Effects of Renal Denervation on the Enhanced Renal Vascular Responsiveness to Angiotensin II in High-Output Heart Failure: Angiotensin II Receptor Binding Assessment and Functional Studies in Ren-2 Transgenic Hypertensive Rats

Detailed mechanism(s) of the beneficial effects of renal denervation (RDN) on the course of heart failure (HF) remain unclear. The study aimed to evaluate renal vascular responsiveness to angiotensin II (ANG II) and to characterize ANG II type 1 (AT1) and type 2 (AT2) receptors in the kidney of Ren-2 transgenic rats (TGR), a model of ANG II-dependent hypertension. HF was induced by volume overload using aorto-caval fistula (ACF). The studies were performed two weeks after RDN (three weeks after the creation of ACF), i.e., when non-denervated ACF TGR enter the decompensation phase of HF whereas those after RDN are still in the compensation phase. We found that ACF TGR showed lower renal blood flow (RBF) and its exaggerated response to intrarenal ANG II (8 ng); RDN further augmented this responsiveness. We found that all ANG II receptors in the kidney cortex were of the AT1 subtype. ANG II receptor binding characteristics in the renal cortex did not significantly differ between experimental groups, hence AT1 alterations are not responsible for renal vascular hyperresponsiveness to ANG II in ACF TGR, denervated or not. In conclusion, maintained renal AT1 receptor binding combined with elevated ANG II levels and renal vascular hyperresponsiveness to ANG II in ACF TGR influence renal hemodynamics and tubular reabsorption and lead to renal dysfunction in the high-output HF model. Since RDN did not attenuate the RBF decrease and enhanced renal vascular responsiveness to ANG II, the beneficial actions of RDN on HF-related mortality are probably not dominantly mediated by renal mechanism(s).

Inhalation of particulate matter containing free radicals leads to decreased vascular responsiveness associated with an altered pulmonary function

Particulate matter (PM) resulting from the combustion of organic matter is known to contribute to cardiopulmonary disease. Despite hypotheses that cardiovascular dysfunction occurring after PM exposures is secondary to lung or systemic inflammation, these studies investigating exposures to PM-containing environmentally persistent free radicals (EPFRs) demonstrate that cardiovascular dysfunction precedes pulmonary inflammation. The cardiopulmonary health consequences of EPFRs have yet to be thoroughly evaluated, especially in healthy, adult mice. Our data suggest the vasculature as a direct target of PM exposure, and our studies aimed to elucidate the mechanisms contributing to EPFR-induced vascular dysfunction.

What Is the Role of Steroids for Septic Shock in 2021?

Corticosteroids have been used for decades in the adjunctive treatment of severe infections in intensive care. The most frequent scenario in intensive care is in septic shock, where low doses of glucocorticoids appear to restore vascular responsiveness to norepinephrine. There is a strong body of evidence suggesting that hydrocortisone reduces time on vasopressor, and may modulate the immune response. In this review, we explore the current evidence supporting the use of corticosteroids in septic shock, its benefits, and potential harms. In addition to landmark clinical trials, we will also describe new frontiers for the use of corticosteroids in septic shock which should be explored in future studies.

Renal Sympathetic Denervation Attenuates Congestive Heart Failure in Angiotensin II-Dependent Hypertension: Studies with Ren-2 Transgenic Hypertensive Rats with Aortocaval Fistula

<b><i>Objective:</i></b> We examined if renal denervation (RDN) attenuates the progression of aortocaval fistula (ACF)-induced heart failure or improves renal hemodynamics in Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension. <b><i>Methods:</i></b> Bilateral RDN was performed 1 week after creation of ACF. The animals studied were ACF TGR and sham-operated controls, and both groups were subjected to RDN or sham denervation. In separate groups, renal artery blood flow (RBF) responses were determined to intrarenal ANG II (2 and 8 ng), norepinephrine (NE) (20 and 40 ng) and acetylcholine (Ach) (10 and 40 ng) 3 weeks after ACF creation. <b><i>Results:</i></b> In nondenervated ACF TGR, the final survival rate was 10 versus 50% in RDN rats. RBF was significantly lower in ACF TGR than in sham-operated TGR (6.2 ± 0.3 vs. 9.7 ± 0.5 mL min⁻¹ g⁻¹, <i>p</i> &#x3c; 0.05), the levels unaffected by RDN. Both doses of ANG II decreased RBF more in ACF TGR than in sham-operated TGR (−19 ± 3 vs. −9 ± 2% and −47 ± 3 vs. −22 ± 2%, <i>p</i> &#x3c; 0.05 in both cases). RDN did not alter RBF responses to the lower dose, but increased it to the higher dose of ANG II in sham-operated as well as in ACF TGR. NE comparably decreased RBF in ACF TGR and sham-operated TGR, and RDN increased RBF responsiveness. Intrarenal Ach increased RBF significantly more in ACF TGR than in sham-operated TGR (29 ± 3 vs. 17 ± 3%, <i>p</i> &#x3c; 0.05), the changes unaffected by RDN. ACF creation induced marked bilateral cardiac hypertrophy and lung congestion, both attenuated by RDN. In sham-operated but not in ACF TGR, RDN significantly decreased mean arterial pressure. <b><i>Conclusion:</i></b> The results show that RDN significantly improved survival rate in ACF TGR; however, this beneficial effect was not associated with improvement of reduced RBF or with attenuation of exaggerated renal vascular responsiveness to ANG II.

Programming of Cardiovascular Dysfunction by Postnatal Overfeeding in Rodents

Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short- and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming.

Spinal cord injury and vascular function: Evidence from diameter matched vessels

The effect of a spinal cord injury (SCI) on vascular function has been clouded by both the physiological and mathematical bias of assessing vasodilation in arteries with differing diameters both above and below the lesion and when comparing with healthy, non-disabled controls (CTRL). Thus, we measured vascular function, with flow mediated vasodilation (FMD), in 10 SCI and 10 CTRL with all arteries matched for diameter (≈0.5cm): brachial (BA, arm, functional-limb in both groups) and popliteal artery (PA, leg, disused-limb in SCI, functional-limb in CTRL). PA %FMD was significantly attenuated in SCI (5.6±0.6%) compared to CTRL (8.4±1.3%), with no difference in the BA (SCI: 8.6±0.9%; CTRL: 8.7±0.7%). However, unlike the arm, where muscle mass was preserved, the legs of the SCI were significantly smaller than CTRL (~70%). Thus, reactive hyperemia (RH), which is heavily dependent upon the volume of muscle occluded, in the PA was attenuated in the SCI (144±22ml) compared to CTRL (258±16ml), but not different in the BA. Consequently, shear rate was significantly diminished in the PA of the SCI, such that %FMD/shear rate (vascular responsiveness) was actually greater in the SCI (1.5±0.1%・s-1) than CTRL (1.2±0.1%・s-1). Of note, this was significantly greater than both their own BA (0.9±0.1%・s-1) and that of the CTRL (0.9±0.1%・s-1). Therefore, examining vessels of similar size, this study reveals normal vascular function above the lesion and vascular dysfunction below the lesion. However, below the lesion there was, actually, evidence of increased vascular responsiveness in this population.

Abstract 15823: Diminished Vasoresponsiveness in Patients With Heart Failure

Introduction: Vasoplegia is a severe complication after cardiac surgery and is associated with impaired clinical outcome. Pre-operative heart failure (HF) is considered an independent predictor of post-operative vasoplegia. We hypothesize that HF patients are more susceptible to vasoplegia due to altered vascular responsiveness. In this study, vasoresponsiveness in patients undergoing cardiac surgery for HF is investigated. Methods: A prospective, observational study was conducted at Leiden University Medical Center. We included patients with HF (N=18) and without HF (N=18) who underwent cardiac surgery on cardiopulmonary bypass. Vasoresponsiveness was assessed at 4 different timepoints: 1) before induction, 2) after induction, 3) after cessation of cardiopulmonary bypass and 4) on the first postoperative day. The vascular response was recorded as change in systemic vascular resistance (SVR) after the administration of phenylephrine (bolus 2 μg/kg). Results: Thirty-six patients were included [67 (61-71) years, 78% male]. Vascular responsiveness was significantly attenuated in patients with HF compared to controls. The response to phenylephrine was already diminished at baseline in HF patients and was almost abolished after cessation of cardiopulmonary bypass (Figure). Roughly the same pattern of vasoresponsiveness was found when excluding patients that received norepinephrine. Moreover, HF patients required a significantly higher amount of noradrenaline [169.80 (IQR 14.77-318.97) ug/kg] compared to controls [3.61 (IQR 0-41.60) ug/kg] to maintain similar SVR during the first 24h postoperatively. Conclusions: The vascular responsiveness is altered in patients with HF and this might explain the higher prevalence of vasoplegia in this patient population.