Mean Systemic Arterial Pressure Research Articles

The Action of 2-Aminoethyldiphenyl Borinate on the Pulmonary Arterial Hypertension and Remodeling of High-Altitude Hypoxemic Lambs.

Calcium signaling is key for the contraction, differentiation, and proliferation of pulmonary arterial smooth muscle cells. Furthermore, calcium influx through store-operated channels (SOCs) is particularly important in the vasoconstrictor response to hypoxia. Previously, we found a decrease in pulmonary hypertension and remodeling in normoxic newborn lambs partially gestated under chronic hypoxia, when treated with 2-aminoethyldiphenyl borinate (2-APB), a non-specific SOC blocker. However, the effects of 2-APB are unknown in neonates completely gestated, born, and raised under environmental hypoxia. Accordingly, we studied the effects of 2-APB-treatment on the cardiopulmonary variables in lambs under chronic hypobaric hypoxia. Experiments were done in nine newborn lambs gestated, born, and raised in high altitude (3,600 m): five animals were treated with 2-APB [intravenous (i.v.) 10 mg kg–1] for 10 days, while other four animals received vehicle. During the treatment, cardiopulmonary variables were measured daily, and these were also evaluated during an acute episode of superimposed hypoxia, 1 day after the end of the treatment. Furthermore, pulmonary vascular remodeling was assessed by histological analysis 2 days after the end of the treatment. Basal cardiac output and mean systemic arterial pressure (SAP) and resistance from 2-APB- and vehicle-treated lambs did not differ along with the treatment. Mean pulmonary arterial pressure (mPAP) decreased after the first day of 2-APB treatment and remained lower than the vehicle-treated group until the third day, and during the fifth, sixth, and ninth day of treatment. The net mPAP increase in response to acute hypoxia did not change, but the pressure area under the curve (AUC) during hypoxia was slightly lower in 2-APB-treated lambs than in vehicle-treated lambs. Moreover, the 2-APB treatment decreased the pulmonary arterial wall thickness and the α-actin immunoreactivity and increased the luminal area with no changes in the vascular density. Our findings show that 2-APB treatment partially reduced the contractile hypoxic response and reverted the pulmonary vascular remodeling, but this is not enough to normalize the pulmonary hemodynamics in chronically hypoxic newborn lambs.

Modulation of SIRT1 expression improves erectile function in aged rats.

Silent information regulator 2-related enzyme 1 (SIRT1) is an aging-related protein activated with aging. Herein, we evaluated the role of SIRT1 in aging-related erectile dysfunction. The expression of SIRT1 was modulated in aged Sprague-Dawley rats following intragastric administration of resveratrol (Res; 5 mg kg-1), niacinamide (NAM; 500 mg kg-1) or Res (5 mg kg-1) + tadalafil (Tad; phosphodiesterase-5 [PDE5] inhibitor; 5 mg kg-1) for 8 weeks. Then, we determined erectile function by the ratio of intracavernosal pressure (ICP)/mean systemic arterial pressure (MAP). Cavernosal tissues were extracted to evaluate histological changes, cell apoptosis, nitric oxide (NO)/cyclic guanosine monophosphate (cGMP), the superoxide dismutase (SOD)/3,4-methylenedioxyamphetamine (MDA) level, and the expression of SIRT1, p53, and forkhead box O3 (FOXO3a) using immunohistochemistry, terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling (TUNEL), enzyme-linked immunosorbent assays, and western blot analysis. Compared with the control, Res treatment significantly improved erectile function, reflected by an increased content of smooth muscle and endothelium, NO/cGMP and SOD activity, and reduced cell apoptosis and MDA levels. The effect of Res was improved by adding Tad. In addition, the protein expression of SIRT1 was increased in the Res group, accompanied by decreased p53 and FOXO3a levels. In addition, inhibition of SIRT1 by NAM treatment resulted in adverse results compared with Res treatment. SIRT1 activation ameliorated aging-related erectile dysfunction, supporting the potential of SIRT1 as a target for erectile dysfunction treatment.

Abstract 10027: Pulsatile Load, Rather Than Cardiac Power Output, for the Right Ventricle Determines the Prognosis in Heart Failure Patients

Background: Although cardiac power output (CPO), a parameter of cardiac performance, for the left ventricle (LV) is reported to be a powerful prognostic indicator in heart failure (HF), significance of the right ventricular (RV) CPO in HF has not been elucidated. On the other hand, RV pulsatile load stands for one of the prognostic markers in HF. We thus investigated the relationship of the RV CPO and pulsatile load to the outcome in HF. Methods: Right heart catheterization and echocardiography were performed in 231 HF patients (62±16 years, LV ejection fraction 42±18%). Invasive and noninvasive CPOs were calculated from mean systemic or pulmonary arterial pressures and cardiac output for the LV and RV. LV CPO was then corrected by LV mass (LV CPO/M). Pulmonary artery compliance (PAC) and the ratio of acceleration time to ejection time (AcT/ET) of the RV outflow velocity were used as parameters of RV pulsatile load. Cardiac death, HF hospitalization, ventricular arrhythmia and LVAD implantation after the examination were recorded. Results: Noninvasive CPOs were moderately correlated with invasive ones (LV: R=0.73, RV: R=0.58, P <0.001 for both). During a median follow-up period of 441 days, cardiac events occurred in 57 patients. Using the cut-off of median values, lower LV CPO/M was associated with higher event rates, however, RV CPO did not discriminate the risk of future cardiac events. In contrast, higher RV pulsatile load was associated with higher event rates regardless of the level of LV CPO/M ( Figure ). In multivariable Cox proportional hazard analyses, echocardiographic LV CPO/M and AcT/ET both determined cardiac events independently of age, NYHA classification, LV ejection fraction and plasma brain natriuretic peptide levels. Conclusion: Pulsatile load, rather than CPO, for the RV was associated with cardiac events in HF. Furthermore, combination of echocardiographic LV CPO/M and AcT/ET could become a novel noninvasive prognostic indicator in HF patients.

Acute hyperoxia reveals tonic influence of peripheral chemoreceptors on systemic vascular resistance in heart failure patients

Peripheral chemoreceptors’ (PCh) hyperactivity increases sympathetic tone. An augmented acute ventilatory response to hypoxia, being a marker of PCh oversensitivity, was also identified as a marker of poor prognosis in HF. However, not much is known about the tonic (chronic) influence of PCh on cardio-respiratory parameters. In our study 30 HF patients and 30 healthy individuals were exposed to 100% oxygen for 1 min during which minute ventilation and hemodynamic parameters were non-invasively recorded. Systemic vascular resistance (SVR) and mean arterial pressure (MAP) responses to acute hyperoxia differed substantially between HF and control. In HF hyperoxia caused a significant drop in SVR in early stages with subsequent normalization, while increase in SVR was observed in controls. MAP increased in controls, but remained unchanged in HF. Bilateral carotid bodies excision performed in two HF subjects changed the response to hyperoxia towards the course seen in healthy individuals. These differences may be explained by the domination of early vascular reaction to hyperoxia in HF by vasodilation due to the inhibition of augmented tonic activity of PCh. Otherwise, in healthy subjects the vasoconstrictive action of oxygen remains unopposed. The magnitude of SVR change during acute hyperoxia may be used as a novel method for tonic PCh activity assessment.

Dynamics of GRK2 in the kidney: a putative mechanism for sepsis-associated kidney injury.

Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to α1 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP). Wildtype mice were treated with prazosin 12 h after CLP or nitric oxide synthase 2 (NOS-2) inhibitor, 30 min before and 6 and 12 h after CLP. In vivo experiments and biochemistry assays were performed 24 h after CLP. Sepsis decreased the systemic mean arterial pressure (MAP) and the vascular reactivity to phenylephrine. Sepsis also reduced basal renal blood flow which was normalized by treatment with prazosin. Sepsis led to a substantial decrease in GRK2 level associated with an increase in α1 adrenergic receptor density in the kidney. The disappearance of renal GRK2 was prevented in NOS-2-KO mice or mice treated with 1400 W. Treatment of non-septic mice with an NO donor reduced GRK2 content in the kidney. Therefore, our results show that an NO-dependent reduction in GRK2 level in the kidney leads to the maintenance of a normal α1 adrenergic receptor density. The preservation of the density and/or functionality of this receptor in the kidney together with a higher vasoconstrictor tonus in sepsis lead to vasoconstriction. Thus, the increased concentration of vasoconstrictor mediators together with the preservation (and even increase) of the response to them may help to explain sepsis-induced acute kidney injury.

The thromboxane receptor antagonist NTP42 improves haemodynamics, inhibits remodelling, and restores function within the cardiopulmonary system in preclinical pulmonary arterial hypertension models

Abstract Background Pulmonary arterial hypertension (PAH) is a rare and fatal disease characterised by a progressive increase of pulmonary artery pressure leading to right heart failure. While current PAH therapies provide symptomatic relief and some improvement in quality of life, they show limited benefit in preventing disease progression and often have severe side effects. Recent studies by us reported that a novel thromboxane A2 receptor (TP) antagonist NTP42 attenuated multiple disease hallmarks of PAH in two preclinical models of the disease. Purpose The aim of this study was to assess the efficacy of a novel oral formulation of NTP42 developed for pharmaceutical use on monocrotaline (MCT)-induced PAH in rats across a range of cardiopulmonary parameters, and when compared with standard of care (SOC) PAH therapies. It also aimed to evaluate the expression of the TP, the target receptor for NTP42, in tissues from the MCT-induced PAH model and related disease models. Methods PAH was induced by subcutaneous injection of 60 mg/kg MCT. Rats were randomly assigned to 7 groups: (1) No MCT; (2) MCT Only; (3) MCT+NTP42 Formulation (1 mg/kg); (4) MCT+Sildenafil (50 mg/kg); (5) MCT+Macitentan (30 mg/kg), (6) MCT+Selexipag (1 mg/kg), and (7) MCT+Riociguat (5 mg/kg), where in all cases twice-daily oral dosing was initiated 7 days post-MCT and continued for 22 days. Results The results show that the formulated NTP42 reduced the severity of MCT-induced PAH as determined from haemodynamic measurements of mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), Fulton's Index of cardiac hypertrophy and histological assessments of pulmonary vascular remodelling, pulmonary oedema, inflammation and fibrosis, and right ventricular fibrosis. In addition, these assessments showed that NTP42 inhibited these effects at least to a similar extent relative to the SOC drugs Sildenafil, Macitentan, Selexipag and Riociguat. Notably, unlike most of the PAH SOCs, NTP42 had no adverse effects on liver weight and or on hepatic histopathology. Importantly, NTP42 had no effects on either the systemic mean arterial pressure (mAP) or heart rate (HR). Furthermore, while abundant expression of the target TP was noted in numerous cell and tissue types of both cardiac and pulmonary tissue, there were highly significant upregulations of TP expression observed following PAH-induction (RV, >2-fold, p=0.0002). Conclusions Taken together, these data demonstrate that NTP42 significantly attenuates MCT-induced PAH and to a similar or greater extent relative to market leader PAH SOC drugs. Notably, we reveal that expression of the TP, the target receptor for NTP42, was shown to be highly significantly upregulated throughout the cardiopulmonary system, validating the potential importance of this largely ignored PAH target ripe for pharmaceutical intervention. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Horizon 2020 SME Instrument

Prognostic value of the combination of pulmonary-systemic pressure ratio and a new systemic inflammation-nutrition index in patients admitted for acute decompensated heart failure

Abstract Background Concomitant presence of pulmonary hypertension in heart failure (HF) is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced HF. On the other hand, systemic inflammation plays a critical role in the outcomes of heart failure, and malnutrition is also associated with poor outcome in heart failure patients It has been recently reported that advanced lung cancer inflammation index (ALI), which is calculated as body mass index × serum albumin / neutrophil to lymphocyte ratio (NLR), is an independent prognostic marker in several types of cancer. However, there is no information available on the prognostic value of the combination of MPS ratio and ALI in patients with acute decompensated HF (ADHF). Methods and results We studied 219 patients admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. During a follow up period of 5.1±4.2 yrs, 57 had cardiovascular death (CVD). MPS ratio was significantly greater (0.401±0.107 vs 0.346±0.105, p=0.0009) and ALI was significantly smaller (34.2±18.7 vs 52.0±27.1, p<0.0001) in patients with than without CVD At multivariate Cox analysis, MPS ratio and ALIwere significantly associated with CVD, independently of eGFR and prior heart failure hospitalization, after the adjustment with left ventricular end-diastolic dimension and serum sodium level. The patients with both greater MPS ratio>0.350 (AUC 0.652 [0.569–0.735]) and smaller ALI <35.767 (AUC 0.714 [0.636–0.792]) had a significantly increased risk of CVD than those with either greater MPS or smaller ALI and none of them (67% vs 22% vs 11%, p<0.0001, respectively). Conclusion The combination of MPS ratio and ALI might be useful for stratifying ADHF patients at higher risk for CVD. Funding Acknowledgement Type of funding sources: None.

A randomized porcine study of the hemodynamic and metabolic effects of combined endovascular occlusion of the vena cava and the aorta in normovolemia and in hemorrhagic shock.

BACKGROUNDMortality from traumatic retrohepatic venous injuries is high and methods for temporary circulatory stabilization are needed. We investigated survival and hemodynamic and metabolic effects of resuscitative endovascular balloon occlusion of the aorta (REBOA) and vena cava inferior (REBOVC) in anesthetized pigs.METHODSTwenty-five anesthetized pigs in normovolemia or severe hemorrhagic shock (controlled arterial bleeding in blood bags targeting systolic arterial pressure of 50 mm Hg, corresponding to 40–50% of the blood volume) were randomized to REBOA zone 1 or REBOA+REBOVC zone 1 (n = 6–7/group) for 45 minutes occlusion, followed by 3-hour resuscitation and reperfusion. Hemodynamic and metabolic variables and markers of end-organ damage were measured regularly.RESULTSDuring occlusion, both the REBOA groups had higher systemic mean arterial pressure (MAP) and cardiac output (p < 0.05) compared with the two REBOA+REBOVC groups. After 60 minutes reperfusion, there were no statistically significant differences between the two REBOA groups and the two REBOA+REBOVC groups in MAP and cardiac output. The two REBOA+REBOVC groups had higher arterial lactate and potassium concentrations during reperfusion, compared with the two REBOA groups (p < 0.05). There was no major difference in end-organ damage markers between REBOA and REBOA+REBOVC. Survival after 1-hour reperfusion was 86% and 100%, respectively, in the normovolemic REBOA and REBOA+REBOVC groups, and 67% and 83%, respectively, in the corresponding hemorrhagic shock REBOA and REBOA+REBOVC groups.CONCLUSIONAcceptable hemodynamic stability during occlusion and short-term survival can be achieved by REBOA+REBOVC with adequate resuscitation; however, the more severe hemodynamic and metabolic impacts of REBOA+REBOVC compared with REBOA must be considered.LEVEL OF EVIDENCEProspective, randomized, experimental animal study. Basic science study, therapeutic.

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers in acute heart failure: invasive hemodynamic parameters and clinical outcomes.

There are limited data regarding the use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) in acute heart failure (AHF). The purpose is to determine the patterns of ACEi/ARB use at the time of admission and discharge in relation to invasive hemodynamic data, mortality, and heart failure (HF) readmissions. This is a retrospective single-center study in patients with AHF who underwent right heart catheterization between January 2010 and December 2016. Patients on dialysis, evidence of shock, or incomplete follow up were excluded. Multivariate logistic regression analysis was used to analyze the factors associated with continuation of ACEi/ARB use on discharge and its relation to mortality and HF readmissions. The final sample was 626 patients. Patients on ACEi/ARB on admission were most likely continued on discharge. The most common reasons for stopping ACEi/ARB were worsening renal function (WRF), hypotension, and hyperkalemia. Patients with ACEi/ARB use on admission had a significantly higher systemic vascular resistance (SVR) and mean arterial pressure (MAP), but lower cardiac index (CI). Patients with RA pressures above the median received less ACEi/ARB (P = 0.025) and had significantly higher inpatient mortality (P = 0.048). After multivariate logistic regression, ACEi/ARB use at admission was associated with less inpatient mortality; OR 0.32 95% CI (0.11 to 0.93), and this effect extended to the subgroup of patients with HFpEF. Patients discharged on ACEi/ARB had significantly less 6-month HF readmissions OR 0.69 95% CI (0.48 to 0.98). ACEi/ARB use on admission for AHF was associated with less inpatient mortality including in those with HFpEF.

Atypical Causes of Severe Pulmonary Hypertension in Infancy.

Pulmonary hypertension (PH) is a progressive disease characterized by elevated pulmonary arterial pressure (PAP). It is defined for both adults and children as mean PAP exceeding 20 mmHg and pulmonary vascular resistance of at least 3 Woods Units (WU; indexed to body surface area in children).1 A more appropriate suggested definition of PH in infants is a ratio of pulmonary artery systolic pressure to the systemic arterial systolic pressure above 0.4.2 In addition, cardiac catheterization derived mean pulmonary artery pressures to mean systemic arterial pressure ratio >0.75 indicating severe pulmonary hypertension has been associated with worse outcome in children.1 PH can be life-threatening and often presents within hours after birth. Persistent PH of the newborn (persistent pulmonary hypertension of the newborn [PPHN]) is a common etiology of PH in infants, occurring in 0.4 to 6 per 1000 live births with increasingly higher frequency reported at earlier gestational ages.1,3,4 However, rare etiologies of pulmonary hypertension can go unrecognized and may present outside the neonatal period.5 We present 4 atypical cases of severe pulmonary hypertension and review how early recognition informed prognosis and guided timely intervention.

The Clinical Significance of Fluctuations in the Minute-to-minute Urine Flow Rate and in its Minute-to-minute Variability During Septic Events in Critically Ill Patients.

BackgroundSeptic events complicated by hemodynamic instability can lead to decreased organ perfusion, multiple organ failure, and even death. Acute renal failure is a common complication of sepsis, affecting up to 50-70 % of cases, and it is routinely diagnosed by close monitoring of urine output. We postulated that analysis of the minute-to-minute changes in the urine flow rate (UFR) and also of the changes in its minute-to-minute variability might lead to earlier diagnosis of renal failure. We accordingly analyzed the clinical significance of these two parameters in a group of critically ill patients suffering from new septic events.MethodsThe study was retrospective and observational. Demographic and clinical data were extracted from the hospital records of 50 critically ill patients who were admitted to a general intensive care unit (ICU) and developed a new septic event characterized by fever with leukocytosis or leukopenia. On admission to the ICU, a Foley catheter was inserted into the urinary bladder of each patient. The catheter was then connected to an electronic urinometer – a collecting and measurement system that employs an optical drop detector to measure urine flow. Urine flow rate variability (UFRV) was defined as the change in UFR from minute to minute.ResultsBoth the minute-to-minute UFR and the minute-to-minute UFRV decreased significantly immediately after each new septic episode, and they remained low until fluid resuscitation was begun (p < 0.001 for both parameters). Statistical analysis by the Pearson method demonstrated a strong direct correlation between the decrease in UFR and the decrease in the systemic mean arterial pressure (MAP) (R = 0.03, p = 0.003) and between the decrease in UFRV and the decrease in the MAP (R = 0.03, p = 0.004). Additionally, both the UFR and the UFRV demonstrated good responses to fluid administration prior to improvement in the MAP.ConclusionWe consider that minute-to-minute changes in UFR and UFRV could potentially serve as early and sensitive signals of clinical deterioration during new septic events in critically ill patients. We also suggest that these parameters might be able to identify the optimal endpoint for the administration of fluid resuscitative measures in such patients.

Sex differences in the prevalence and hemodynamic profiles of hypertensive phenotypes: the HELIUS study

Abstract Background Based on systolic (SBP) and diastolic blood pressure (DBP), patients with hypertension can be classified into different phenotypes. Earlier studies have shown clear sex-differences in the relation between phenotype and cardiovascular outcomes, but large studies addressing underlying sex-differences in hemodynamics are lacking. Purpose To examine sex differences in the prevalence and underlying hemodynamic profile of different hypertensive phenotypes. Methods We used cross-sectional data of 22.112 individuals, 57.8% female, aged between 18–70 years from the HEalthy LIfe in an Urban Setting (HELIUS) study, an ongoing large multi-ethnic prospective cohort study. Based on office BP patients were classified as having: normal (NBP; SBP &amp;lt;140 mmHg and DBP &amp;lt;90 mmHg), isolated systolic hypertension (ISH; SBP ≥140 and DBP &amp;lt;90 mmHg), isolated diastolic hypertension (IDH; SBP &amp;lt;140 and DBP ≥90mmHg) or combined systolic diastolic hypertension (SDH; SBP ≥140 and DBP ≥90 mmHg). We explored sex differences in the prevalence hypertension and the distribution of phenotypes using chi-squared tests after stratification for age (young: &amp;lt;50, old: ≥50 years). In a subgroup of 11.046 participants, continuous non-invasive measurements of cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR) and mean arterial pressure (MAP) were obtained during 3–5 minutes with finger photoplethysmography in the supine position (Nexfin, Edwards Lifesciences, Irvine, CA, USA). Sex-differences between hemodynamic parameters were assessed using ANOVA tests of linear regression models correcting for age. Results In young participants, the overall prevalence of hypertension was significantly higher in men (19.7%) compared to women (11.4%), with a different distribution of phenotypes (both p&amp;lt;0.001). Amongst young hypertensive participants, SDH was the most prevalent phenotype in both men (46%) and women (52%), ISH had a prevalence of respectively 23% in men and 26% in women. In older subjects, overall prevalence of hypertension was 40.2% in men and 35.9% in women (p&amp;lt;0.001), with a different phenotypical distribution (p&amp;lt;0.001). SDH was the most predominant phenotype in men (50%), whilst ISH was the most prevalent phenotype in women (55%). Both young and old participants with ISH showed an elevated cardiac output, ranging from 0.38–0.47 ml/min compared to normotensives. Older men with SDH and IDH had both elevated SVR and CO, while older women had only an elevation in SVR (Figure 1). Conclusions There are important age-dependent sex-differences in the prevalence of hypertension, which translate into a different hemodynamic profile. The pattern of cardiac output alterations across phenotypes was different between older men and women, suggesting sex differences in the underlying pathophysiology of elevated blood pressure. These findings contribute to a better understanding of the pathogenesis of hypertension and could impact treatment responses. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): The Academic Medical Center (AMC) of Amsterdam and the Public Health Service of Amsterdam (GGD Amsterdam) provided core financial support for HELIUS. The HELIUS study is also funded by research grants of the Dutch Heart Foundation (Hartstichting; grant no. 2010T084), the Netherlands Organization for Health Research and Development (ZonMw; grant no. 200500003), the European Integration Fund (EIF; grant no. 2013EIF013) and the European Union (Seventh Framework Programme, FP-7; grant no. 278901).

Prognostic value of pulmonary-systemic pressure ratio and fibrosis-4 index in patients admitted for acute decompensated heart failure

Abstract Background Concomitant presence of pulmonary hypertension in heart failure (HF) is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. An increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is reported to be associated with worse clinical outcomes in patients with advanced HF. On the other hand, cardiohepatic interactions have been a focus of attention in HF, and liver dysfunction in HF patients is caused by liver congestion, which is related to liver stiffness. It has been recently shown that liver stiffness assessed by non-invasive fibrosis marker such as Fibrosis-4 (FIB4) index predicts the mortality in HF patients. However, there is no information available on the prognostic value of the combination of MPS ratio and FIB4 index in patients with acute decompensated heart failure (ADHF). Methods and results We studied 238 patients admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. MPS ratio was obtained at the admission. FIB4 index was calculated by the formula: age (yrs) × AST [U/L] / (platelets [103/μL] × √(ALT[U/L])). FIB4 index &amp;gt;2.67 was defined as abnormal, as previously reported. During a follow up period of 5.2±4.4 yrs, 93 patients died. At multivariate Cox analysis, MPS ratio (p=0.01) and FIB4 index (p=0.01) were significantly associated with the total mortality, independently of creatinine level and prior heart failure hospitalization, after the adjustment with hemoglobin, albumin levels and body mass index. The patients with both MPS ratio ≥0.388 (determined by ROC analysis; AUC 0.613 [0.541–0.687]) and abnormal FIB4 index had a significantly increased risk of the total mortality than those with either greater MPS or abnormal FIB4 index and none of them (52% vs 40% vs 28%, p=0.0068, respectively). Conclusion The combination of MPS ratio and FIB4 index might be useful for stratifying ADHF patients at higher risk for the total mortality. Funding Acknowledgement Type of funding source: None

Long-term prognostic value of the combination of malnutrition and pulmonary-systemic pressure ratio in patients admitted with acute decompensated heart failure

Abstract Background Malnutrition is associated with increased mortality risk in patients (pts) with acute decompensated heart failure (ADHF). On the other hand, concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is no information available on the long-term prognostic value of the combination of malnutrition and MPS ratio in pts admitted for ADHF. Methods and results We studied 248 pts admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. Malnutrition was assessed by geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI) and controlling nutritional status score (CONUT). During a mean follow-up period of 5.2±4.4 yrs, 62 pts had cardiovascular death (CVD). MPS ratio was significantly greater in pts with than without CVD (0.408±0.114 vs 0.347±0.102, p=0.0001). GNRI and PNI were significantly lower, CONUT was significantly greater in pts with than without CVD. At multivariate Cox regression analysis, GNRI and MPS ratio were significantly associated with CVD, independently of prior heart failure hospitalization, eGFR, and serum sodium level and anemia, although PNI and CONUT showed the association with CVD at unvariate analysis. Pts with malnutrition (GNRI≤median value=96.5) and greater MPS ratio (≥median value=0.346) had a significantly higher CVD risk than those with either and none of them (51% vs 20% vs 12%, p&amp;lt;0.0001, respectively). Conclusions The combination of malnutrition and MPS ratio might be useful for stratifying pts at risk for CVD in patients with ADHF. Funding Acknowledgement Type of funding source: None

Hemodynamic Reserve Predicts Early Right Heart Failure After LVAD Implantation

Background Right heart failure (RHF) remains a major source of morbidity and mortality after left ventricular assist device (LVAD) implantation, yet efforts to predict RHF have proved only modestly successful. Acute pharmacologic unloading of the LV to assess ventricular and hemodynamic reserve may better predict post-implant RHF. Objectives To compare pre-implant baseline and post-vasodilator hemodynamic predictors of INTERMACS defined severe or severe-acute RHF after LVAD implantation. Methods After IRB approval, we performed a retrospective analysis of all subjects implanted with a durable LVAD at our institution between February 2017 and April 2020 (n=108). Only those who underwent vasodilator testing with nitroprusside during their pre-implant right heart catheterization were ultimately included (n=29). Continuous variables were compared with t-test and Levene's test of equality of variances; categorical via Fisher's Exact test. Logistic regression was used to determine predictors of severe or severe-acute RHF. Results Ten subjects met criteria for severe or severe-acute RHF (34%) after implant. There were no significant differences in demographics, HF etiology, INTERMACS profile, echo assessment of LV/RV function, or pre-implant baseline hemodynamics including RAP:PAWP ratio and PAPi between groups (TABLE). Both groups saw a similar reduction in systemic mean arterial pressure with nitroprusside, which led to significant and similar reductions in PAWP and pulmonary pressures. Compared to the group with severe or severe-acute RHF, those without significant RHF achieved higher peak cardiac index (CI) with nitroprusside infusion, suggesting better cardiac reserve. Peak CI was a significant predictor of RHF (p= 0.022), even after controlling for baseline values (p=0.048). No subject achieving a peak CI > 2.66 L/min/m2 developed severe or severe-acute RHF, and every 0.25 L/min/m2 decrease in peak CI was associated with 2.3 fold increased risk. Mortality was higher and hospital length of stay longer in the severe or severe-acute RHF group. Conclusion Peak CI with nitroprusside infusion predicts post-implant LVAD RHF better than resting hemodynamics in this small cohort. Hemodynamic reserve measurements may prove to be an important risk stratification tool when assessing LVAD candidacy.

Vascular actions of peripheral CGRP in migraine-like photophobia in mice.

Calcitonin gene-related peptide is recognized as a key player in migraine, yet the mechanisms and sites of calcitonin gene-related peptide action remain unknown. The efficacy of calcitonin gene-related peptide-blocking antibodies as preventative migraine drugs supports a peripheral site of action, such as the trigeminovasculature. Given the apparent disconnect between the importance of vasodilatory peptides in migraine and the prevailing opinion that vasodilation is an epiphenomenon, the goal of this study was to test whether vasodilation plays a role in calcitonin gene-related peptide-induced light aversive behavior in mice. Systemic mean arterial pressure and light aversive behavior were measured after intraperitoneal administration of calcitonin gene-related peptide and vasoactive intestinal peptide in wild-type CD1 mice. The functional significance of vasodilation was tested by co-administration of a vasoconstrictor (phenylephrine, endothelin-1, or caffeine) with calcitonin gene-related peptide to normalize blood pressure during the light aversion assay. Both calcitonin gene-related peptide and vasoactive intestinal peptide induced light aversion that was associated with their effect on mean arterial pressure. Notably, vasoactive intestinal peptide caused relatively transient vasodilation and light aversion. Calcitonin gene-related peptide-induced light aversion was still observed even with normalized blood pressure. However, two of the agents, endothelin-1 and caffeine, did reduce the magnitude of light aversion. We propose that perivascular calcitonin gene-related peptide causes light-aversive behavior in mice by both vasomotor and non-vasomotor mechanisms.

Left ventricular function and remodelling in rats exposed stepwise up to extreme chronic intermittent hypoxia

The main aim was to find out whether long-lasting stepwise exposure to extreme hypoxia affects left ventricular (LV) geometry and systolic function. Adult male rats were exposed to intermittent hypobaric hypoxia (8 h/day) with increasing altitude in steps of 1000 m every 3 weeks up to 8000 m. While the LV cavity diastolic diameter did not change over the whole range of hypoxia, the wall thickness increased significantly at the altitude of 8000 m. LV fractional shortening ranged between 48.1 % and 50.1 % and remained unaffected even at the most severe hypoxia. At the end of experiment, haematocrit reached 83 %, mean systemic arterial pressure 120 % and relative LV weight 154 % of normoxic values while RV systolic pressure and relative RV weight doubled. Myocyte hypertrophy and myocardial fibrosis were more pronounced in RV than in LV. In conclusion, LV systolic function was preserved after chronic stepwise exposure of rats to extreme intermittent hypoxia despite moderate concentric hypertrophy and myocardial remodelling.

Central And Systemic Haematological Responses Are Similar Between Continuous And Intermittent Blood Flow Restricted Resistance Exercise

Resistance training (RT) with blood flow restriction (BFR) induces similar adaptations to traditional RT but uses markedly lower training loads. However, information about the acute exercise pressor, hemodynamic, and local metabolic cost of this training approach is sparse. These data are needed to understand the acute safety implications of this training approach and help identify an optimal BFR protocol. PURPOSE: To compare the acute central and systemic cardiovascular, and local metabolic responses to resistance exercise performed with continuous (BFR-C) and intermittent (BFR-I) BFR. METHODS: 12 resistance-trained males (mean ± SD) aged 22.3 ± 3.2yrs, 1.82 ± 0.06m, and 84.1 ± 9.0kg performed 4 separate acute resistance training sessions in a random order, each separated by 7 days. Training sessions involved four sets of squat-based RT at 30% of individuals’ 1 repetition maximum with 1) no BFR (CON), 2) BFR-C, 3) BFR-I, and 4) traditional high load training at 70% of 1 repetition maximum with no BFR (HL). Systemic blood pressure and derivatives of cardiac output, central aortic blood pressure pulse wave characteristics, and local blood volume and metabolism were assessed periodically during, and after each training session. Data were assessed by two-way ANOVA with Bonferroni-corrected post-hoc comparisons. RESULTS: All sessions similarly increase average metabolic demand, seen by a decreased tissue saturation index (-15%, 95% CI 13.3 to 17.4, p<0.0001) with no difference between conditions (p>0.05). Whilst changes in haemoglobin-derived Vastus Lateralis blood volumes were similar between conditions, they were higher with BFR-C than CON (6.97 μmol/L, 95% CI 0.2 to 13.6, p=0.04) and HL (7.9 μmol/L, 95% CI 1.2 to 14.8, p=0.01). Training equally increased mean systemic mean arterial pressure (MAP) (+70.5 to 76.6 mmHg, p<0.001) and cardiac output (+0.74 to 0.96 L, p<0.001) above baseline, with no difference between conditions. Training also equally increased mean aortic MAP (+14.8 to 24.2 mmHg, p<0.001) above baseline across conditions. CONCLUSIONS: BFR-C and BFR-I cause similar exercise pressor responses comparable with both traditional resistance training, and training without BFR. Adding BFR to resistance training didn’t exacerbate the magnitude or duration of the associated cardiovascular stress.

Extracorporeal Life Support Organization (ELSO): Guidelines for Neonatal Respiratory Failure.

Extracorporeal Life Support Organization (ELSO): Guidelines for Neonatal Respiratory Failure.

Resuscitative endovascular balloon occlusion of the aorta in zone I versus zone III in a porcine model of non-traumatic cardiac arrest and cardiopulmonary resuscitation: A randomized study

IntroductionResuscitative endovascular balloon occlusion of the aorta (REBOA) in zone I increases systemic blood pressure during cardiopulmonary resuscitation (CPR), while also obstructing the blood flow to distal organs. The aim of the study was to compare the effects on systemic blood pressure and visceral blood flow of REBOA-III (zone III, infrarenal) and REBOA-I (zone I, supraceliac) during non-traumatic cardiac arrest and CPR. MethodsCardiac arrest was induced in 61 anesthetized pigs. Thirty-two pigs were allocated to a hemodynamic study group where the primary outcomes were systemic arterial pressures and 29 pigs were allocated to a blood flow study group where the primary outcomes were superior mesenteric arterial (SMA) and internal carotid arterial (ICA) blood flow. After 7–8 min of CPR with a mechanical compression device, REBOA-I, REBOA-III or no aortic occlusion (control group) were initiated after randomization. ResultsSystemic mean and diastolic arterial pressures were statistically higher during CPR with REBOA-I compared to REBOA-III (50 mmHg and 16 mmHg in REBOA-I vs 38 mmHg and 1 mmHg in REBOA-III). Systemic systolic, mean and diastolic arterial pressures were statistically elevated during CPR in the REBOA-I group compared to the controls. The SMA blood flow increased by 49% in REBOA-III but dropped to the levels of the controls within minutes. The ICA blood flow increased the most in REBOA-I compared to REBOA-III and the control group (54%, 19% and 0%, respectively). ConclusionIn experimental non-traumatic cardiac arrest and CPR, REBOA-I increased systemic blood pressures more than REBOA-III, and the potential enhancement of visceral organ blood flow by REBOA-III was short-lived.