Lower Systemic Blood Pressure Research Articles

High-Soluble-Fiber Diet Attenuates Hypoxia-Induced Vascular Remodeling and the Development of Hypoxic Pulmonary Hypertension.

Hypoxic pulmonary hypertension is a difficult disease to manage that is characterized by sustained elevation of pulmonary vascular resistance and pulmonary artery pressure due to vasoconstriction, perivascular inflammation, and vascular remodeling. Consumption of soluble-fiber is associated with lower systemic blood pressure, but little is known about its ability to affect the pulmonary circulation. Mice were fed either a low- or high-soluble-fiber diet (0% or 16.9% inulin) and then exposed to hypoxia (FiO2, 0.10) for 21 days to induce pulmonary hypertension. The impact of diet on right ventricular systolic pressure and pulmonary vascular resistance was determined in vivo or in ex vivo isolated lungs, respectively, and correlated with alterations in the composition of the gut microbiome, plasma metabolome, pulmonary inflammatory cell phenotype, and lung proteome. High-soluble-fiber diet increased the abundance of short-chain fatty acid-producing bacteria, with parallel increases in plasma propionate levels, and reduced the abundance of disease-related bacterial genera such as Staphylococcus, Clostridioides, and Streptococcus in hypoxic mice with parallel decreases in plasma levels of p-cresol sulfate. High-soluble-fiber diet decreased hypoxia-induced elevations of right ventricular systolic pressure and pulmonary vascular resistance. These changes were associated with reduced proportions of interstitial macrophages, dendritic cells, and nonclassical monocytes. Whole-lung proteomics revealed proteins and molecular pathways that may explain the effect of soluble-fiber supplementation. This study demonstrates for the first time that a high-soluble-fiber diet attenuates hypoxia-induced pulmonary vascular remodeling and the development of pulmonary hypertension in a mouse model of hypoxic pulmonary hypertension and highlights diet-derived metabolites that may have an immuno-modulatory role in the lung.

Prevalence and clinical significance of right ventricular pulmonary arterial uncoupling in cardiac amyloidosis

BackgroundThis study aims to evaluate the prevalence and the clinical significance of the right ventricular pulmonary arterial (RV-PA) uncoupling in patients with cardiac amyloidosis (CA). MethodsThe study population consisted in 92 consecutive patients with CA (age 71.1 ± 12.2 years, 71% males; 47% with immunoglobulin light chain (AL), 53% with transthyretin [ATTR]). A pre-specified tricuspid anulus plane systolic excursion on pulmonary arterial systolic pressure (TAPSE/PASP) value <0.31 mm/mmHg was used to define RV-PA uncoupling and to dichotomize the study population. ResultsThirty-two patients (35%) showed RV-PA uncoupling at baseline evaluation (15/44 [34%] AL and 17/48 [35%] ATTR). Patients with RV-PA uncoupling, in both AL and ATTR, showed worse NYHA functional class, lower systemic blood pressure, and more pronounced left ventricular and RV systolic dysfunction than those with RV-PA coupling.During a median follow-up of 8 months (IQR 4–13), 26 patients (28%) experienced cardiovascular death. Patients with RV-PA uncoupling showed lower survival at 12 months follow-up than those with RV-PA coupling (42.7% [95%CI 21.7–63.7%] vs. 87.3% [95%CI 78.3–96.3%], p-value<0.001). Multivariate analysis identified high-sensitivity troponin I values (HR 1.01 [95%CI 1.00–1.02] per 1 pg/mL increase; p-value 0.013) and TAPSE/PASP (HR 1.07 [95%CI 1.03–1.11] per 0.01 mm/mmHg decrease; p-value 0.002) as independent predictors of cardiovascular death. ConclusionsRV-PA uncoupling is common among patient with CA, and it is a marker of advanced disease and worse outcome. This study suggest that TAPSE/PASP ratio has the potential to improve risk stratification and guide management strategies in patients with CA of different etiology and advanced disease.

C63 PREVALENCE AND CLINICAL SIGNIFICANCE OF RIGHT VENTRICULAR PULMONARY ARTERIAL UNCOUPLING IN CARDIAC AMYLOIDOSIS

Abstract Background This study aims to evaluate the prevalence and clinical significance of the right ventricular pulmonary arterial (RV–PA) uncoupling in patients with cardiac amyloidosis (CA). Methods The study population consisted in 92 consecutive patients with CA (age 71.1±12.2 years, 71% males; 47% with immunoglobulin light chain (AL), 53% with transthyretin [ATTR]). All patients underwent a comprehensive evaluation. A pre–specified tricuspid annulus plane systolic excursion on pulmonary arterial systolic pressure (TAPSE/PASP) value &amp;lt;0.31 mm/mmHg was used to define RV–PA uncoupling and to dichotomize the study population. Results Thirty–two patients (35%) showed RV–PA uncoupling at baseline evaluation (15/44 [34%] AL and 17/48 [35%] ATTR). Patients with RV–PA uncoupling in both AL and ATTR showed worse NYHA functional class, lower systemic blood pressure, and more pronounced left and right ventricular systolic dysfunction than those with RV–PA coupling. During a median follow–up of 8 months (IQR 4–13), 26 patients (28%) experienced cardiovascular death. Patients with RV–PA uncoupling showed lower survival at 12 months follow–up than those with RV–PA coupling (42.7% [95%CI 21.7–63.7%] vs. 87.3% [95%CI 78.3–96.3%], p–value&amp;lt;0.001). Multivariate analysis identified high–sensitivity troponin I values (HR 1.01 [95%CI 1.00–1.02] per 1 pg/mL increase; p–value 0.013) and TAPSE/PASP (HR 1.07 [95%CI 1.03–1.11] per 0.01 mm/mmHg decrease; p–value 0.002) as independent predictors of cardiovascular death. Conclusions RV–PA uncoupling is common among patients with CA, and it is a marker of advanced disease and worse outcomes. This study suggest that TAPSE/PASP ratio has the potential to improve risk stratification and guide management strategies in patients with CA.

PS-B05-6: FABRY DISEASE MOUSE IS RESISTANT TO HIGH-SALT DIET-INDUCED HYPERTENSION PROBABLY VIA DYSFUNCTIONAL SODIUM TRANSPORTS AND AQUAPORIN 2

Background: Fabry disease is a rare X-linked lysosomal storage disorder resulting from an error in glycosphingolipid metabolism caused by the GLA gene mutation. Patients with Fabry disease often have near normal or even low systemic blood pressure although the mechanism underlying such observed finding remains unexplained. This study examined whether a high salt intake could affect transport of sodium and water and induce hypertension in mice with Fabry disease. Methods: Fabry disease model mice (B6;129-Glatm1Kul/J) and wild-type (WT) mice received 8% or normal NaCl salt diet for 2 weeks. Results: A high-salt diet for 2 weeks generated higher blood pressure in WT mice but not in Fabry disease mice. Free water clearance (FWC) and electrolyte free water clearance (EFWC) in groups fed with a high salt diet were lower than those in groups fed with a normal salt diet. Both high salt-fed WT and Fabry disease mice had decreased gamma-subunit of epithelial Na channel (ENaC) compared with normal salt-fed groups. In Fabry disease mice fed a high-salt diet, there was an decrease in renal expressions of Na+/H+ exchanger isoform 3 (NHE3) and Na+-Cl- cotransporter (NCC) compared with WT mice fed a high-salt diet. Although renal expression of vasopressin V2 receptor (V2R) was upregulated in Fabry mice fed with a high salt diet, renal aquaporin 2 (AQP2) level failed to increase up to the level in WT mice fed with a high salt diet. Conclusion: These findings suggest that the decreased expression of NHE3 and NCC and impaired response of AQP2 in kidneys of Fabry disease to a salt load could be one of mechanisms by which Fabry disease could have resistance to the development of hypertension.

A Review of the Roles of Apelin and ELABELA Peptide Ligands in Cardiovascular Disease, Including Heart Failure and Hypertension.

Apelin and ELABELA (ELA), which are peptides belonging to the adipokines group, are endogenous peptide ligands of their receptor, APJ, which together constitute the apelinergic system. The apelinergic system is expressed in numerous human tissues and organs, including the heart, blood vessels, adipose tissue, central nervous system, lungs, kidneys, and liver. Apelin, being the most widely studied member of the apelinergic system, plays a key role in the cardiovascular system and exerts a pleiotropic effect in tissues. Under physiological conditions, the peripheral actions of apelin include augmented cardiac contractility, increased left ventricular stroke volume, vasodilation, increased diuresis, and lowered systemic blood pressure. Multiple studies suggest that activation of the apelinergic system exerts beneficial effects on the treatment of cardiovascular diseases (CVD), including hypertension and heart failure, whereas the silencing of the apelin/APJ axis results in attenuation of inflammatory processes and prevents formation of atherosclerotic plaques. As numerous effects of apelin are not entirely explained, further studies of the cardiovascular actions of apelin and ELA are necessary to help establish effective pharmacological treatments of CVDs. This article aims to review the roles of apelin and elabela peptide ligands in cardiovascular diseases, including heart failure and hypertension.

Behavioral and cardiovascular effects of a single dose of gabapentin or melatonin in cats: a randomized, double-blind, placebo-controlled trial.

The aim of this study was to verify whether a single oral dose of gabapentin (100 mg) or melatonin (3 mg) given 60 mins before a cardiac evaluation would reduce anxiety without interfering with heart rate (HR), systemic blood pressure (SBP), electrocardiogram (ECG) and echocardiographic indexes. Seventy-five client-owned healthy cats underwent two sets of cardiac assessments 60 mins apart, randomly divided into gabapentin, melatonin and placebo groups. The interval between treatment and the second ECG and SBP measurement was 60 mins, and 70 mins for echocardiography. A compliance score (CS) classified the behavior, focusing on the ease of handling. Most variables did not change between the examinations. The placebo group showed more significant changes (SBP, tricuspid annular plane systolic excursion, HR during echocardiography, aortic flow velocity, S' wave from lateral mitral annulus), but they were not considered to be hemodynamically relevant. Gabapentin and melatonin significantly increased the cats' compliance without interfering with cardiac assessment. Eight cats presented with mild sedation, seven after gabapentin and one after melatonin. No major side effects were observed. Gabapentin tranquilized the cats when it was given 60 mins prior to ECG and SBP measurement, and 70 mins prior to echocardiography, without interfering with systolic echocardiographic indexes. Melatonin also decreased the CS, but without sedation in most cases. The waiting period may have relaxed the cats in the placebo group, resulting in lower SBP measurements. However, this tranquility did not last as some echocardiographic changes signaled a sympathetic predominance.

Abstract 15389: Insulin Like Growth Factor Binding Proteins 1 and 2 Are Prognostic Survival Markers in Intermediate Risk Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PH) is an often fatal disease of the pre-capillary pulmonary vasculature. Recognizing high risk PH in ambulatory patients is important for optimization of therapy to improve outcomes. We previously identified insulin like growth factor binding proteins 1 and 2 (IGFBP1, IGFBP2) as prognostic markers in severe PH; here, we evaluated IGFBP1/2 as prognostic markers in PH with intermediate risk features. Methods: A multiplex ELISA assay measured serum IGFBP1/2 in the multicenter PH Biobank (N=2450), and independent validation cohorts (Johns Hopkins, N=145, Vanderbilt N= 128, 388 observations over time). IGFBP1/2 concentrations were compared to hemodynamics, six-minute walk (6MW), and WHO functional class using linear/logistic regression adjusted for age and sex. Time to death/transplant by IGFBP1/2 levels was assessed by Cox proportional hazard models. Analysis was repeated in subjects with low to intermediate risk features defined as WHO functional class 1-2, 6MW &gt;300 m, and NT-proBNP &lt;1500 pg/mL, based on the REVEAL and ERS risk scores. 1, 2 Results: In all cohorts, increased IGFBP1 and IGFBP2 were associated with lower cardiac output, higher mean pulmonary artery pressure and pulmonary vascular resistance (PVR, p&lt;0.05 for all). In each sub-analysis, a higher IGFBP1 and IGFBP2 was associated with lower cardiac output, lower systemic blood pressure, and higher PVR (p&lt;0.05 for all). Higher IGFBP1 and IGFBP2 were associated with shorter time to death/transplant in the overall cohort and each of the intermediate risk PH cohorts (Table 1), although underpowered in the Vanderbilt cohort. Conclusions: Identifying patients who will have adverse outcome in intermediate risk PH has proven challenging. These data suggest IGFBP1/2 are good prognostic markers in PH where functional class and exertional tolerance is preserved. IGFBP1/2 could further discriminate adverse outcomes in patients with low to intermediate risk PH.

Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is reported to produce beneficial cardiovascular effects including a reduction in arterial contractility, and blood pressure. However, whether canagliflozin could directly relax resistance mesenteric arteries, underlying molecular mechanism and its role in regulating systemic blood pressure remain unclear. Here, we investigated the mechanism of regulation of small mesenteric artery contractility and its relevance for blood pressure regulation. Our pressure myography data showed that canagliflozin application rapidly produces a concentration-dependent vasodilation in mesenteric arteries. Such vasodilation was inhibited by concurrent inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 (by 1 μM DPO-1), KV2.1 (by 100 nM guangxitoxin), and KV7 (by 10 μM linopirdine) but not by the inhibition of small-, intermediate-, and large-conductance Ca2+-activated K+ channels (SKCa by 1 μM apamin, IKCa 10 μM TRAM-34, and BKCa by 10 μM paxilline, respectively), ATP-sensitive (KATP) channels (by 10 μM glibenclamide), or SERCA pump (by 0.1 μM thapsigargin). Inhibition of SGLTs (by 1 μM phlorizin or the inhibition of endothelial signaling did not alter canagliflozin-evoked vasodilation. Consistently, acute canagliflozin treatment (4 mg/kg body weight) lowered systemic blood pressure in vivo. Overall, our data suggests that canagliflozin stimulates KV1.5, KV2.1, and KV7 channels, leading to vasodilation and a reduction of systemic blood pressure.

Chinese Classical Music Lowers Blood Pressure and Improves Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats.

High blood pressure (BP) plays an important role in the pathogenesis and development of cardiovascular diseases and multi-organ damages. Music has been well known to elicit emotional changes, such as anxiolytic effects. However, whether music therapy lowers BP in spontaneously hypertensive rats (SHR) and the potential mechanism remains unknown. SHRs were, respectively exposed to white noise (WN), Western classical music (WM), Chinese classical music (CCM), rock music (RM), and bisoprolol treatment. WN and WM did not lower systemic BP, but CCM and RM significantly lowered BPs in SHRs. The effects of CCM therapy on lowering systemic BPs is comparable to that of bisoprolol at the dose of low to medium. Combination of CCM treatment with bisoprolol further improved systemic BPs and myocardial hypertrophy in SHRs, compared to CCM treatment or bisoprolol alone. Furthermore, IHC and WB analysis indicated that CCM therapy inhibited the β1/cAMP/PKA and α1/PLC/PKC signalings, but didn’t alter the β2/PI3K/Akt signaling. Above all, CCM therapy lowers systemic BPs and alleviates myocardial hypertrophy in hypertensive rats, which may be caused by the inhibitions of β1/cAMP/PKA and α1/PLC/PKC signalings.

Reduced blood pressure in sickle cell disease is associated with decreased angiotensin converting enzyme (ACE) activity and is not modulated by ACE inhibition.

BackgroundSickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD.MethodsBP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR.ResultsDiastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice.ConclusionRelative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD.

Pulmonary Hypertension in Pregnancy: A Positive Outcome with a Multidisciplinary Team and Individualized Treatment Plan

PULMONARY HYPERTENSION (PH) is a challenging disease to treat and is associated with a great degree of morbidity and mortality. When a right ventricle, which is accustomed to operating at low pressure, faces the increased afterload that is conferred with PH, especially in the acute setting, it is prone to failure and ultimately can result in hemodynamic collapse. The normal physiologic changes of pregnancy, particularly increased blood volume, lower systemic vascular resistance and systemic blood pressure, and increased cardiac output, are particularly deleterious in the patient with PH. Here, the authors describe a case of a woman who was diagnosed with severe PH during pregnancy and was safely navigated through a cesarean section and the subsequent postpartum period.

Biomarker Association with Hypertension in Mild Versus Severe Sickle Cell Disease Genotypes of a Single Center Cohort, in Comparison with African Americans from the Nhanes Study

Introduction: Previous studies have reported that patients with sickle cell disease (SCD) have lower systemic blood pressures when compared with age-, sex-, and race-matched controls. We compared systolic and diastolic blood pressure (SBP and DBP) measurements in an SCD patient cohort followed at our clinical center with values obtained from background population using African Americans from the National Health and Nutrition Examination Survey (NHANES) study. Furthermore, we evaluated the association of SBP and DBP with clinical and laboratory variables in our patient cohort in comparison to NHANES.Methods: We cross-sectionally analyzed 442 adult SCD patients receiving medical care at the University of Illinois at Chicago (UIC) between 2009-2018, categorized as severe (HbSS/Sβ 0-thalassemia; n=342) or mild (HbSC/Sβ +-thalassemia; n=100) genotypes. 884 African American from the NHANES were age-, sex-, and race- matched as control in a 2:1 ratio. We evaluated associations between systolic and diastolic BP and 32 clinical and laboratory variables. Evaluation of medians, interquartile range (IQR), Wilcoxon rank sum and the χ2 test, were performed on covariates. Clinical associations between biomarkers and primary outcomes of SBP, DBP, were determined by first applying single marker regression with covariates. Significant biomarkers were then analyzed by multi-marker regression and model selection to predict the relative strength of outcome association for these biomarkers. All variables included were normally distributed or transformed to normal distribution.Results: The median age of participants ranged from 31-38 years for both SCD cohorts and NHANES control. 16%, 21% and 8% of the mild genotype patients, severe genotype patients and NHANES controls, respectively were on at least one antihypertensive medication for either hypertension or proteinuria. The median (IQR) for systolic and diastolic BP for the patients with mild genotype were 122 mm Hg (112-130) and 78mmHg (70-84); severe genotype 119 mmHg (110-128) and 70 mmHg (64-75); NHANES 118(110-128) and 70 mmHg (62-78). Systolic blood pressures did not differ among the SCD groups versus NHANES, but diastolic blood pressures were higher in the mild SCD genotype patients than severe SCD patients (P<0.0001) or NHANES (P<0.0001), regardless of antihypertensive therapy. After controlling for covariates, in the severe genotype patients SBP associated significantly with gender and prior diagnosis of hypertension, but SBP associated only with hemoglobin level in the mild genotype patients. In contrast diastolic BP associated with gender and hemoglobin in the mild genotype but had no significant association in the severe genotype patients. In the NHANES controls, we observed that SBP was significantly associated with age, gender, BMI, prior hypertension, LDH, total bilirubin, urine albumin-creatinine ratio; and DBP associated with age, BMI, WBC count (Table 1).Discussion: Our SCD patient cohorts demonstrate a much higher median SBP, and for the mild genotype patients, higher DBP than was described for their age group in the cooperative study of sickle cell disease (Pegelow et al 1997). When compared with a contemporary NHANES cohort, we failed to observe a lower SBP or DBP as was expected. Higher systolic blood pressure has been reported as risk factor for the development of silent cerebral infarct in HbSS children (DeBaun et al 2014). Our study also shows that BP changes in SCD may be less influenced by traditional anthropometric measures and clinical markers. [Display omitted] DisclosuresSaraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy.

Dual-Functional MN-08 Attenuated Pulmonary Arterial Hypertension Through Vasodilation and Inhibition of Pulmonary Arterial Remodeling.

[Figure: see text].

Role of the superior salivatory nucleus in parasympathetic control of choroidal blood flow and in maintenance of retinal health

The vasodilatory pterygopalatine ganglion (PPG) innervation of the choroid is under the control of preganglionic input from the superior salivatory nucleus (SSN), the parasympathetic portion of the facial motor nucleus. We sought to confirm that choroidal SSN drives a choroid-wide vasodilation and determine if such control is important for retinal health. To the former end, we found, using transscleral laser Doppler flowmetry, that electrical activation of choroidal SSN significantly increased choroidal blood flow (ChBF), at a variety of choroidal sites that included more posterior as well as more anterior ones. We further found that the increases in ChBF were significantly reduced by inhibition of neuronal nitric oxide synthase (nNOS), thus implicating nitrergic PPG terminals in the SSN-elicited ChBF increases. To evaluate the role of parasympathetic control of ChBF in maintaining retinal health, some rats received unilateral lesions of SSN, and were evaluated functionally and histologically. In eyes ipsilateral to choroidal SSN destruction, we found that the flash-evoked scotopic electroretinogram a-wave and b-wave peak amplitudes were both significantly reduced by 10 weeks post lesion. Choroidal baroregulation was evaluated in some of these rats, and found to be impaired in the low systemic arterial blood pressure (ABP) range where vasodilation normally serves to maintain stable ChBF. In retina ipsilateral to SSN destruction, the abundance of Müller cell processes immunolabeled for glial fibrillary acidic protein (GFAP) and GFAP message were significantly upregulated. Our studies indicate that the SSN-PPG circuit mediates parasympathetic vasodilation of choroid, which appears to contribute to ChBF baroregulation during low ABP. Our results further indicate that impairment in this adaptive mechanism results in retinal dysfunction and pathology within months of the ChBF disturbance, indicating its importance for retinal health.

Pulmonary vasodilation by sildenafil in acute intermediate-high risk pulmonary embolism: a randomized explorative trial

BackgroundTo investigate if acute pulmonary vasodilation by sildenafil improves right ventricular function in patients with acute intermediate-high risk pulmonary embolism (PE).MethodsSingle center, explorative trial. Patients with PE were randomized to a single oral dose of sildenafil 50 mg (n = 10) or placebo (n = 10) as add-on to conventional therapy. The time from hospital admission to study inclusion was 2.3 ± 0.7 days. Right ventricular function was evaluated immediately before and shortly after (0.5–1.5 h) randomization by right heart catheterization (RHC), trans-thoracic echocardiography (TTE), and cardiac magnetic resonance (CMR). The primary efficacy endpoint was cardiac index measured by CMR.ResultsPatients had acute intermediate-high risk PE verified by computed tomography pulmonary angiography, systolic blood pressure of 135 ± 18 (mean ± SD) mmHg, increased right ventricular/left ventricular ratio 1.1 ± 0.09 and increased troponin T 167 ± 144 ng/L. Sildenafil treatment did not improve cardiac index compared to baseline (0.02 ± 0.36 l/min/m2, p = 0.89) and neither did placebo (0.00 ± 0.34 l/min/m2, p = 0.97). Sildenafil lowered mean arterial blood pressure (− 19 ± 10 mmHg, p < 0.001) which was not observed in the placebo group (0 ± 9 mmHg, p = 0.97).ConclusionA single oral dose of sildenafil 50 mg did not improve cardiac index but lowered systemic blood pressure in patients with acute intermediate-high risk PE. The time from PE to intervention, a small patient sample size and low pulmonary vascular resistance are limitations of this study that should be considered when interpreting the results.Trial Registration: The trial was retrospectively registered at www.clinicaltrials.gov (NCT04283240) February 2nd 2020, https://clinicaltrials.gov/ct2/show/NCT04283240?term=NCT04283240&draw=2&rank=1.

The Association Between Arterial Oxygen Level and Outcome in Neurocritically Ill Patients is not Affected by Blood Pressure

BackgroundIn neurocritically ill patients, one early mechanism behind secondary brain injury is low systemic blood pressure resulting in inadequate cerebral perfusion and consequent hypoxia. Intuitively, higher partial pressures of arterial oxygen (PaO2) could be protective in case of inadequate cerebral circulation related to hemodynamic instability.Study purposeWe examined whether the association between PaO2 and mortality is different in patients with low compared to normal and high mean arterial pressure (MAP) in patients after various types of brain injury.MethodsWe screened the Finnish Intensive Care Consortium database for mechanically ventilated adult (≥ 18) brain injury patients treated in several tertiary intensive care units (ICUs) between 2003 and 2013. Admission diagnoses included traumatic brain injury, cardiac arrest, subarachnoid and intracranial hemorrhage, and acute ischemic stroke. The primary exposures of interest were PaO2 (recorded in connection with the lowest measured PaO2/fraction of inspired oxygen ratio) and the lowest MAP, recorded during the first 24 h in the ICU. PaO2 was grouped as follows: hypoxemia (< 8.2 kPa, the lowest 10th percentile), normoxemia (8.2–18.3 kPa), and hyperoxemia (> 18.3 kPa, the highest 10th percentile), and MAP was divided into equally sized tertiles (< 60, 60–68, and > 68 mmHg). The primary outcome was 1-year mortality. We tested the association between hyperoxemia, MAP, and mortality with a multivariable logistic regression model, including the PaO2, MAP, and interaction of PaO2*MAP, adjusting for age, admission diagnosis, premorbid physical performance, vasoactive use, intracranial pressure monitoring use, and disease severity. The relationship between predicted 1-year mortality and PaO2 was visualized with locally weighted scatterplot smoothing curves (Loess) for different MAP levels.ResultsFrom a total of 8290 patients, 3912 (47%) were dead at 1 year. PaO2 was not an independent predictor of mortality: the odds ratio (OR) for hyperoxemia was 1.16 (95% CI 0.85–1.59) and for hypoxemia 1.24 (95% CI 0.96–1.61) compared to normoxemia. Higher MAP predicted lower mortality: OR for MAP 60–68 mmHg was 0.73 (95% CI 0.64–0.84) and for MAP > 68 mmHg 0.80 (95% CI 0.69–0.92) compared to MAP < 60 mmHg. The interaction term PaO2*MAP was nonsignificant. In Loess visualization, the relationship between PaO2 and predicted mortality appeared similar in all MAP tertiles.ConclusionsDuring the first 24 h of ICU treatment in mechanically ventilated brain injured patients, the association between PaO2 and mortality was not different in patients with low compared to normal MAP.

Risk Factors for Advanced Atherosclerosis Detected on Computed Tomography Coronary Angiography in Patients with Liver Cirrhosis

Traditionally, a low systemic blood pressure and impaired lipid metabolism in liver cirrhosis has been thought to be protective against development of coronary atherosclerosis. Whether conventional cardiovascular risk factors in these patients predispose to the development of advanced atherosclerosis is unclear.

Care Right Where You Are: Treating in Place to Avoid an Emergency Department Visit or Hospitalization

Care Right Where You Are: Treating in Place to Avoid an Emergency Department Visit or Hospitalization

Milrinone Use in Persistent Pulmonary Hypertension of the Newborn.

Failure of the normal transition from in utero to ex utero physiology leads to "persistent" pulmonary hypertension of the newborn (PPHN). PPHN is frequently associated with low systemic blood pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction. The general management of newborns with PPHN is geared toward maintenance of normothermia, normal serum electrolytes, normal intravascular volume, correction of acidosis, adequate sedation/analgesia, adequate ventilation and oxygenation with optimal lung recruitment, and avoidance of hyperoxia. Inotropic and vasoactive agents are commonly initiated early to increase cardiac output, maintain adequate systemic blood pressure, and enhance oxygen delivery to the tissue. Unfortunately, there is not much evidence on the choice, timing of initiation, dosing, monitoring, and titrating of vasoactive agents in this patient population. In this review, we will discuss the pathophysiology of PPHN and review the use of inotropic, lusitropic, and vasoactive agents in the management of PPHN, with particular attention to milrinone.

The role of the red blood cell and platelet in the evolution of mammalian and avian endothermy.

This review presents evidence to support the hypothesis that the reduced O2 during the Permian/Triassic period was the impetus for the evolutionary selection of endothermic animals. The evolution of smaller red blood cells with greater surface areas along with increased: capillary density, capillary surface area, hematocrits, blood pressure, blood flow rates, and shear rates were critical for efficient gas exchange in endothermy. The evolution of the four-chambered mammalian/avian heart allowed for low pulmonary and high systemic blood pressure. It is proposed that hypoxia-induced angiogenesis led to increased vascularization in endothermic animals. The increased blood pressure, flow rates, and shear forces likely required changes in hemostatic mechanisms that were met in mammals by the evolution of anucleate platelets. The evolution of mammals and birds occurred in a parallel fashion with further genetic changes to anucleate RBCs/platelets occurring in mammals. Although it is possible that the evolution of endothermy in birds and mammals occurred as two independent events, it is more likely that a common ancestor developed genetic mutations that laid down the road map for parallel alterations of their cardiovascular system in response to environmental pressures. Model systems to support the proposed changes from ectotherm to endotherm were developed from published data. The evolutionary development of endothermy occurred over millions of years with a continuum of genetic alterations that involved skeletal, soft tissue, cardiovascular macrochanges along with numerous molecular alterations. Genetic signals and potential regulators for the evolutionary changes of endothermic blood cells from their bipotential stem cells are also proposed.