Electrophysiology of human iPSC-derived vascular smooth muscle cells and cell autonomous consequences of Cantu Syndrome mutations.

OBJECTIVE: Cantu Syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by GoF variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels, and is characterized by low systemic vascular resistance, as well as tortuous, dilated vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell-autonomously within vascular smooth muscle cells (VSMCs), or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. APPROACH AND RESULTS: Whole-cell voltage-clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were consistent with those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance, and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae, and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs, suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. CONCLUSIONS: The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs.

In silico modelling of stroke volume, cardiac output and systemic vascular resistance in cardiovascular safety pharmacology studies by telemetry.

The principle of proportionality of the systolic area of the central aortic pressure to stroke volume (SV) has been long known. The aim of the present work was to evaluate an in silico solution derived from this principle for modelling SV (iSV model) in cardiovascular safety pharmacology studies by telemetry. Blood pressure was measured in the abdominal aorta in accordance with standard practice. Central aortic pressure was modelled from the abdominal aortic pressure waveform using the N-point moving average (NPMA) method for beat-to-beat estimation of SV. First, the iSV was compared to the SV measured by ultrasonic flowmetry in the ascending aorta (uSV) after various pharmacological challenges in beagle dogs anaesthetised with etomidate/fentanyl. The iSV showed minimal bias (0.2 mL i.e. 2%) and excellent agreement with uSV. Then, previous telemetry studies including reference vasoactive and inotropic compounds were retrospectively reanalysed to model drug effects on stroke volume (iSV), cardiac output (iCO) and systemic vascular resistance (iSVR). Among them, the examples of nicardipine and isoprenaline highlight risks of erroneous or biased estimation of drug effects from the abdominal aortic pressure due to pulse pressure amplification. Furthermore, the examples of verapamil, quinidine and moxifloxacin show that iSV, iCO and iSVR are earlier biomarkers than blood pressure itself for predicting drug effect on blood pressure. This in silico modelling approach included in vivo telemetry safety pharmacology studies can be considered as a New Approach Methodology (NAM) that provides valuable additional information and contribute to improving non-clinical translational research to the clinic.

The relative potential contribution of volume load and vascular mechanisms to hypertension in non-dialysis and dialysis chronic kidney disease patients.

Background: Hypertension is highly prevalent and particularly difficult to treat adequately in patients with chronic kidney disease (CKD). The relative contribution of volume overload and vascular mechanisms to blood pressure measures in CKD and whether these effects differ in non-dialysis compared to dialysis patients is unknown. Methods: We determined the potential impact of volume load (stroke volume) and vascular mechanisms (inverse of total arterial compliance (inv TAC) and systemic vascular resistance (SVR)) on mean and brachial and aortic systolic blood pressures in 67 non-dialysis and 48 dialysis chronic kidney disease (CKD) patients. Relationships were determined in confounder adjusted regression models. Results: Stroke volume (p value = 0.003) was more strongly associated with mean arterial pressure than SVR (p value = 0.9) (p value for difference = 0.03). When stroke volume and SVR were entered in the same regression model (model R2 = 0.324), they contributed equally to the variation in mean arterial pressure (p value for difference = 0.5). Stroke volume (p value ≤ 0.002) and inv TAC (p value ≤ 0.001) contributed equally to the variation in systolic pressures (p value for difference ≥ 0.9). When stroke volume and inv TAC were entered in the same regression model (model R2 = 0.752 to 0.765), they contributed equally to the variation in systolic blood pressures (p value for difference = 0.7). Stroke volume, TAC and SVR were similar (p value ≥ 0.5) and associated to the same extent with blood pressure measures in non-dialysis and dialysis CKD patients (p value for difference ≥ 0.1). In receiver operator characteristic curve analysis, elevated systolic blood pressure was determined by stroke volume (p value = 0.005) and inv TAC (p value = 0.03) but not SVR (p value = 0.8). The calculated power of the study was 0.999 based on α = 0.05. Conclusions: The present investigation suggests that both volume load and vascular mechanisms should be considered in the management of hypertension among patients with CKD. The extent and relative potential impact of volume load and vascular mechanisms on blood pressure measures are as large in non-dialysis compared to dialysis CKD patients.

Correlation between the radial artery resistance index and the systemic vascular resistance index: a cross-sectional study.

INTRODUCTION: Ultrasound measurement of the radial resistance index (RRI) in the anatomical snuffbox has been proposed as a useful method for assessing the systemic vascular resistance index (SVRI). This study aims to establish the correlation between SVRI measured by pulmonary artery catheter (PAC) and RRI. METHODS: A cross-sectional study included all consecutive patients undergoing postoperative (POP) cardiac surgery with hemodynamic monitoring using PAC. Hemodynamic assessment was performed using PAC, and RRI was measured with ultrasound in the anatomical snuffbox. The Pearson correlation test was used to establish the correlation between RRI and SVRI measured using PAC. Hemodynamic behavior concerning RRI with a cutoff point of 1.1 (described to estimate under SVRI) was examined. Additionally, consistency between two evaluators was assessed for RRI using the intraclass correlation coefficient and Bland-Altman analysis. RESULTS: A total of 35 measurements were obtained. The average cardiac index (CI) was 2.73 ± 0.64 L/min/m², and the average SVRI was 1967.47 ± 478.33 dyn·s·m²/cm5. The correlation between RRI and SVRI measured using PAC was 0.37 [95% CI 0.045-0.62]. The average RRI was 0.94 ± 0.11. RRI measurements > 1.1 had a mean SVRI of 2120.79 ± 673.48 dyn·s·m²/cm5, while RRI measurements ≤ 1.1 had a mean SVRI of 1953.1 ± 468.17 dyn·s·m²/cm5 (p = 0.62). The consistency between evaluators showed an intraclass correlation coefficient of 0.88 [95% CI 0.78-0.93], and Bland-Altman analysis illustrated adequate agreement of RRI evaluators. CONCLUSIONS: For patients in cardiac surgery POP, the correlation between the SVRI measured using PAC and the RRI measured in the anatomical snuffbox is low. Using the RRI as a SVRI estimator for patients is not recommended in this clinical scenario.

Nitric oxide donor increases umbilical vein blood flow and fetal oxygenation in fetal growth restriction. A pilot study.

INTRODUCTION: To evaluate the maternal and fetal hemodynamic effects of treatment with a nitric oxide donor and oral fluid in pregnancies complicated by fetal growth restriction. METHODS: 30 normotensive participants with early fetal growth restriction were enrolled. 15 participants were treated until delivery with transdermal glyceryl trinitrate and oral fluid intake (Treated group), and 15 comprised the untreated group. All women underwent non-invasive assessment of fetal and maternal hemodynamics and repeat evaluation 2 weeks later. RESULTS: In the treated group, maternal hemodynamics improved significantly after two weeks of therapy compared to untreated participants. Fetal hemodynamics in the treated group showed an increase in umbilical vein diameter by 18.87 % (p < 0.01), in umbilical vein blood flow by 48.16 % (p < 0.01) and in umbilical vein blood flow corrected for estimated fetal weight by 30.03 % (p < 0.01). In the untreated group, the characteristics of the umbilical vein were unchanged compared to baseline. At the same time, the cerebro-placental ratio increased in the treated group, while it was reduced in the untreated group, compared to baseline values. The treated group showed a higher birthweight centile (p = 0.03) and a lower preeclampsia rate (p = 0.04) compared to the untreated group. DISCUSSION: The combined therapeutic approach with nitric oxide donor and oral fluid intake in fetal growth restriction improves maternal hemodynamics, which becomes more hyperdynamic (volume-dominant). At the same time, in the fetal circuit, umbilical vein flow increased and fetal brain sparing improved. Although a modest sample size, there was less preeclampsia and a higher birthweight suggesting beneficial maternal and fetal characteristics of treatment.

Controlled Mechanical Ventilation in Critically Ill Patients and the Potential Role of Venous Bagging in Acute Kidney Injury.

A very low incidence of acute kidney injury (AKI) has been observed in COVID-19 patients purposefully treated with early pressure support ventilation (PSV) compared to those receiving mainly controlled ventilation. The prevention of subdiaphragmatic venous congestion through limited fluid intake and the lowering of intrathoracic pressure is a possible and attractive explanation for this observed phenomenon. Both venous congestion, or "venous bagging", and a positive fluid balance correlate with the occurrence of AKI. The impact of PSV on venous return, in addition to the effects of limiting intravenous fluids, may, at least in part, explain this even more clearly when there is no primary kidney disease or the presence of nephrotoxins. Optimizing the patient-ventilator interaction in PSV is challenging, in part because of the need for the ongoing titration of sedatives and opioids. The known benefits include improved ventilation/perfusion matching and reduced ventilator time. Furthermore, conservative fluid management positively influences cognitive and psychiatric morbidities in ICU patients and survivors. Here, it is hypothesized that cranial lymphatic congestion in relation to a more positive intrathoracic pressure, i.e., in patients predominantly treated with controlled mechanical ventilation (CMV), is a contributing risk factor for ICU delirium. No studies have addressed the question of how PSV can limit AKI, nor are there studies providing high-level evidence relating controlled mechanical ventilation to AKI. For this perspective article, we discuss studies in the literature demonstrating the effects of venous congestion leading to AKI. We aim to shed light on early PSV as a preventive measure, especially for the development of AKI and ICU delirium and emphasize the need for further research in this domain.

Hormonal Control of Blood Viscosity.

The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities. Accordingly, the risk of turbulence, which is dictated by the Reynolds and Dean numbers, also varies. Relatively high blood viscosity is needed to prevent turbulence in the left ventricle and aorta, where high-velocity blood changes direction several times. Low blood viscosity is needed in the capillaries, where erythrocytes pass through vessels with a diameter smaller than their own. In addition, higher blood viscosity is necessary when the cardiac output and peak blood velocity increase as a part of a sympathetic response or anemia, which occurs following significant hemorrhage. Blood viscosity, as reflected in systemic vascular resistance and vascular wall shear stress, is sensed, respectively, by cardiomyocyte stretching in the left ventricle and mechanoreceptors for wall shear stress in the carotid sinus. By controlling blood volume and red blood cell mass, the renin-aldosterone-angiotensin system and the systemic vascular resistance response control the hematocrit, the strongest intrinsic determinant of blood viscosity. These responses provide gross control of blood viscosity. Fine-tuning of blood viscosity in transient conditions is provided by hormonal control of erythrocyte deformability. The short half-life of some of these hormones limits their activity to specific vascular beds. Hormones that modulate blood viscosity include erythropoietin, angiotensin II, brain natriuretic factor, epinephrine, prostacyclin E2, antidiuretic hormone, and nitric oxide.

Body Positions Alter Hemodynamics and Respiration in Healthy Adults: A Systematic Review and Meta-Analysis.

Objective Different body positions can exert both positive and negative physiological effects on hemodynamics and respiration. This study aims to conduct a literature review and examine hemodynamic and respiratory alterations to different body positions.Methods The study protocol was registered with the International Prospective Registry of Systematic Reviews (register no. CRD42021291464). Two independent reviewers evaluated the methodological quality of all included studies using the Down and Black checklist, while the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations approach. The overall effects of different body positions were reported from random effects meta-analysis.Results Three studies with low risk of bias and ten with high risk of bias met the eligibility criteria. The supine resulted in the highest cardiac output compared to the 70 deg head-up tilt, sitting, and standing positions (very low- to moderate-quality evidences) and the lowest systemic vascular resistance compared to the 70 deg head-up tilt and standing positions (moderate-quality evidence). Additionally, the supine was associated with the highest total respiratory resistance compared to the 70 deg head-up tilt, left lateral, and standing positions (very low-to moderate-quality evidence) and higher alveolar ventilation than the prone (low-quality evidence).Conclusions The supine position has the most positive association with hemodynamic variables, resulting in the highest cardiac output and the lowest systemic vascular resistance. The upright positions (70 deg head-up tilt and standing positions) has the most positive association with the respiratory variables, resulting in the lowest total respiratory resistance.

Systemic Vascular Resistance and Myocardial Work Analysis in Hypertrophic Cardiomyopathy and Transthyretin Cardiac Amyloidosis with Preserved Left Ventricular Ejection Fraction.

Background: The pathophysiological impact of systemic vascular resistance (SVR) and pressure-strain loop-derived global myocardial work index (GWI) in hypertrophic cardiomyopathy (HCM) and transthyretin cardiac amyloidosis (ATTR) has been randomly investigated. Methods: Both SVR and GWI were assessed in outpatients consecutively referred at two Italian cardiology departments for heart failure with preserved left ventricular ejection fraction (LVEF), affected by either nonobstructive HCM or wild-type ATTR. Based on relevant cross-tabulations, the patients were gathered into 4 functional classes according to cut-off values of 1440 dyne/s/cm-5 for SVR, and 1576 mm Hg% for GWI, as suggested by previous studies. Results: A total of 60 patients, 30 in each group, aged 61 ± 16 years, with 78% males, were studied. HCM patients were younger than those with ATTR and in a better clinical condition (23% HCM vs. 77% ATTR were NYHA class II-III, p < 0.001). Overall, 51 patients (85%) showed a high SVR, 21/30 HCM (70%), and 30 ATTR (100%) (p < 0.005). Both SVR and GWI (expressions of ventricular-arterial coupling) were impaired in 43% of HCM patients (showing greater LV concentric hypertrophy) and 93% of ATTR patients (in advanced NYHA functional class) (p < 0.001). Conclusions: A substantial percentage of present study population showed impaired SVR and/or GWI, despite preserved LVEF. The proposed classification may shed further light on the pathophysiological and clinical characteristics of such hypertrophic phenotypes.

Use of non-invasive cardiac monitoring to guide discontinuation of postpartum magnesium sulfate in individuals with preeclampsia with severe features.

OBJECTIVES: To determine the utility of using total peripheral systemic vascular resistance assessed using non-invasive cardiac monitor for individualizing the duration of postpartum magnesium sulfate in individuals with preeclampsia with severe features. STUDY DESIGN: Single center pilot randomized controlled trial in which singleton pregnant individuals with preeclampsia with severe features were randomized to 24 h of postpartum magnesium sulfate per standard of care (control group) or individualized duration of postpartum magnesium sulfate based on reduction in post-delivery systemic vascular resistance (intervention group). Systemic vascular resistance was assessed with non-invasive cardiac monitoring using the Cheetah® system. A 30 % reduction (maintained for 1 h) from baseline post-delivery systemic vascular resistance was used as a cutoff for discontinuation of postpartum magnesium sulfate. Our primary outcome was duration of postpartum magnesium sulfate use in hours. Secondary outcomes included a composite of maternal morbidities associated with preeclampsia. RESULTS: Of 53 individuals enrolled, we excluded 6 from this analysis due to insufficient data to assess primary outcome. Baseline characteristics of the control (n = 26) and intervention (n = 21) groups were similar. Six (28.6 %) individuals in intervention group met the systemic vascular resistance criteria and had their postpartum magnesium sulfate discontinued before 24 h. The duration of postpartum magnesium sulfate infusion was shorter in the intervention group (21.6 ± 4.7 h; range: 7-24 h) compared with control group (24 h, p = 0.02). There was no difference in secondary outcomes between the two groups. There was no difference in adverse outcomes in individuals that had magnesium discontinued earlier than 24 h. CONCLUSION: Non-invasive monitoring of systemic vascular resistance can be a valuable tool to individualize the duration of postpartum magnesium sulfate for preeclampsia with severe features. These findings should be conformed in a larger trial.

Hemodynamic evaluation in preterm infants using ultrasonic cardiac output monitor (USCOM).

We aimed to establish reference ranges for USCOM parameters in preterm infants, determine factors that affect cardiac output, and evaluate the measurement repeatability. This retro-prospective study was performed at Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. We included infants below 32 weeks of gestational age (GA) and/or 1500 g of birth weight (BW). We excluded infants with congenital heart diseases or hemodynamic instability. Measurements were performed at 3 ± 1, 7 ± 2, and 14 ± 2 postnatal days. We analyzed 204 measurements from 92 patients (median GA = 30.57 weeks, BW = 1360 g). The mean (SD) cardiac output (CO) was 278 (55) ml/min/kg, cardiac index (CI) was 3.1 (0.5) L/min/m2, and systemic vascular resistance (SVRI) was 1292 (294) d*s*cm-5/m2. CO presented a negative correlation with postmenstrual age (PMA), while SVRI presented a positive correlation with PMA. The repeatability coefficient was 31 ml/kg/min (12%).  Conclusion: This is the first study describing reference values for USCOM parameters in hemodynamically stable preterm infants and factors affecting their variability. Further studies to investigate the usefulness of USCOM for the longitudinal assessment of patients at risk for cardiovascular instability or monitoring the response to therapies are warranted. What is Known: • The ultrasonic cardiac output monitoring (USCOM) has been widely used on adult and pediatric patients and reference ranges for cardiac output (CO) by USCOM have been established in term infants. What is New: • We established reference values for USCOM parameters in very preterm and very-low-birth-weight infants; the reference ranges for CO by USCOM in the study population were 198-405 ml/kg/min. • CO normalized by body weight presented a significant negative correlation with postmenstrual age (PMA); systemic vascular resistance index presented a significant positive correlation with PMA.

Reference ranges for third-trimester maternal cardiovascular function parameters measured in normotensive pregnant women using a non-invasive cardiac output monitor: A study based on data from the prospective PEACH cohort study.

OBJECTIVE: We defined reference ranges for maternal cardiac output, systemic vascular resistance, and stroke volume measured in the third trimester of pregnancy using the Ultrasound Cardiac Output Monitor 1A. DESIGN: Based on data from the prospective PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension) cohort study. SETTING: Rigshospitalet and Hvidovre Hospital, Denmark. SAMPLE: Normotensive pregnant women aged 18-45 years with singleton pregnancies, enrolled in the PEACH study in 2016-2018. METHODS: We modelled cardiac output, systemic vascular resistance and stroke volume as a function of gestational age using multilevel linear models with fractional polynomials. MAIN OUTCOME MEASURES: Unconditional and conditional reference ranges for cardiovascular parameters measured in gestational weeks 28-40. RESULTS: Our study cohort included 405 healthy pregnant women who contributed 1210 cardiovascular function measurements for analysis. Maximum cardiac output and stroke volume values were measured in gestational weeks 30-32 and decreased over the third trimester, whereas systemic vascular resistance increased during the same period. We created reference ranges for eight combinations of maternal height, age and parity. We also created a simple calculator to allow for implementation of the reference ranges in clinical practice. CONCLUSIONS: Our reference ranges allow the use of a bedside ultrasound device to non-invasively assess cardiac function in pregnancy and identify women at risk of complications. The unconditional ranges allow clinicians to evaluate isolated measurements and identify women needing follow-up. The conditional ranges incorporate information from previous measurements and improve monitoring over time.

Systemic vascular resistance predicts high-output cardiac failure in patients with high-flow arteriovenous fistula.

AIMS: Patients with high-flow arteriovenous (AV) access are at risk of developing high-output cardiac failure (HOCF) and subsequent hospitalization. However, diagnosing HOCF is challenging and often requires invasive procedures. The role of systemic vascular resistance (SVR) in diagnosing HOCF is underestimated, and its predictive value is limited. Our study aims to identify non-invasive risk factors for HOCF to facilitate early diagnosis and timely surgical interventions. METHODS AND RESULTS: We included 109 patients with high-flow AV access who underwent serial echocardiography. The retrospective cohort was divided into two groups based on their hospitalization due to HOCF. The two groups were matched for age and gender. After a mean follow-up of 25.1 months, 19 patients (17.4%) were hospitalized due to HOCF. The two groups had similar baseline characteristics. However, the HOCF group had a higher value of vascular access blood flow (Qa) (2168 ± 856 vs. 1828 ± 617 mL/min; P = 0.045). Echocardiographic analysis revealed that the HOCF group had more pronounced left ventricular diastolic dysfunction (E/e': 21.1 ± 7.3 vs. 16.2 ± 5.9; P = 0.002), more severe pulmonary hypertension (right ventricular systolic pressure: 41.4 ± 16.7 vs. 32.2 ± 12.8; P = 0.009), a higher Doppler-derived cardiac index (CI) (4.3 ± 0.8 vs. 3.7 ± 1.1; P = 0.031), and a lower Doppler-derived estimated SVR (eSVR) value (5.5 ± 0.3 vs. 6.9 ± 0.2; P = 0.002) than the non-HOCF group. Using multivariable Cox regression analysis, a low eSVR value (<6) emerged as an independent predictor of HOCF hospitalization with a hazard ratio of 9.084 (95% confidence interval, 2.33-35.39; P = 0.001). Receiver operating characteristic curve analysis indicated that CI/eSVR values more accurately predicted HOCF hospitalization [sensitivity: 94.7%, specificity: 51.0%, area under the curve (AUC): 0.75, P < 0.001] than the Qa/cardiac output ratio (AUC: 0.50, P = 0.955), Qa values ≥ 2000 mL/min (AUC: 0.60, P = 0.181), and Qa values indexed for height in metres (AUC: 0.65, P = 0.040). CONCLUSIONS: In patients with high-flow AV access, low eSVR values obtained through non-invasive Doppler echocardiography were associated with a high rate of HOCF hospitalizations. Therefore, routine eSVR screening in these patients might expedite the diagnosis of HOCF.

Dilemmas of Adopting Goal-Directed Perfusion in Extracorporeal Circulation: A Narrative Review.

OBJECTIVE: Extracorporeal circulation (ECC) is generally based on standards established in the last decade. In recent years, a concept of perfusion management during ECC, goal-directed perfusion (GDP), has emerged to create optimal conditions for oxygen delivery and extraction, initiated by Rannuci et al. The aim of the present work was to determine whether the ECC procedure can truly be optimized with the current state of knowledge and understanding of human physiology. METHODS: Discussed articles from 2017 to 2022 were selected from the MEDLINE (PubMed) database using the keywords "cardiopulmonary bypass" AND "cardiac surgery" AND "oxygen delivery" with the conditions of "clinical trial" OR "randomized controlled trial." RESULTS: The concept of GDP is an attempt to reproduce the physiological conditions of tissue respiration during ECC. Published articles, also due to their retrospective nature, are based on standards and recommendations that do not fully fit the field of physiological circulation. There are still insufficient tools to assess the relationship between volemia, perfusion pressure, and pump performance. Limitations include indications for vasoactive drugs. Methodology has rarely taken into account the period of starting and stopping the heart-lung machine, the most pronounced periods of circulatory destabilization with reduced oxygen delivery. CONCLUSIONS: Problems associated with ECC such as acute kidney injury, liver failure, vasoplegic syndrome, and others must await its resolution. The use of advanced monitoring technology and data engineering may allow the development of baseline hemodynamic models, which may make the ECC procedure more physiologic and thus improve the safety of the procedure.

Hemodynamic Determinants of Elevated Blood Pressure and Hypertension in the Middle to Older-Age UK Population: A UK Biobank Imaging Study.

BACKGROUND: Increased systemic vascular resistance and, in older people, reduced aortic distensibility, are thought to be the hemodynamic determinants of primary hypertension but cardiac output could also be important. We examined the hemodynamics of elevated blood pressure and hypertension in the middle to older-aged UK population participating in the UK Biobank imaging studies. METHODS: Cardiac output, systemic vascular resistance, and aortic distensibility were measured from cardiac magnetic resonance imaging in 31 112 (distensibility in 21 178) participants (46.3% male, mean age±SD 63±7 years). Body composition including visceral adipose tissue volume and abdominal subcutaneous adipose tissue volume were measured in 19 645 participants. RESULTS: Participants with higher blood pressure had higher cardiac output (higher by 17.9±26.6% in hypertensive compared with those with optimal blood pressure) and higher systemic vascular resistance (higher by 11.4±27.9% in hypertensive compared with those with optimal blood pressure). These differences were little changed after adjustment for body size and adiposity. The contribution of cardiac output relative to systemic vascular resistance was more marked in younger compared with older subjects. Aortic distensibility decreased with age and was lower in participants with higher compared with lower blood pressure but with a greater difference in younger compared with older subjects. CONCLUSIONS: In the middle to older-aged UK population, cardiac output plays an important role in contributing to elevated mean arterial blood pressure, particularly in younger compared with older subjects. Reduced aortic distensibility contributes to a rise in pulse pressure and systolic blood pressure at all ages.

The prognostic value of systemic vascular resistance in heart failure patients with permanent atrial fibrillation: a retrospective study.

Heart failure (HF) and permanent atrial fibrillation (AF) interact mutually, exacerbating hemodynamic effects and causing adverse outcomes and increased healthcare costs. Monitoring hemodynamic indicators in patients with these comorbidities is crucial for effective clinical management. Transthoracic impedance cardiography (ICG) has been widely employed in assessing hemodynamic status in clinical settings. Given the limited research on the prognostic significance of ICG parameters in HF with permanent AF, we undertook this study. A total of 66 HF patients with permanent AF were included in this retrospective study, and the primary outcome was rehospitalization due to worsening HF within 180-day post-discharge. Cox regression analysis was performed to explore the connection between ICG-evaluated parameters and the outcome risk. Receiver operating characteristic (ROC) curve analysis determined the optimal cutoff values of risk factors, subsequently applied in plotting Kaplan Meier (KM) survival curves. Multivariate Cox regression analysis revealed that systemic vascular resistance (SVR) both on admission and at discharge independently predicted rehospitalization for worsening HF. ROC analysis established optimal SVR cutoff values: 320.89 (kPa s/L) on admission and 169.94 (kPa s/L) at discharge (sensitivity 70%, specificity 94.4%, area under the curve (AUC) 0.831, respectively, sensitivity 90%, specificity 55.6%, AUC 0.742). KM survival curves analysis showed that patients with SVR > 320.89 (kPa s/L) on admission had an 8.14-fold (P < 0.001) increased risk of the end-point event compared with those with SVR ≤ 320.89 (kPa s/L). Similarly, patients with SVR > 169.94 (kPa s/L) at discharge faced a risk elevated by 6.57 times (P = 0.002) relative to those with SVR ≤ 169.94 (kPa s/L). In HF patients with permanent AF, SVR measured by ICG emerges as an independent risk factor and clinical predictor for HF deterioration-related readmission within 180 days after discharge. Higher SVR levels, both upon admission and at discharge, correlate with an incremental rehospitalization risk.

New Onset Anemia, Worsened Plasma Creatinine Concentration, and Hyperviscosity in a Patient With a Monoclonal IgM Paraprotein.

A 76-year-old female followed closely for five years with IgM monoclonal gammopathy of uncertain significance developed anemia, worsened plasma creatinine concentration, and markedly elevated serum viscosity. This case illustrates the scope of pathology that can be caused by elevated blood viscosity. Our patient's anemia was a homeostatic response to normalize systemic vascular resistance and resulted from activation of the systemic vascular resistance response. The elevated plasma creatinine resulted from decreased renal perfusion because of elevated blood viscosity. Recent insights in hemorheology (the study of blood flow) are discussed, namely the recent identification of preferential blood flow patterns and erythrocyte autoregulation of deformability. These insights confirm that blood viscosity is part of the "milieu intérieur."

Factors leading to supranormal cardiac index in pediatric pulmonary hypertension patients treated with parenteral prostanoid therapy.

Parenteral prostanoid therapy (PPT) can result in supranormal cardiac index (SCI; >4 L/min/m2) in pediatric pulmonary hypertension (PPH) patients. We evaluated the incidence, hemodynamic factors, and outcomes associated with SCI in PPH. This retrospective cohort study included 22 PPH patients on PPT from 2005 to 2020. Hemodynamic profiles were compared between the baseline and 3-6 month follow-up catheterization in the SCI and non-SCI cohorts. Cox regression analysis examined time to composite adverse outcome (CAO; Potts shunt, lung transplant, or death) controlling for initial disease severity. SCI developed in 17 (77%) patients, of whom 11 (65%) developed SCI within 6 months. The SCI cohort was characterized by significant augmentation of cardiac index (CI) and stroke volume (SV) as well as reductions in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR). Conversely, the non-SCI cohort had unchanged SV despite a modest rise in CI as well as persistent vasoconstriction. After median follow-up of 4.3 years (range 0.2-13 years), non-SCI patients were at significantly increased risk for the CAO (5/5: three deaths, two Potts shunts) compared with SCI patients (5/17: two deaths, three lung transplants; adjusted hazard ratio 14.0 [95% confidence interval: 2.1-91.3], p < 0.001). A majority of PPH patients developed SCI within 6-12 months of starting PPT and demonstrated lower risk of adverse outcomes compared with non-SCI patients. These data suggest that change in SVR and SV after 3-6 months of PPT may be early markers of therapeutic response and prognosis.

Fontan Heart: Insight Into the Physiological Role of the Right Heart.

BACKGROUND: Cardiac output (CO) is almost normal in children born without a functional right ventricle (RV), and a Fontan repair, so why is RV dysfunction such a clinical problem? We tested the hypotheses that increased pulmonary vascular resistance (PVR) is the dominant factor and volume expansion by any means is of limited benefit. METHODS: We removed the RV from a previously used MATLAB model and altered vascular volume, venous compliance (Cv), PVR, and measures of left ventricular (LV) systolic and diastolic function. CO and regional vascular pressures were the primary outcome measures. RESULTS: RV removal decreased CO by 25%, and raised mean systemic filling pressure (MSFP). A 10 mL/kg increase in stressed volume only moderately increased CO with or without the RV. Decreasing systemic Cv increased CO but also markedly increased pulmonary venous pressure. With no RV, increasing PVR had the greatest effect on CO. Increasing LV function had little benefit. CONCLUSIONS: Model data indicate that increasing PVR dominates the decrease in CO in Fontan physiology. Increasing stressed volume by any means only moderately increased CO and increasing LV function had little effect. Decreasing systemic Cv unexpectedly markedly increased pulmonary venous pressures even with the RV intact.