemic stroke.

The Calcium Signaling Mechanisms in Arterial Smooth Muscle and Endothelial Cells.

The contractile state of resistance arteries and arterioles is a crucial determinant of blood pressure and blood flow. Physiological regulation of arterial contractility requires constant communication between endothelial and smooth muscle cells. Various Ca2+ signals and Ca2+ -sensitive targets ensure dynamic control of intercellular communications in the vascular wall. The functional effect of a Ca2+ signal on arterial contractility depends on the type of Ca2+ -sensitive target engaged by that signal. Recent studies using advanced imaging methods have identified the spatiotemporal signatures of individual Ca2+ signals that control arterial and arteriolar contractility. Broadly speaking, intracellular Ca2+ is increased by ion channels and transporters on the plasma membrane and endoplasmic reticular membrane. Physiological roles for many vascular Ca2+ signals have already been confirmed, while further investigation is needed for other Ca2+ signals. This article focuses on endothelial and smooth muscle Ca2+ signaling mechanisms in resistance arteries and arterioles. We discuss the Ca2+ entry pathways at the plasma membrane, Ca2+ release signals from the intracellular stores, the functional and physiological relevance of Ca2+ signals, and their regulatory mechanisms. Finally, we describe the contribution of abnormal endothelial and smooth muscle Ca2+ signals to the pathogenesis of vascular disorders. © 2021 American Physiological Society. Compr Physiol 11:1831-1869, 2021.

Discoveries from the study of longstanding type 1 diabetes.

Award programmes that acknowledge the remarkable accomplishments of long-term survivors with type 1 diabetes have naturally evolved into research programmes to determine the factors associated with survivorship and resistance to chronic complications. In this review, we present an overview of the methodological sources of selection bias inherent in survivorship research (selection of those with early-onset diabetes, incidence-prevalence bias and bias from losses to follow-up in cohort studies) and the breadth and depth of literature focusing on this special study population. We focus on the learnings from the study of longstanding type 1 diabetes on discoveries about the natural history of insulin production loss and microvascular complications, and mechanisms associated with them that may in future offer therapeutic targets. We detail descriptive findings about the prevalence of preserved insulin production and resistance to complications, and the putative mechanisms associated with such resistance. To date, findings imply that the following mechanisms exist: strategies to maintain or recover beta cells and their function; activation of specific glycolytic enzymes such as pyruvate kinase M2; modification of AGE production and processing; novel mechanisms for modification of renin-angiotensin-aldosterone system activation, in particular those that may normalise afferent rather than efferent renal arteriolar resistance; and activation and modification of processes such as retinol binding and DNA damage checkpoint proteins. Among the many clinical and public health insights, research into this special study population has identified putative mechanisms that may in future serve as therapeutic targets, knowledge that likely could not have been gained without studying long-term survivors.

Hypertension preserves the magnitude of microvascular flow-mediated dilation following transient elevation in intraluminal pressure.

ObjectiveThe objective of this study was to measure flow‐mediated dilation (FMD) prior to and following transient increases in intraluminal pressure (IILP) in resistance arterioles isolated from subjects with and without coronary artery disease (CAD) (CAD and non‐CAD) and non‐CAD subjects with hypertension.MethodsArterioles were isolated from discarded surgical tissues (adipose and atrial) from patients without coronary artery disease (non‐CAD; ≤1 risk factor, excluding hypertension), with CAD, and non‐CAD patients with hypertension (hypertension as the only risk factor). To simulate transient hypertension, increased IILP was generated (150 mmHg, 30 min) by gravity. Arterioles were constricted with endothelin‐1, followed by FMD and endothelial‐independent dilation prior to and following exposure to IILP.ResultsIILP reduced FMD in non‐CAD and CAD arterioles relative to pre‐IILP (p <.05 at 100 cmH2O). In contrast, arterioles from non‐CAD hypertensive subjects exhibited no reduction in maximal FMD following IILP (p = .84 at 100 cmH2O). FMD was reduced by L‐NAME prior to IILP in non‐CAD hypertensive patients (p < .05 at 100 cmH2O); however, following IILP, FMD was inhibited by peg‐cat (p < .05 at 100 cmH2O), indicating a switch from NO to H2O2 as the mechanism of dilation.ConclusionsAcute exposure (30 min) to IILP (150 mmHg) attenuates the magnitude of FMD in non‐CAD and CAD resistance arterioles. The presence of clinically diagnosed hypertension in non‐CAD resistance arterioles preserves the magnitude of FMD following IILP as a result of a compensatory switch from NO to H2O2 as the mechanism of dilation.

Association of Noise Annoyance with Measured Renal Hemodynamic Changes

Background: Chronic mental stress is recognized as a modifiable risk factor for cardiovascular disease. The aim of this study was to demonstrate that noise annoyance-induced stress is associated with changes in renal hemodynamics. Methods: Renal hemodynamic parameters were measured using steady-state input clearance with infusion of para-aminohippuric acid and inulin in individuals with normal, high normal, and elevated blood pressure. All individuals ranked subjective annoyance due to noise in everyday life on a 7-grade Likert scale. The median of all rankings was used as a cutoff point to divide the group into noise-annoyed and non-noise-annoyed individuals. Different renal hemodynamic parameters were calculated based on the Gomez equation. Results: Noise-annoyed individuals (n = 58) showed lower renal plasma flow (599 ± 106 vs. 663 ± 124 mL/min, p = 0.009), lower renal blood flow (1,068 ± 203 vs. 1,172 ± 225 mL/min, p = 0.047), higher filtration fraction (22.7 ± 3.3 vs. 21.3 ± 3.0, p = 0.012), higher renal vascular resistance (88.9 ± 25.6 vs. 75.8 ± 22.9 mm Hg/[mL/min], p = 0.002), and higher resistance of afferent arteriole (2,439.5 ± 1,253.4 vs. 1,849.9 ± 1,242.0 dyn s⁻¹ cm⁻⁵, p = 0.001) compared to non-noise-annoyed individuals (n = 55). There was no difference in measured glomerular filtration rate (133 ± 11.8 vs. 138 ± 15 mL/min, p = 0.181), resistance of efferent arteriole (2,419.4 ± 472.2 vs. 2,245.8 ± 370.3 dyn s⁻¹ cm⁻⁵, p = 0.060), and intraglomerular pressure (64.0 ± 3.1 vs. 64.6 ± 3.5 mm Hg, p = 0.298) between the groups. After adjusting for age, renal plasma flow, renal blood flow, and renal vascular resistance remained significantly different between the groups, with a trend in increased afferent arteriolar resistance and filtration fraction. Conclusion: In this study, noise annoyance was associated with reduced renal perfusion attributed to increased renal vascular resistance predominantly at the afferent site. Long-term consequences of this renal hemodynamic pattern due to noise annoyance need to be investigated.

Extracellular matrix degradation pathways and fatty acid metabolism regulate distinct pulmonary vascular cell types in pulmonary arterial hypertension.

Pulmonary arterial hypertension describes a group of diseases characterised by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles. Left untreated, patients die from right heart failure. Pulmonary vascular remodelling involves all cell types but to date the precise roles of the different cells is unknown. This study investigated differences in basal gene expression between pulmonary arterial hypertension and controls using both human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells. Human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells from pulmonary arterial hypertension patients and controls were cultured to confluence, harvested and RNA extracted. Whole genome sequencing was performed and after transcript quantification and normalisation, we examined differentially expressed genes and applied gene set enrichment analysis to the differentially expressed genes to identify putative activated pathways. Human pulmonary microvascular endothelial cells displayed 1008 significant (p ≤ 0.0001) differentially expressed genes in pulmonary arterial hypertension samples compared to controls. In human pulmonary artery smooth muscle cells, there were 229 significant (p ≤ 0.0001) differentially expressed genes between pulmonary arterial hypertension and controls. Pathway analysis revealed distinctive differences: human pulmonary microvascular endothelial cells display down-regulation of extracellular matrix organisation, collagen formation and biosynthesis, focal- and cell-adhesion molecules suggesting severe endothelial barrier dysfunction and vascular permeability in pulmonary arterial hypertension pathogenesis. In contrast, pathways in human pulmonary artery smooth muscle cells were mainly up-regulated, including those for fatty acid metabolism, biosynthesis of unsaturated fatty acids, cell–cell and adherens junction interactions suggesting a more energy-driven proliferative phenotype. This suggests that the two cell types play different mechanistic roles in pulmonary arterial hypertension pathogenesis and further studies are required to fully elucidate the role each plays and the interactions between these cell types in vascular remodelling in disease progression.

Six-Week Exercise Training With Dietary Restriction Improves Central Hemodynamics Associated With Altered Gut Microbiota in Adolescents With Obesity.

PurposeObesity in children and in adolescents can lead to adult cardiovascular diseases, and the gut microbiota plays a crucial role in obesity pathophysiology. Exercise and diet interventions are typical approaches to improve physical condition and to alter the gut microbiota in individuals with obesity. However, whether central hemodynamic parameters including subendocardial viability ratio, the augmentation index standardized to a heart rate of 75/min (AIx75), resting heart rate, and blood pressure, correlate with gut microbiota changes associated with exercise and diet is unclear.MethodsAdolescents (n = 24, 12.88 ± 0.41 years) with obesity completed our 6-week program of endurance and strength exercises along with dietary restriction. Blood and fecal samples were collected, and physical parameters were measured before and 24 h after the last session of the intervention program. Pulse wave analysis using applanation tonometry provided the subendocardial viability ratio, a surrogate measure of microvascular myocardial perfusion, and AIx75, a measure of arterial stiffness and peripheral arteriolar resistance. Correlation analysis detected any associations of anthropometric or central hemodynamic parameters with gut microbiome composition.ResultsExercise and diet interventions significantly reduced body weight, body mass index, body fat, and waist-to-hip ratio, and lowered levels of fasting blood glucose, serum triglycerides, and high-density lipoprotein cholesterol. AIx75 and resting heart rate were also significantly reduced after the intervention without changes to systolic or diastolic blood pressure. The ratio of intestinal microbiota Firmicutes to Bacteroidetes displayed a marked increase after intervention. Interventional changes in gut microbiota members were significantly associated with anthropometric and metabolic parameters. Microbial changes were also significantly correlated with central hemodynamic parameters, including subendocardial viability ratio, AIx75, and resting heart rate.ConclusionExercise and diet interventions significantly improved measures of central hemodynamics, including subendocardial viability ratio, AIx75, and resting heart rate, which were correlated with altered gut microbiota in adolescents with obesity. Our findings shed light on the effects and mechanisms underlying exercise and diet interventions on obesity and suggest this approach for treating patients with both cardiovascular disease and obesity.

Critical Interaction Between Telomerase and Autophagy in Mediating Flow-Induced Human Arteriolar Vasodilation.

Coronary artery disease (CAD) is associated with a compensatory switch in mechanism of flow-mediated dilation (FMD) from nitric oxide (NO) to H2O2. The underlying mechanism responsible for the pathological shift is not well understood, and recent reports directly implicate telomerase and indirectly support a role for autophagy. We hypothesize that autophagy is critical for shear stress-induced release of NO and is a crucial component of for the pathway by which telomerase regulates FMD. Approach and Results: Human left ventricular, atrial, and adipose resistance arterioles were collected for videomicroscopy and immunoblotting. FMD and autophagic flux were measured in arterioles treated with autophagy modulators alone, and in tandem with telomerase-activity modulators. LC3B II/I was higher in left ventricular tissue from patients with CAD compared with non-CAD (2.8±0.2 versus 1.0±0.2-fold change; P<0.05), although p62 was similar between groups. Shear stress increased Lysotracker fluorescence in non-CAD arterioles, with no effect in CAD arterioles. Inhibition of autophagy in non-CAD arterioles induced a switch from NO to H2O2, while activation of autophagy restored NO-mediated vasodilation in CAD arterioles. In the presence of an autophagy activator, telomerase inhibitor prevented the expected switch (Control: 82±4%; NG-Nitro-l-arginine methyl ester: 36±5%; polyethylene glycol catalase: 80±3). Telomerase activation was unable to restore NO-mediated FMD in the presence of autophagy inhibition in CAD arterioles (control: 72±7%; NG-Nitro-l-arginine methyl ester: 79±7%; polyethylene glycol catalase: 38±9%). We provide novel evidence that autophagy is responsible for the pathological switch in dilator mechanism in CAD arterioles, demonstrating that autophagy acts downstream of telomerase as a common denominator in determining the mechanism of FMD.