Infusion Of Sodium Nitroprusside Research Articles

MITRACLIP TREATMENT FOR CARDIOGENIC SHOCK DUE TO ACUTE MITRAL REGURGITATION IN A PATIENT WITH POSTINFARCTION PAPILLARY MUSCLE RUPTURE

Abstract A 85–year–old woman presented to ED with worsening dyspnea for 24 hours; no other related symptom. Her medical history included hypertension, dyslipidemia, type 2 DM and surgical coronary revascularization 13 years before for multiple critical coronary artery disease (LIMA to LAD and sequential SVG to PDA and OM branch). The ECG promptly revealed a subacute infero–lateral STEMI. Transthoracic echocardiography (TTE) showed inferior and postero–lateral wall akinesia with severely reduced left ventricle ejection fraction (LVEF), mildly reduced right ventricle systolic function and severe mitral regurgitation (MR) due to posterior papillary muscle (PM) rupture (Fig.1). Clinical scenario was complicated by pulmonary edema and cardiogenic shock treated with diuretics and sodium nitroprusside infusion, non–invasive ventilation and IABP insertion. Urgent coronary angiography revealed a thrombotic occlusion of the venous graft for OM branch. Surgical correction was excluded due to hemodynamic instability. Graft occlusion was treated with manual thromboaspiration, balloon dilatations and abciximab infusion. After an initial stabilization, transesophageal echocardiography (TEE) was performed confirming severe MR resulting from rupture of one head of a bifid posterior PM (red arrows, Fig.1) and prolapse of the anterior leaflet combined with restrictive systolic movement of the posterior leaflet due to wall motion abnormalities. 3 days later a transcatheter mitral valve edge–to–edge repair (MTEER) was performed using a MitraClip device (1 XTR clip and 1 NTR clip, Fig.2). TEE with 3D and TrueVue vision confirmed the correct placement of clips (Fig.3), a mild–to–moderate residual MR, absence of significant transmitral gradient and a mildly reduced LVEF. No clinical events were reported during recovery; patient was discharged after 2 weeks. Conclusion MTEER is an established therapy for reducing degenerative and functional MR. Little data is available on its use in the setting of PM rupture. This rare complication of AMI carries a mortality rate of 80% during the first week without surgical correction but more than half of patients are excluded because of prohibitive operative risk. TEER may be an alternative for these patients. In this case report we described the utility of MTEER in the setting of cardiogenic shock secondary to acute ischemic MR with papillary muscle partial rupture. This procedure can be useful with acceptable safety and procedural success.

Divergent Vasodilator Mechanisms to Endothelial-Dependent Agonists with Advancing Age

Introduction: Microvascular function is maintained by a number of vasodilating factors, with nitric oxide (NO) and endothelial hyperpolarizing factors (EDHF) predominating. Advancing age is an independent risk factor in the development of cardiovascular disease, and NO-mediated vasodilation declines, or is unchanged, depending on the vascular bed examined, number of cardiovascular risk factors, or specific endothelial-dependent agonist used. Mechanisms contributing to cutaneous microvascular dysfunction with age have been attributed largely to reductions in NO signaling, but the role of EDHF-mediated dilation, particularly to acetylcholine (ACh), remains unclear. The purpose of this study was to determine the endothelial mechanisms contributing to age-induced cutaneous microvascular function and compare cutaneous microvascular function responses to those from isolated adipose arteriole preparations. We hypothesized that cutaneous microvascular vasodilation to ACh in older adults will be mediated primarily by EDHFs relative to young adults and that isolated adipose arteriole preparations will corroborate these findings. Methods: Four intradermal microdialysis fibers were placed in the skin of the ventral forearm of 9 young (3F/6M; 29±7 yrs) and 3 older adults (3F/0M; 59±11 yrs) for infusion of Ringer’s solution; L-NAME (10 mM), an NO synthase inhibitor; tetraethylammonium chloride (TEA; 50 mM), a non-specific K+ channel inhibitor; and a combination of L-NAME and TEA. Laser Doppler flowmetry and brachial mean arterial pressure were measured during infusion of ACh (10 mM and 100 mM) and in response to local heating to 39°C. Maximal vasodilation was assessed with heating to 43°C and infusion of sodium nitroprusside (28 mM). Adipose resistance arterioles for pressure myography were obtained from a gluteal biopsy or from surgical discard tissue, which were pre-constricted (ET-1), and ACh responses (10−9–10−4 M) were assessed in the presence of the above inhibitors. Cutaneous vascular conductance (CVC) and isolated arteriole responses are presented as % maximum vasodilation. Results: In response to local heating in young adults, L-NAME reduced vasodilator magnitude (Ringers 69.0±18.1% vs. L-NAME 30.3±12.1%; p< 0.05) while TEA did not have any effect (69±18% vs. 49±28%; p=0.20). Combined L-NAME and TEA reduced vasodilation (69±18% vs. 19±6%; p<0.05). Conversely, vasodilator magnitude to ACh was not different across the Ringers, L-NAME, or TEA sites (p=0.93-0.94), while combined inhibition of NOS and K+ channels with L-NAME and TEA, respectively, reduced vasodilator responsiveness (p<0.05). In isolated resistance arterioles, there were no differences in %max dilation to ACh across inhibitor sites (p=0.19) in young adults. In older adults, neither independent nor combined inhibition of NOS or K+ channels impacted vasodilator responses to local heating, while vasodilator magnitude to ACh was most impacted by combined inhibition with L-NAME and TEA (83±14% vs. 32±15%; p<0.05). Conclusion: Our data demonstrate that vasodilator plasticity in response to local heating is divergent with advancing age, relying on non-NO or K+ mechanisms relative to young adults, while NO and K+ mechanisms are suffcient to maintain ACh-mediated vasodilation. These findings further support the concept of diversity in vasodilator mechanisms within the microvasculature. NHLBI K99-HL161491 (WEH), K08-HL150340 (JJM), R01-HL160752 (JKF), R01-HL133029 (AB), and NICHD R01-HD099340 (MJD). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

What Is the Role of the Carotid Baroreflex in Exaggerating the Exercise Pressor Reflex in Male UCD-Type 2 Diabetes Mellitus Rats?

Previous studies have shown that exercise evokes an excessive increase in blood pressure in individuals with type 2 diabetes mellitus (T2DM), which is mediated, in part, by an altered exercise pressor reflex. Importantly, in healthy individuals the arterial baroreflex modulates the pressor response to exercise; however, the effects of T2DM on this modulatory effect of the baroreflex remain unclear. Therefore, the purpose of this study was to characterize the arterial baroreflex function in T2DM rats and to determine whether the carotid baroreflex plays a role in exaggerating the exercise pressor reflex. We hypothesized that T2DM rats would present a baroreflex dysfunction that likely contributes to the exaggerated pressor response during muscle contraction. Experiments were performed on adult (8 ± 2 months old), male University of California Davis (UCD)-T2DM ( n=7; body weight: 640 ± 43 g) and healthy Sprague-Dawley rats ( n=3; body weight: 485 ± 29 g). Female rats were not included in this study because they become diabetic when they are much older (>10 months old). Cardiac baroreflex function was characterized in anesthetized T2DM and healthy rats using the modified Oxford technique, which involved sequential bolus infusions of sodium nitroprusside (10 μg/kg) and phenylephrine (10 μg/kg) to induce blood pressure decreases and increases, respectively. Overall cardiac baroreflex gain (i.e., slope of the relationship between systolic blood pressure and R-R interval) was calculated using logistic regression, while gains to blood pressure falling and rising were calculated separately using piecewise and linear regression. The role of the carotid baroreflex in exaggerating the exercise pressor reflex was tested by statically contracting the hindlimb muscles for 30 s after surgical sinoaortic denervation (SAD) in decerebrated T2DM ( n=1; body weight: 555 g) and healthy ( n=1; body weight: 519 g) rats. Carotid barointact T2DM ( n=8; body weight: 521 ± 38 g) and healthy rats ( n=8; body weight: 482 ± 56 g) were included as controls. The pressor responses were calculated as a change (Δ) in peak mean arterial pressure during 30 s contraction relative to baseline. Data are presented as mean ± SD. T2DM rats presented with lower overall baroreflex sensitivity (T2DM: 0.07 ± 0.02 ms/mmHg, healthy: 0.61 ± 0.81 ms/mmHg, p=0.044), as well as sensitivity to increases in blood pressure (T2DM: 0.14 ± 0.10 ms/mmHg , healthy: 0.28 ± 0.15 ms/mmHg, p=0.049) compared to healthy controls. In contrast, cardiac baroreflex gain during decreases in blood pressure were not different between groups (T2DM: 0.16 ± 0.07 ms/mmHg, healthy: 0.10 ± 0.06 ms/mmHg, p=0.109). Notably, SAD did not alter blood pressure response to muscle contraction in the T2DM rat (SAD: Δ32 mmHg vs barointact: Δ32 ± 12 mmHg), but evoked an exaggerated blood pressure response in healthy rat (SAD: Δ34 mmHg vs barointact: Δ12 ± 3 mmHg). Our preliminary findings suggest that despite an attenuated cardiac baroreflex function in T2DM rats, specifically during acute increases in blood pressure, carotid baroreflex dysfunction may not contribute significantly to the exaggerated exercise pressor reflex in diabetes. This project was supported by NIH R01 HL144723. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Eight weeks of treatment with mineralocorticoid receptor blockade does not alter vascular function in individuals with and without type 2 diabetes.

Aldosterone has been suggested to be involved in the microvascular complications observed in type 2 diabetes. We aimed to investigate the effect of mineralocorticoid receptor (MR) blockade on endothelial function in individuals with type 2 diabetes compared to healthy controls. We included 12 participants with type 2 diabetes and 14 controls. We measured leg hemodynamics at baseline and during femoral arterial infusion of acetylcholine and sodium nitroprusside before and 8 weeks into treatment with MR blockade (eplerenone). Acetylcholine infusion was repeated with concomitant n-acetylcysteine (antioxidant) infusion. No difference in leg blood flow or vascular conductance was detected before or after the treatment with MR blockade in both groups and there was no difference between groups. Infusion of n-acetylcysteine increased baseline blood flow and vascular conductance, but did not change the vascular response to acetylcholine before or after treatment with MR blockade. Skeletal muscle eNOS content was unaltered by MR blockade and no difference between groups was detected. In conclusion, we found no effect of MR blockade endothelial function in individuals with and without type 2 diabetes. As the individuals with type 2 diabetes did not have vascular dysfunction, these results might not apply to individuals with vascular dysfunction.

Abstract P197: Dietary Quality Determined by Healthy Eating Index-2015 and Endothelial Function in Healthy Adults

The Healthy Eating Index (HEI) is a measure of diet quality based on Dietary Guidelines for Americans and developed in collaboration with the US Department of Health and Human Services and the US Department of Agriculture. Clinical interest in HEI has increased due to its association with obesity, inflammatory biomarkers and risk of coronary heart disease and stroke. Indeed, higher HEI-2015 score has been linked with reduced cardiovascular risk, morbidity, and mortality. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation, is a central etiological factor underlying cardiovascular risk and events. We and others have previously demonstrated that diets high in saturated fat and other proatherogenic diets are associated with endothelial vasodilator dysfunction. It is currently unknown whether HEI-2015 dietary score is associated with endothelial function. If so, assessing dietary quality based on HEI-2015 may provide targeted nutritional guidance for enhancing vascular health and mitigating cardiovascular risk. The aim of this study was to determine whether HEI-2015 score is associated with endothelial vasodilator function in healthy adults. Using data from 4-day dietary records, HEI-2015 scores were determined in 103 adults (65 M/38 F; age 44-68 years) free of overt cardiometabolic disease. The HEI-2015 score is based on 13 components summed to yield a total score from 0 to 100; higher score representing higher diet quality. The adults were stratified by HEI-2015 score quartiles: Q1: HEI < 52.5 (n=25; 23 M/2 F); Q2: HEI 52.6-59.1 (n=26; 14 M/12 F); Q3: HEI 59.2-66.0 (n=26; 15 M/11 F); and Q4: HEI > 66.0 (n=26; 13 M/13 F). Endothelium-dependent vasodilation was determined by forearm blood flow (FBF) (via plethysmography) responses to intra-arterial infusion of acetylcholine (ACh: 4.0, 8.0, and 16.0 μg/100 mL tissue/min) and sodium nitroprusside (NTP: 1.0, 2.0, and 4.0 μg/100 mL tissue/min). There were no significant differences in endothelium-dependent vasodilation across the HEI-2015 score quartiles. FBF blood responses to ACh were remarkably similar between Q1 (5.1±0.2 to 13.0±0.7 mL/100 mL tissue/min), Q2 (4.3±0.2 to 12.1±0.7 mL/100 mL tissue/min), Q3 (4.4±0.2 to 13.0±0.7 mL/100 mL tissue/min) and Q4 (4.5±0.2 to 14.4±0.6 mL/100 mL tissue/min). Moreover, HEI scores were not significantly associated with the vasodilator response to either ACh (r=0.15, P=0.13) or NTP (r=-0.04; P=0.72). In summary, although diet quality determined by HEI-2015 score has been shown to be associated with increased risk of cardiovascular disease and events, HEI-2015 was not associated endothelial function in mid-life and older adults. Given the established experimental and pathophysiological evidence linking between diet, endothelial vasodilator function and cardiovascular risk, HEI-2015 score is not a sensitive dietary indicator/biomarker of vascular function.

The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8weeks, they were given 40mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43±0.45l/min, P=0.006) and leg vascular conductance (Δ 5.38±5.67ml/min/mmHg, P=0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.

Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist.

Buloxibutid (also known as C21) is a potent and selective angiotensin II type 2 receptor (AT2R) agonist, in development for oral treatment of fibrotic lung disease. This phase I, open-label, pharmacodynamic study investigated vascular effects of buloxibutid in five healthy male volunteers. Subjects were administered intra-arterial infusions of buloxibutid for 5 min in ascending doses of 3, 10, 30, 100, and 200 μg/min, infused sequentially in the forearm. Infusions of sodium nitroprusside (SNP) solution in doses of 0.8-3.2 μg/min were administered as a positive control. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Safety and tolerability of intra-arterial administrations of buloxibutid were evaluated. Following infusion of buloxibutid in doses of 3-200 μg/min, the range of increase in FBF was 27.8%, 17.2%, 37.0%, 28.5%, and 60.5%, compared to the respective baseline. The largest increase was observed in the highest dose group. Infusions of SNP as a positive control, increased FBF 230-320% compared to baseline. Three adverse events (AEs) of mild intensity, not related to buloxibutid or SNP, were reported for two subjects. Two of these AEs were related to study procedures. There were no clinically relevant changes in arterial blood pressure during the study period. Intra-arterial infusion of buloxibutid in low, ascending doses increased FBF, indicating that buloxibutid may be effective in conditions associated with endothelial dysfunction. Venous occlusion plethysmography was found to be a useful method to explore pharmacodynamic vascular effects of novel AT2R agonists, while avoiding systemic adverse effects.

Fractional-order PID controller for blood pressure regulation using genetic algorithm

In this paper, fractional order PID controller [FOPID] is designed for automatic blood pressure regulation. One of the most common problems faced by post-operative patients is abnormal blood pressure (BP). Infusion of sodium nitroprusside (SNP) into the patient reduces blood pressure by relaxing the peripheral vasculature's muscles. The patient’s BP must be continuously monitored by an expert and the correct dose has to be given to the patient. It will be difficult to give the desired dosage to a patient manually because drug sensitivity is different for different patients. So, an appropriate controller must be designed to regulate blood pressure and minimize clinical expenses. A fractional-order PID controller is proposed in this paper to regulate mean arterial pressure, and FOPID parameters are optimized as a function of minimizing integral absolute error (IAE), integral squared error (ISE), and integral time absolute error (ITAE) using genetic algorithm. The performance of the proposed system is improved in terms of undershoot, settling time, and maximum peak overshoot. A MATLAB environment was used for the simulation of the system and the implementation of the algorithm.

Endothelial dysfunction is associated with reduced myocardial mechano-energetic efficiency in drug-naïve hypertensive individuals.

Impaired myocardial mechano-energetics efficiency (MEE) was shown to predict incident heart failure, but pathophysiological mechanisms linking impaired MEE with heart failure have not been elucidated. Endothelial dysfunction is a plausible candidate because it has been associated with heart failure. This study aims to investigate the association between MEE and endothelium-dependent vasodilation, among drug-naïve hypertensive individuals. 198 Drug-naïve hypertensive individuals participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study were included. All participants underwent to an oral glucose tolerance test and to an echocardiogram for myocardial LVM-normalized mechano-energetic efficiency (MEEi) measurement. Endothelial-dependent and endothelial-independent vasodilatation were measured by strain-gauge plethysmography during intra-arterial infusion of acetylcholine and sodium nitroprusside, respectively. A multivariate linear regression analysis was conducted to investigate the independent association between maximal endothelial-dependent vasodilation and MEEi. Maximal ACh-stimulated forearm blood flow (FBF) was associated to decreased myocardial MEEi (β = 0.205, p = 0.002) independently of well-established cardiovascular risk factors including age, sex, BMI, waist circumference, smoking status, total and HDL cholesterol, triglycerides, hsCRP, glucose tolerance status, and HOMA-IR index of insulin resistance. Conversely, no association was observed between SNP-stimulated vasodilation and MEEi. Endothelium-mediated vasodilation may contribute to reduce myocardial MEEi independently of several potential confounders. Because diminished myocardial MEE has been previously associated with incident heart failure, a non-invasive assessment of myocardial MEEi may improve the identification of individuals at higher cardiovascular risk who may benefit from the initiation of pharmacological treatments ameliorating the endothelial dysfunction.

#6650 SGLT2-INHIBITION IMPROVES VASCULAR FUNCTION IN TYPE 2 DIABETES: A DOUBLE BLIND, RANDOMIZED, PLACEBO CONTROLLED CROSSOVER TRIAL

Abstract Background and Aims Sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular events and protects kidney function in type 2 diabetes (DM2) patients. These benefits may partly be related to improvement of vascular function. In this study we examined the effects of SGLT2i treatment on vasodilatory capacity in patients with DM2. Method Using a double-blind, randomized, placebo-controlled cross-over study design, we included 15 patients with DM2 and preserved kidney function (eGFR > 60 ml/min/1.73 m2). Each participant received four weeks of SGLT2i treatment (empagliflozin 10 mg once daily) or matching placebo. After a two-week wash-out period, each participant was crossed over to four weeks of the opposite treatment. At the end of each treatment period, vascular function was evaluated by venous occlusion plethysmography. Forearm blood flow (FBF) was measured during intra-arterial infusion of increasing concentrations of acetylcholine (ACh) and sodium nitroprusside (SNP), assessing endothelium-dependent and independent vasodilation, respectively. Repeated measures two-way ANOVA was performed to compare absolute FBF between groups. Results 11/15 (73%) of participants were male. Mean age was 68±9 (SD) years (range 49-82), eGFR was 81±10 ml/min/1.73 m2 and duration of diabetes was 15.8±9 years. 11/15 (73%) had hypertension and 9/15 (60%) received treatment with an ACE-inhibitor or Angiotensin-II blocker. 4/15 (27%) had cardiovascular disease. The median albumin-to-creatinine ratio was 29 mg/g (range: 4-1293). Both ACh and SNP dose-dependently increased FBF (Figure 1 and 2). FBF during SNP infusion was significantly higher during empagliflozin treatment as compared to placebo (p = 0.004), whereas there was no difference between empagliflozin and placebo in FBF during ACh infusion (P = 0.399). Conclusion Empagliflozin improves endothelium-independent vasodilatation in patients with DM2, whereas no changes could be observed in endothelium-dependent vasodilation. These results suggest that SGLT2i positively affects vascular function and that the effect is not related to nitric oxide from the endothelium.

P284 POTENTIAL PROARRHYTHMIC SIDE EFFECT OF HIGH DOSE AND PROLONGED SODIUM NITROPRUSSIDE INFUSION THROUGH CALCIUM ION REDUCTION

Abstract Patient presentation. A fifty y/o male patient with a history of congenital aortic stenosis surgically corrected previously and with chronic heart failure due to severe left ventricular dysfunction presented to our emergency department complaining dyspnea. Due to acute decompensated heart failure with ongoing cardiogenic shock, he was admitted to our intensive cardiology unit. Initial work up. The blood exams showed a normal renal and liver function, normal total and free calcium, 9.4 mg/dL and 1.16 mmol/L respectively, lactates were mildly increased. The chest x–ray showed pulmonary congestion. At the echocardiography we found severe biventricular dysfunction, moderate mitral regurgitation, severe pulmonary hypertension. Since the patient was unstable, adrenaline, high–dose sodium nitroprusside (SNP), and intra–aortic balloon pump were started. The right heart catheterization revealed combined pulmonary hypertension reversible with SNP and, therefore, the patient was inserted in the heart transplant list. Diagnosis and Management. One of the side effects of SNP is the thiocyanate toxicity. A high dose of SNP was necessary for this patient (2.2 mcg/kg/min). Thus, thiocyanate levels increased up to 10 mg/100 mL (NV<3). Importantly, the patient was asymptomatic despite these levels. However, the free calcium ion progressively decreased up to 0.94 mmol/L, despite normal total calcium and calcium supplementation iv and orally. Since arrhythmic burden markedly increased, we started lidocaine which was not effective. Follow–up. Since we suspected a possible causative role of thiocyanate, which might bond the double positive charged free calcium ion with its two negatively charged sulfur atoms, explaining the normal total calcium level and the low calcium ion, we carefully reduced SNP dose within days. This allowed us to reduce thiocyanate to 6 mg/100 mL, without compromising patient hemodynamics. Concomitantly, the free calcium ion tended to normalize, lowering the arrhythmic burden. Conclusions We describe for the first time a proarrhythmic side effect of prolonged SNP infusion, likely related to thiocyanate accumulation and free calcium ion binding, which, despite aggressive calcium supplementation, was normalized only after SNP down titration.

Arterial baroreflex control of heart rate in young and older adults and in patients with heart failure with preserved ejection fraction

Background: The arterial baroreflex (ABR) plays an important role in evoking appropriate cardiovascular adjustments in response to perturbations such as exercise. The ABR control of heart rate (HR) becomes attenuated with advancing age and in a variety of patient populations, but limited information is available in patients with heart failure with preserved ejection fraction (HFpEF). The present study tested the hypothesis that the ABR control of HR is attenuated to a greater extent in patients with HFpEF compared to older and young controls. Methods: Six patients with HFpEF (71±6 years; 35.3±6.6 kg/m2), 4 older controls (68±4 years; 25.1±3.4 kg/m2), and 7 young controls (27±4 years; 26.6±3.9 kg/m2) underwent sequential bolus infusions of sodium nitroprusside (50-100 μg) and phenylephrine (150 μg) (modified Oxford technique) to provoke acute hypotension (“BP falls”) and hypertension (“BP rises”), respectively. Cardiac baroreflex gain was quantified as the weighted linear regression slope between the R-R interval and systolic blood pressure (BP). Results: Compared to young controls (10.7±3.4 ms/mmHg), overall cardiac baroreflex gain was reduced in older controls (3.4±1.6 ms/mmHg) and patients with HFpEF (2.1±1.8 ms/mmHg) (p<0.05), with no difference between the older controls and patients with HFpEF (p=0.718). During BP falls, cardiac baroreflex gain was not different between groups (p=0.06), but was qualitatively lower in patients with HFpEF (0.6±1.5 ms/mmHg) compared to young (5.3±5.5 ms/mmHg) and older controls (5.2±1.9 ms/mmHg). During BP rises, cardiac baroreflex gain was not different between older controls (2.6±0.8 ms/mmHg) and patients with HFpEF (2.3±2.0 ms/mmHg) (p>0.05); however, responses in patients with HFpEF were attenuated compared to young controls 10.7±5.8 ms/mmHg) (p<0.05). Conclusion: These findings suggest an age-related attenuation in the overall ARB control of HR that does not appear to be further exacerbated in patients with HFpEF. However, patients with HFpEF may exhibit a selective attenuation in ABR-mediated tachycardia in response to acute reductions in BP that may pose an increased risk of hypotension and frank syncope. This work was funded in part by the U.S. Department of Veterans Affairs (RX001311, to D.W.W.; IK2RX003670, to K.B.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SHDB mutant functional metastatic paraganglioma: The efficacy of Lutetium-177 DOTATE

Abstract Introduction Therapeutic options for metastatic paraganglioma (PGL) are limited, especially in the presence of uncontrolled secondary hypertension (HTN). Early findings from Lutetium-177 (Lu-177) DOTATE show promise for efficacy, although data on HTN control and survival are uncertain. Herein, we presented the successful treatment of a patient with metastatic PGL and uncontrolled HTN with Lu-177 DOTATE. Clinical Case A 16-year-old woman was admitted to the emergency department with severe headache, nausea and vomiting. She also reported stomach and low back pain for three months. The patient's blood pressure was 220/140 mmHg and a sodium nitroprusside infusion was started to treat the hypertensive crisis. On physical examination she had abdominal tenderness. A computer tomography (CT) examination revealed 6 cm mass, multiple metastatic nodular lesions in the lung and liver, as well as lytic lesions in all bones, and metastatic lymph nodes in thorax and abdomen. She is referred to our department for further evaluation HTN. Laboratory examinations revealed that plasma norepinephrine 24926 ng/L (70–480), 24-hour urine norepinephrine 1335 µg/day (20–81), metanephrine 534 µg/day (52–341), 3-metoksitiramine 771 µg/day (0–451), normetanephrine 20456 µg/day (88–444). Other laboratory findings were normal range. MIBG I131 scan which showed pathological uptake of MIBG was demonstrated in the regions described on CT. Genetic panel by next-generation sequencing (NGS) identify germline mutation and she had heterozygous mutations in SHDB (c.725 G>A) and BUB1B (c.1378 C>T). Surgical treatment was performed, and pathological finding reported 6cm mass, Ki-67 labeling index: %2, chromogranin A diffuse positive and there was vascular invasion. It was confirmed to be malignant PGL. 131I-MIBG therapy couldn't be given because of drugs interaction that used by patient. She received 13 cycles chemotherapy (cyclophosphamide, vincristine, dacarbazine) and palliative radiotherapy to metastatic bone lesions. She continued, however, to suffer from low back pain and HTN. Rising plasma and urine catecholamine levels. Therefore, conventional chemotherapy had been discontinued and he was commenced on Lu-DOTATATE therapy. Up to now, she has received 2 cycles at intervals of three months. Her clinical response was excellent with gradual improvement of symptoms and quality of life. Blood pressure is now within normal values without medication. There was significant reduction in the size of overall metastatic disease on Ga-68 DOTATE scanning. Conclusion Lu-177 DOTATE has potential advantages (drug interaction, radiation-safety) compared with 131I-MIBG therapy and chemotherapy. Our case demonstrates significant clinical and biochemical success in patients with metastatic PGL in addition to excellent disease management with low toxicity from PRRT. Lu-177 DOTATATE therapy is an effective and safe modality of treatment for patients with metastatic PGL.

The Hemodynamic-Stabilizing Properties of Dexmedetomidine on Adrenalectomy For Pheochromocytoma: A Case Report

Pheochromocytoma is a catecholamine-secreting neuroendocrine tumor and represents a challenge to the anesthesiologist. Without adequate preoperative preparation, excessive catecholamine release can result in life-threatening cardiovascular complications. To control blood pressure during the surgery, an infusion of sodium nitroprusside and dexmedetomidine was administered. Dexmedetomidine helps prevent hemodynamic instability during the tumor resection and was a way of interrupting the catecholamine release. This report attempts to address the preoperative and intraoperative issues in managing these challenging tumors with an emphasis on other therapeutic options to control the adrenergic crisis during the surgery.

854 SODIUM NITROPRUSSIDE IN ACUTE HEART FAILURE: EFFECTS ON LV AFTERLOAD AND VENTRICULO-ARTERIAL COUPLING

Abstract Background Acute heart failure (AHF) with left ventricle (LV) dysfunction is characterized by a condition of afterload mismatch without preload reserve. LV ejection fraction (LVEF) and stroke volume (SV) become thus dependent on the afterload. Owing to its arteriolar vasodilator properties, sodium nitroprusside (SNP) may reduce LV afterload and result particularly beneficial in this setting, improving LV ejection and ventriculo-arterial coupling (VAC). Hypothesis We aimed to assess the effect of SNP on LV afterload (arterial elastance, Ea), LV contractility (end-systolic elastance, Ees) and VAC (Ea/Ees ratio) in AHF patients. Methods Patients with AHF receiving SNP were prospectively enrolled and underwent Ea and Ees estimation with a single-beat echocardiographic method, before and after SNP infusion. The method was described by Chen et al (J Am Coll Cardiol, 2001) and Kelly et al (Circulation, 1992). Echocardiography was analyzed by a physician blinded to the images timing. Results A total of 36 AHF patients [69% male, age 70 (68, 76) years] received SNP infusion and were enrolled. Patients were admitted for acute coronary syndrome (47%) and for worsening heart failure (53%). SNP median dose was low: 0.30 (0.21-0.57) mcg/kg/min. SNP led to a trend to SBP reduction [140 (131-150) vs 158 (140-168) mmHg; p=0.002]. Heart rate did not change: 84 (75, 92) vs 83 (72, 94) bpm; p=0.800. Afterload (Ea) was reduced following SNP infusion: 2.2 (1.9, 2.7) vs 2.8 (2.4, 3.4) mmHg/mL; p<0.001. LV contractility (Ees) was unchanged: 1.3 (0.8, 2.2) vs 1.5 (0.9, 3.4) mmHg/mL; p=0.13. End-diastolic volume did not change: 148 (110, 205) vs 146 (108, 213) mL; p=0.880. These effects led to an increased SV: 56 (47, 67) vs 50 (38, 56) mL; p<0.001; p<0.001 and, subsequently to an increased EF [40 (30, 50) vs 30 (20, 40)%; p<0.001]. The VAC did not significantly change after SNP infusion: 1.5 (0.9-2.8) vs 1.6 (0.9-2.7); p=0.64. Conclusion In this report on consecutive AHF, low-dose SNP did not significantly affect VAC but led to a significant reduction in LV afterload and to a significant increase in SV and LVEF.

Sodium nitroprusside in acute heart failure: A multicenter historic cohort study

AimsDespite evidence of hemodynamic benefit of sodium nitroprusside (SNP) treatment for acute heart failure (AHF), there are limited data about its efficacy and safety. This study aimed to assess the effectiveness and safety of SNP treatment, to explore the impact of N-terminal pro-B natriuretic peptide (NT-proBNP) reduction on clinical endpoints and to identify possible predictors of clinical response. Methods and resultsMulticenter retrospective cohort study of 200 patients consecutively admitted for AHF in 2 Italian Centers. Primary endpoint was the reduction of NT-proBNP levels ≥25% from baseline values within 48 h from the onset of SNP infusion. Secondary and safety endpoints included all-cause mortality, rehospitalization for HF at 1, 3 and 6 months, length of hospital stay (LOS) and severe hypotension. 131 (66%) patients experienced a NT-proBNP reduction ≥25% within 48 h from treatment onset, irrespective of initial systolic blood pressure (SBP). Left ventricular end diastolic diameter (LVEDD) was the only independent predictor of treatment efficacy. Patients who achieved the primary endpoint (i.e., ‘responders’) had lower LOS (median 15 [IQR:10–27] vs 19 [IQR:12–35] days, p-value = 0.033) and a lower incidence of all-cause mortality and rehospitalization for HF at 1 and 3 months compared to “non responders” (p-value <0.050). Severe hypotension was observed in 10 (5%) patients, without any adverse clinical consequence. ConclusionSNP is a safe and effective treatment of AHF, particularly in patients with dilated left ventricle. Reduced NT-proBNP levels in response to SNP is associated to shorter LOS and lower risk of 1- and 3-month re-hospitalizations for HF.Clinical trial registration.http://www.clinicaltrials.gov. Unique identifier: NCT05027360

Ramping Up the Pressure on the Right Ventricle.

HomeCirculation: Heart FailureVol. 15, No. 6Ramping Up the Pressure on the Right Ventricle Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBRamping Up the Pressure on the Right Ventricle Simone L. Savaris, MD, MSc, Isaac S. Chang, PhD, Stephen P. Wright, MSc, PhD and Susanna Mak, MD, PhD Simone L. SavarisSimone L. Savaris Correspondence to: Simone L. Savaris, MD, MSc, Division of Cardiology, Mount Sinai Hospital, 600 University Ave, Toronto, ON M5G 1X5, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0002-9049-1805 Division of Cardiology, Mount Sinai Hospital, Toronto, ON, Canada (S.L.S., S.M.). Search for more papers by this author , Isaac S. ChangIsaac S. Chang Mount Sinai Hospital, Toronto, ON, Canada (I.S.C.). Search for more papers by this author , Stephen P. WrightStephen P. Wright Centre for Heart, Lung, and Vascular Health, School of Health and Exercise Sciences, University of British Columbia, Kelowna, Canada (S.P.W.). Search for more papers by this author and Susanna MakSusanna Mak https://orcid.org/0000-0003-2193-602X Division of Cardiology, Mount Sinai Hospital, Toronto, ON, Canada (S.L.S., S.M.). Search for more papers by this author Originally published21 Apr 2022https://doi.org/10.1161/CIRCHEARTFAILURE.122.009671Circulation: Heart Failure. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 21, 2022: Ahead of Print A 49-year-old man underwent Heartmate 3 left ventricular assist device implantation as bridge to transplant candidacy for cardiogenic shock due to an ischemic cardiomyopathy which was complicated by a flail mitral valve leaflet resulting in severe regurgitation.Right heart catheterization was performed to assess residual pulmonary hypertension. Right ventricular (RV) and pulmonary artery (PA) pressures were recorded continuously. At baseline, mean PA pressure was 24 mm Hg and pulmonary vascular resistance was 3.0 WU at a speed of 5600 rpm. PA wedge pressure was altered by adjusting speed from 4600 to 5800 rpm. Further increases in speed did not change hemodynamics. Vasoreactivity testing with sodium nitroprusside was also used, based on recent evidence that even mildly elevated PA loading confers increased mortality risk.1,2 Pmax, a theoretical maximal RV systolic pressure derived by extrapolating the isovolumic portions of the waveform, was averaged over 10 cardiac cycles to calculate a single-beat estimate of RV end-systolic elastance, along with PA elastance and the end-systolic elastance:elastance ratio.3The incremental decline in the PA wedge pressure with attenuation of the V wave can be seen as left ventricular assist device speed was increased, and then with infusion of the vasodilator sodium nitroprusside (Figure and Table from left to right). Concomitant reductions in PA pressure and elastance were associated with shortening of the time to peak RVSP, and improved RV-PA coupling as reflected by increasing end-systolic elastance:elastance ratio. Importantly, mixed venous O2 saturation, stroke volume, and cardiac output increased steadily with afterload reduction.Table. Hemodynamics and Values Derived From Single-Beat Estimation of the Ees:Ea RatioUnsupportedRelatively unsupportedBaselineSNP (0.75 μg/kg per min)SNP (1.5 μg/kg per min)Speed4600 rpm5000 rpm5600 rpm5600 rpm5600 rpmMAP, mm Hg9492969065PAWP (a/v/mean), mm Hg18/37/1817/35/1710/24/1011/28/115/9/3PAP (S/D/M), mm Hg51/14/3047/13/2941/10/2441/9/2432/5/17RAP, mm Hg44320PVR, d/s per cm5192200240176168SVR, d/s per cm51532143613781193765MVO2, %61.663.365.168.573.3CO, L/min4.74.95.45.96.8SVi, mL/m2 per beat3941454955RVSP, mm Hg4946424334Time to RVSP, ms318226221210146Pmax, mm Hg166136143147142Ea, mm Hg/mL0.60.470.370.340.2Ees:Ea ratio2.72.73.63.76.7CO indicates cardiac output; Ea, pulmonary artery arterial elastance; Ees, RV end-systolic elastance; MAP, mean arterial pressure; MVO2, mixed venous oxygen saturation; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; Pmax, maximal predicted RV pressure; PVR, pulmonary vascular resistance; RAP, right atrium pressure; RV, right ventricle; RVSP, right ventricle systolic pressure; SNP, sodium nitroprusside; SVi, stroke volume index; and SVR, systemic vascular resistance.Download figureDownload PowerPointFigure. The figure shows that with alterations in speed and with a vasodilator challenge (from left to right), pulmonary artery wedge pressure (PAWP) and pulmonary artery pressure (PAP) declined, with measurable changes in the morphology of the right ventricular pressure (RVP) waveform. Pmax, the theoretical maximal RVP, and graphical representations of the coordinates employed for single-beat estimation of RV end-systolic elastance (Ees) are also illustrated. Ea indicates pulmonary artery arterial elastance; Pes, estimated end-systolic pressure; Pmax, maximal predicted RVP; RVSP, right ventricle systolic pressure; SNP, sodium nitroprusside; and SV, stroke volume.This case reinforces the effect of systemic vasodilation and venodilation to optimize hemodynamics in the setting of heart failure with reduced ejection fraction, mitral regurgitation, and a continuous flow left ventricular assist device. The upstream effects of adequate unloading of the left ventricle to improve the function of the RV-PA circulatory unit are also illustrated.Article InformationSources of FundingNone.Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 645.Correspondence to: Simone L. Savaris, MD, MSc, Division of Cardiology, Mount Sinai Hospital, 600 University Ave, Toronto, ON M5G 1X5, Canada. Email simonelouise.[email protected]ca

Acute Heat Exposure Improves Microvascular Function in Skeletal Muscle of Aged Humans

Acute heat exposure improves microvascular function in the leg of aged adults as assessed using post‐occlusive reactive hyperemia. However, reactive hyperemia measures whole‐limb blood flow and cannot isolate perfusion among various tissues. Thus, it is unclear if the skeletal muscle circulation contributes to the improvement in microvascular function observed following acute heat exposure. We tested the hypothesis that acute hot water immersion would improve microvascular function in the vastus lateralis of aged adults. Seven aged adults (1 man, 71 ± 4 yrs) were immersed to the umbilicus for 60 min in thermoneutral (36 °C) or hot (40 °C) water. Body core temperature was measured via a telemetric pill. Two microdialysis probes were placed in the vastus lateralis ~30 min after immersion. Microdialysis was utilized to bypass the cutaneous circulation and directly assess endothelial‐dependent and endothelial‐independent microvascular function in skeletal muscle by measuring the local blood flow response to a graded infusion of acetylcholine (ACh, 27.5 and 55.0 mM) and sodium nitroprusside (SNP, 21 and 42 mM), respectively. Local blood flow was measured using the ethanol washout technique. Body core temperature increased by Δ1.1 ± 0.3 °C during hot water immersion but was relatively unchanged during thermoneutral immersion (Δ0.1 ± 0.3 °C). Baseline skeletal muscle blood flow did not differ between thermal conditions for the ACh probe (P= 0.9), nor the SNP probe (P= 0.7). The hyperemic response to 27.5 mM ACh did not differ between thermal conditions (thermoneutral immersion, Δ11.3 ± 11.5 ml/min/100g vs. hot water immersion, Δ18.6 ± 16.8 ml/min/100g; P = 0.7). However, the hyperemic response to 55.0 mM ACh was increased with prior hot water immersion (thermoneutral immersion, Δ30.7 ± 16.9 ml/min/100g vs. hot water immersion, Δ56.2 ± 19.7 ml/min/100g; P &lt; 0.01). Similarly, the hyperemic response to 21 mM SNP did not differ between thermal conditions (thermoneutral immersion, Δ16.9 ± 16.8 ml/min/100g vs. hot water immersion, Δ18.2 ± 18.8 ml/min/100g; P= 0.9), but was increased with prior hot water immersion during the infusion of 42 mM SNP (thermoneutral immersion, Δ29.3 ± 14.4 ml/min/100g vs. hot water immersion, Δ58.5 ± 31.2 ml/min/100g; P = 0.02). These data suggest that acute heat exposure improves endothelial‐dependent and endothelial‐independent microvasculature function in skeletal muscle of aged humans. Furthermore, these data highlight the therapeutic potential of heat therapy to attenuate the hypoperfusion of skeletal muscle that occurs in aged adults during conditions that require an elevated blood supply such as exercise.

Exercise Training Lowers Arterial Blood Pressure Independently of Pannexin 1 in Men with Essential Hypertension.

Regular exercise training reduces arterial blood pressure, but the underlying mechanisms are unclear. Here, we evaluated the potential involvement of pannexin 1, an ATP releasing channel, in the blood pressure-reducing effect of training. Middle-age men, 13 normotensive and 14 nonmedicated stage 1 hypertensive, completed 8 wk of intensive aerobic cycle training. Before and after training, blood pressure and changes in leg vascular conductance, induced by femoral arterial infusion of tyramine (induces endogenous noradrenaline release), acetylcholine, or sodium nitroprusside, were measured during control conditions and after acute pannexin 1 inhibition by probenecid. A skeletal muscle biopsy was obtained from the thigh, pre- and posttraining. Exercise training reduced mean systolic and diastolic blood pressure by ~5 ( P = 0.013) and 5 mm Hg ( P < 0.001), respectively, in the hypertensive group only. The reduction in blood pressure was not related to changes in pannexin 1 function because mean arterial blood pressure and tyramine-induced vasoconstriction remain unaltered by pannexin 1 inhibition after training in both groups. After training, pannexin 1 inhibition enhanced leg vascular conductance in the normo- and hypertensive groups at baseline (41.5%, P = 0.0036, and 37.7%, P = 0.024, respectively) and in response to sodium nitroprusside infusion (275%, P = 0.038, and 188%, P = 0.038, respectively). Training did not alter the pannexin 1 protein expression in skeletal muscle. Training enhanced the vasodilator response to acetylcholine infusion and increased the expression of microvascular function-relevant proteins. The exercise training-induced lowering of arterial blood pressure in nonmedicated hypertensive men does not involve an altered function of pannexin 1.

Is the Pannexin-1 Channel a Mechanism Underlying Hypertension in Humans? a Translational Study of Human Hypertension

In preclinical models, the pannexin-1 channel has been shown to be involved in blood pressure regulation through an effect on peripheral vascular resistance. Pannexin-1 releases ATP, which can activate constrictive purinergic receptors on the smooth muscle cells. Pannexin-1 opening is proposed to be mediated by α-adrenergic receptors to potentiate sympathetic constriction. This positions pannexin-1 as a putative pharmacological target in blood pressure regulation in humans. The aim was to provide the first translational evidence for a role of pannexin-1 in essential hypertension in humans by use of an advanced invasive mechanistic approach. Middle-aged stage-1 hypertensive (n=13; 135.7±6.4 over 83.7±3.7 mm Hg) and normotensive men (n=12; 117.3±5.7 over 72.2±3.5 mm Hg) were included. Blood pressure and leg vascular resistance were determined during femoral arterial infusion of tyramine (α-adrenergic receptor stimulation), sodium nitroprusside, and acetylcholine. Measurements were made during control conditions and with pannexin-1 blockade (3000 mg probenecid). Expression of Pannexin-1, purinergic- and α-adrenergic receptors in skeletal muscle biopsies was determined by Western blot. The changes in leg vascular resistance in response to tyramine (+289% versus +222%), sodium nitroprusside (-82% versus -78%) and acetylcholine (-40% versus -44%) infusion were not different between the 2 groups (P>0.05) and pannexin-1 blockade did not alter these variables (P>0.05). Expression of pannexin-1 and of purinergic- and α-adrenergic receptors was not different between the 2 groups (P>0.05). Contrary to our hypothesis, the data demonstrate that pannexin-1 does not contribute to the elevated blood pressure in essential hypertension, a finding, which also opposes that reported in preclinical models.