AIMS:Cross-correlation baroreflex sensitivity (xBRS) and heart rate variability (HRV) are measures of autonomic cardiac control and are associated with hypertension. However, their value in predicting new-onset hypertension and changes in systolic blood pressure (SBP) remains elusive. METHODS AND RESULTS:We used longitudinal data of participants with and without a history of cardiovascular disease from the HEalthy Life In an Urban Setting (HELIUS) study. A non-invasive continuous finger blood pressure measurement at baseline was used to calculate xBRS and HRV. In normotensives at baseline, we calculated the odds ratio (OR) of developing hypertension at follow-up. In the full cohort, we assessed the change in SBP between baseline and follow-up using linear regression. Subgroup analyses were performed in the younger (<50 years) and older (≥50 years) participants. Median follow-up was 6.6 years (interquartile range 5.8-7.4). A 50% lower xBRS at baseline was independently associated with a 1.31 higher OR [95% confidence interval (CI) 1.09-1.57] of developing hypertension at follow-up. No significant associations between the standard deviation of the normal-to-normal interval (SDNN) or the square root of the mean of successive differences between adjacent normal-to-normal intervals (RMSSD), and new-onset hypertension were found. Compared to the lowest tertile, an xBRS in the highest tertile was associated with a 3.61 mmHg (95% CI 2.50-4.71) higher increase in SBP over time, whereas this was 1.11 mmHg (95% CI 0.12-2.09) and 1.76 mmHg (95% CI 0.73-2.79) for SDNN and RMSSD. CONCLUSION:In the general population, a lower xBRS is associated with increased odds of developing hypertension, and a steeper increase in SBP over time.

OBJECTIVE:People with HIV have an increased cardiovascular disease risk. Persistent inflammation and mitochondrial dysfunction are considered important contributors to impaired autonomic cardiovascular control, as evidenced by decreased baroreflex sensitivity (BRS) and heart rate variability (HRV). We assessed differences in cross-correlation BRS (xBRS) and HRV between people with and without HIV and explored associations with HIV-specific characteristics. DESIGN:We included participants with and without HIV from the AGE h IV cohort study, and general population participants from the multiethnic HEalthy LIfe in an Urban Setting (HELIUS) study, all European men aged 50-70 years. METHODS:Using a noninvasive continuous blood pressure measurement, we calculated xBRS and two HRV parameters [successive differences in normal-to-normal intervals (SDNN) and the root mean square of differences between successive normal-to-normal intervals (RMSSD)]. Regression models, adjusted for traditional cardiovascular risk factors, assessed differences in xBRS and HRV between the participant groups and associated HIV-specific characteristics. RESULTS:xBRS, SDNN, and RMSSD were significantly higher in both control groups compared to participants with HIV. Longer time since HIV diagnosis and longer prior use of dideoxynucleosides and thymidine analogues were significantly associated with lower xBRS. Nadir CD4 + cell count was positively associated with SDNN, while longer duration of thymidine analogue use was negatively associated with SDNN and prior use of dideoxynucleosides with lower RMSSD. CONCLUSION:Impaired autonomic cardiovascular control in men with HIV, potentially related to prior antiretroviral drug exposure and prior immunodeficiency, might contribute to HIV-associated cardiovascular disease risk.

Hypertension is an important modifiable risk factor for dementia, but the role of blood pressure (BP) in the development of dementia is not fully understood. Emerging data links increased BP variability and abnormal BP dynamics to dementia risk, but the relationship between baroreflex sensitivity (BRS), a fundamental physiological mechanism for maintaining stable BP, and dementia risk is unknown. We investigated the association of BRS with the risk of dementia in community-based older adults from the Rotterdam Study in the Netherlands. We determined cardiac BRS using a 5-minute continuous beat-to-beat recording of BP and heart rate measured in a supine position between 1997 and 1999 and ascertained incident dementia cases using a standardized protocol from baseline through January 1, 2020. We quantified the association of cardiac BRS with dementia risk using adjusted cause-specific hazard ratios. Of 1,819 participants (63% women; mean [SD] age, 71.0 [6.3] years), 421 developed dementia during a median follow-up of 14.8 years. The association of cardiac BRS with dementia risk differed by antihypertensive medication use ( P for interaction = 0.03) and was only observed in participants not taking antihypertensive medication. Specifically, reduced BRS was associated with a higher risk of dementia (cause-specific hazard ratio [HR] comparing bottom versus top quintiles: 1.62; 95% confidence interval [CI]: 1.08-2.42, P for trend = 0.02) and all-cause mortality (corresponding HR: 1.77; 95%CI: 1.33-2.37, P for trend<0.001) after adjusting for age, sex, APOE genotype, and traditional vascular risk factors. The association remained after additional adjustment for sitting BP level and beat-to-beat BP variability. Among older adults not taking antihypertensive medication, reduced cardiac BRS was associated with a higher long-term risk of dementia and all-cause death over 23 years. Impaired BRS may be a novel biomarker of significant clinical relevance for early detection and prevention of dementia in older adults.

BACKGROUND:Systolic blood pressure (SBP) amplification is a physiological phenomenon related to the level of pressure difference between the aorta and brachial artery and is associated with cuff blood pressure (BP) measurement inaccuracy. However, knowledge on the invasively measured level of aortic-to-brachial SBP amplification is limited. This study aimed to explore this, as well as anticipated effects on hypertension classification. METHODS:A systematic review and individual participant data meta-analysis identified invasive brachial and aortic BP recorded in 1151 participants (62±12 years, 72% male). SBP amplification was calculated as brachial SBP minus aortic SBP. Hypertension classification (defined according to previously described thresholds for brachial and aortic BP) was compared between the aortic and brachial BP measures. RESULTS:There was a wide range of SBP amplification, which was similar between male and female (mean±SD, 8±9 mm Hg and 7±10 mm Hg, respectively) and decreased with increasing age. High SBP amplification (>15 mm Hg) was observed in 17.4% (male, 16.8% versus female, 19.5%; P=0.44), and low SBP amplification (<5 mm Hg) in 37.3% of participants (male, 37.2% versus female, 37.4%; P=0.95). The overall level of agreement between hypertension classification based on brachial and aortic BP was moderate (κ, 0.67; P<0.001; agreement, 87.4%). Agreement in hypertension classification was 65.0%, 38.1%, and 92.7% across classifications of optimal, prehypertension, and hypertension, respectively. CONCLUSIONS:In males and females there is wide variability in aortic-to-brachial SBP amplification. There were major theoretical differences in hypertension classification based on brachial versus aortic BP. This knowledge may help toward innovations for improving cuff BP measurement accuracy.

The incidence of aortic valve stenosis (AoS) increases with age, and once diagnosed, symptomatic severe AoS has a yearly mortality rate of 25%. AoS is diagnosed with transthoracic echocardiography (TTE), however, this gold standard is time consuming and operator and acoustic window dependent. As AoS affects the arterial blood pressure waveform, AoS-specific waveform features might serve as a diagnostic tool. Aim of the present study was to develop a novel, non-invasive, AoS detection model based on blood pressures waveforms. This cross-sectional study included patients with AoS undergoing elective transcatheter or surgical aortic valve replacement. AoS was determined using TTE, and patients with no or mild AoS were labelled as patients without AoS, while patients with moderate or severe AoS were labelled as patients with AoS. Non-invasive blood pressure measurements were performed in awake patients. Ten minutes of consecutive data was collected. Several blood pressure-based features were derived, and the median, interquartile range, variance, and the 1st and 9th decile of the change of these features were calculated. The primary outcome was the development of a machine-learning model for AoS detection, investigating multiple classifiers and training on the area under the receiver-operating curve (AUROC). In total, 101 patients with AoS and 48 patients without AoS were included. Patients with AoS showed an increase in left ventricular ejection time (0.02 s, p = 0.001), a delayed maximum upstroke in the systolic phase (0.015 s, p < 0.001), and a delayed maximal systolic pressure (0.03 s, p < 0.001) compared to patients without AoS. With the logistic regression model, a sensitivity of 0.81, specificity of 0.67, and AUROC of 0.79 were found. The majority of the population without AoS was male (85%), whereas in the population with AoS this was evenly distributed (54% males). Age was significantly (5 years, p < 0.001) higher in the population with AoS. In the present study, we developed a novel model able to distinguish no to mild AoS from moderate to severe AoS, based on blood pressure features with high accuracy. Clinical registration number: The study entailing patients with TAVR treatment was registered at ClinicalTrials.gov (NCT03088787, https://clinicaltrials.gov/ct2/show/NCT03088787 ). The study with elective cardiac surgery patients was registered with the Netherland Trial Register (NL7810, https://trialsearch.who.int/Trial2.aspx?TrialID=NL7810 ).

BACKGROUND:Increased blood pressure (BP) variability is linked to dementia risk, but the relationship between baroreflex sensitivity (BRS), a fundamental mechanism for maintaining stable BP, and dementia risk is undetermined. METHODS:We tested the hypothesis that impaired BRS is associated with increased dementia risk in 1819 older adults (63% women; age, 71.0±6.3 years) from the community-based Rotterdam Study. Cardiac BRS was determined from a 5-minute beat-to-beat BP recording at supine rest between 1997 and 1999. Cardiac BRS measures the correlation between changes in consecutive beat-to-beat systolic BP and subsequent responses in heartbeat intervals, with a higher value indicating better BRS. The primary outcome was incident dementia ascertained from baseline through January 1, 2020; the secondary outcome was all-cause mortality. RESULTS:During a median follow-up of 14.8 years, 421 participants developed dementia. The association of cardiac BRS with dementia risk differed by antihypertensive medication use (Pinteraction=0.03) and was only observed in participants not taking antihypertensives. Specifically, in those not taking antihypertensive medication, reduced BRS was associated with a higher risk of dementia (adjusted hazard ratio comparing bottom versus top quintiles, 1.60 [95% CI, 1.07-2.40]; Ptrend=0.02). Reduced BRS was also associated with an increased risk of death (corresponding hazard ratio, 1.76 [95% CI, 1.32-2.35]). The association remained after adjusting for average BP and BP variability. CONCLUSIONS:Impaired BRS partly explains hypertension-related brain damage and excessive dementia risk beyond conventional BP measures, making it a potential novel biomarker for the early detection and prevention of dementia.

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges.

Objective: Cross-correlation baroreflex sensitivity (xBRS) and heart rate variability (HRV) provide valuable insight into neurocardiovascular control. However, their prospective utility in predicting new-onset hypertension and increases in systolic blood pressure (SBP) over time within the general population has not yet been demonstrated. Design and method: Data was collected from participants of the HEalthy Life In an Urban Setting (HELIUS) study. A non-invasive continuous finger blood pressure (BP) measurement at baseline was used to calculate xBRS, standard deviation of the normal-to-normal interval (SDNN) and the squared root of mean squared successive differences between normal-to-normal intervals (RMSDD). In the normotensive individuals at baseline, we used logistic regression models to calculate the odds ratio (OR) of developing hypertension at follow-up, and in the full cohort we assessed the change in SBP, corrected for the use of antihypertensive medication, between baseline and follow-up using linear regression with tertiles and splines where appropriate. A subgroup analyses was performed in the younger (aged < 50 years) and older (aged > 50 years) part of the cohort. Both the logistic and linear regression models were corrected for demographic and confounding factors. Results: Follow-up data from 4,910 participants were available, mean follow-up time was 6.6 years (SD 1.1 years). A 50% reduction in xBRS was associated with an OR of 1.31 (95% CI 1.09–1.57) for developing hypertension at follow-up, with no significant difference between the younger and older subgroups of the cohort. No significant association between SDNN or RMSDD and new-onset hypertension was found. Splines depicting the relation between delta SBP and xBRS, SDNN and RMSDD are depicted in Figure 1. Compared to the lowest tertile, an xBRS in the highest tertile was associated with a 3.61 mmHg (95%CI 2.50-4.71) higher change in SBP over time, whereas this was 1.11 mmHg (95%CI 0.12-2.09) and 1.76 mmHg (95%CI 0.73-2.79) for SDNN and RMSDD, respectively. Conclusions: In the general population, a lower xBRS is associated with increased odds of developing hypertension, and a steeper increase in SBP over time.

Maintaining an optimal acid base is important for the patient. The theory underlying acid-base balance can be challenging for clinicians and educators. These considerations justify creating simulations that include realistic changes to the partial pressure of carbon dioxide, pH, and bicarbonate ion concentration in a range of conditions. Our explanatory simulation application requires a model that derives these variables from total carbon dioxide content and runs in real time. The presented model is derived from the Stewart model, which is based on physical and chemical principles, and takes into account the effects of weak acids and strong ions on the acid-base balance. An inventive code procedure allows for efficient computation. The simulation results match target data for a broad range of clinically and educationally relevant disturbances of the acid-base balance. The model code meets the real-time goals of the application and can be applied in other educational simulations. Python model source code is made available.

Objective:Hypertension management is directed by cuff blood pressure (BP), but this may be inaccurate, potentially influencing cardiovascular disease (CVD) events and health costs. This study aimed to determine the impact on CVD events and related costs of the differences between cuff and invasive SBP.Methods:Microsimulations based on Markov modelling over one year were used to determine the differences in the number of CVD events (myocardial infarction or coronary death, stroke, atrial fibrillation or heart failure) predicted by Framingham risk and total CVD health costs based on cuff SBP compared with invasive (aortic) SBP. Modelling was based on international consortium data from 1678 participants undergoing cardiac catheterization and 30 separate studies. Cuff underestimation and overestimation were defined as cuff SBP less than invasive SBP and cuff SBP greater than invasive SBP, respectively.Results:The proportion of people with cuff SBP underestimation versus overestimation progressively increased as SBP increased. This reached a maximum ratio of 16 : 1 in people with hypertension grades II and III. Both the number of CVD events missed (predominantly stroke, coronary death and myocardial infarction) and associated health costs increased stepwise across levels of SBP control, as cuff SBP underestimation increased. The maximum number of CVD events potentially missed (11.8/1000 patients) and highest costs ($241 300 USD/1000 patients) were seen in people with hypertension grades II and III and with at least 15 mmHg of cuff SBP underestimation.Conclusion:Cuff SBP underestimation can result in potentially preventable CVD events being missed and major increases in health costs. These issues could be remedied with improved cuff SBP accuracy.

BACKGROUND Precapillary pulmonary hypertension (precPH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness.OBJECTIVES This study aimed to investigate RA function using pressure-volume (PV) loops, isolated cardiomyocyte, and histological analyses.METHODS RA PV loops were constructed in control subjects (n = 9) and precPH patients (n = 27) using magnetic resonance and catheterization data. RA stiffness (pressure rise during atrial filling) and right atrioventricular coupling index (RA minimal volume / RV end-diastolic volume) were compared in a larger cohort of patients with moderate (n = 39) or severe (n = 41) RV diastolic stiffness. Cardiomyocytes were isolated from RA tissue collected from control subjects (n = 6) and precPH patients (n = 9) undergoing surgery. Autopsy material was collected from control subjects (n = 6) and precPH patients (n = 4) to study RA hypertrophy, capillarization, and fibrosis.RESULTS RA PV loops showed 3 RA cardiac phases (reservoir, passive emptying, and contraction) with dilatation and elevated pressure in precPH. PrecPH patients with severe RV diastolic stiffness had increased RA stiffness and worse right atrioventricular coupling index. Cardiomyocyte cross-sectional area was increased 2-to 3-fold in precPH, but active tension generated by the sarcomeres was unaltered. There was no increase in passive tension of the cardiomyocytes, but end-stage precPH showed reduced number of capillaries per mm2 accompanied by interstitial and perivascular fibrosis.CONCLUSIONS RA PV loops show increased RA stiffness and suggest atrioventricular uncoupling in patients with severe RV diastolic stiffness. Isolated RA cardiomyocytes of precPH patients are hypertrophied, without intrinsic sarcomeric changes. In end-stage precPH, reduced capillary density is accompanied by interstitial and perivascular fibrosis. (J Am Coll Cardiol 2023;82:704-717) (c) 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Sympathovagal balance is important in the pathogenesis of hypertension and independently associated with mortality. We evaluated the value of automated analysis of cross-correlation baroreflex sensitivity (xBRS) and heart rate variability (HRV) and its relationship with clinical covariates in 13,326 participants from the multi-ethnic HELIUS study. Finger blood pressure (BP) was continuously recorded, from which xBRS, standard deviation of normal-to-normal intervals (SDNN), and squared root of mean squared successive difference between normal-to-normal intervals (RMSDD) were determined. A subset of 3356 recordings > 300 s was used to derive the minimally required duration by comparing shortened to complete recordings, defined as intraclass correlation (ICC) > 0.90. For xBRS and SDNN, 120 s and 180 s were required (ICC 0.93); for RMSDD, 60 s (ICC 0.94) was sufficient. We included 10,252 participants (median age 46 years, 54

Arterial pulse waves (PWs) such as blood pressure and photoplethysmogram (PPG) signals contain a wealth of information on the cardiovascular (CV) system that can be exploited to assess vascular age and identify individuals at elevated CV risk. We review the possibilities, limitations, complementarity, and differences of reduced-order, biophysical models of arterial PW propagation, as well as theoretical and empirical methods for analyzing PW signals and extracting clinically relevant information for vascular age assessment. We provide detailed mathematical derivations of these models and theoretical methods, showing how they are related to each other. Finally, we outline directions for future research to realize the potential of modeling and analysis of PW signals for accurate assessment of vascular age in both the clinic and in daily life.

Background: Accurate blood pressure (BP) measurement is critical for optimal cardiovascular risk management. Age-related trajectories for cuff-measured BP accelerate faster in women compared with men, but whether cuff BP represents the intraarterial (invasive) aortic BP is unknown. This study aimed to determine the sex differences between cuff BP, invasive aortic BP, and the difference between the 2 measurements. Methods: Upper-arm cuff BP and invasive aortic BP were measured during coronary angiography in 1615 subjects from the Invasive Blood Pressure Consortium Database. This analysis comprised 22 different cuff BP devices from 28 studies. Results: Subjects were 64±11 years (range 40–89) and 32% women. For the same cuff systolic BP (SBP), invasive aortic SBP was 4.4 mm Hg higher in women compared with men. Cuff and invasive aortic SBP were higher in women compared with men, but the sex difference was more pronounced from invasive aortic SBP, was the lowest in younger ages, and the highest in older ages. Cuff diastolic blood pressure overestimated invasive diastolic blood pressure in both sexes. For cuff and invasive diastolic blood pressure separately, there were sex*age interactions in which diastolic blood pressure was higher in younger men and lower in older men, compared with women. Cuff pulse pressure underestimated invasive aortic pulse pressure in excess of 10 mm Hg for both sexes in older age. Conclusions: For the same cuff SBP, invasive aortic SBP was higher in women compared with men. How this translates to cardiovascular risk prediction needs to be determined, but women may be at higher BP-related risk than estimated by cuff measurements.

Background: Hypertension can be classified into different phenotypes based on systolic and diastolic blood pressure (BP) that carry a different prognosis and may therefore be differently associated with sympathetic activity. We assessed the association between cardiac autonomic function determined from continuous finger BP recordings and hypertensive phenotypes. Methods: We included 10,221 individuals aged between 18-70 years from the multi-ethnic HELIUS study. Finger BP was recorded continuously for 3-5 minutes from which cross-correlation baroreflex sensitivity (xBRS) and heart rate variability (HRV) were determined. Hypertension was classified into isolated systolic (ISH; ≥140/<90), diastolic (IDH; <140/≥90) and combined systolic and diastolic hypertension (SDH; ≥140/≥90). Differences were assessed after stratification by age (younger: ≤40, older: >40 years) and sex, using regression with correction for relevant covariates. For xBRS, values were log-transformed. Results: In younger adults with ISH, xBRS was comparable to normotensive individuals in men (ratio 0.92; 95%CI 0.84-1.01) and women (1.00; 95%CI 0.84-1.20), while xBRS was significantly lower in IDH and SDH (ratios between 0.67 and 0.80). In older adults, all hypertensive phenotypes had significantly lower xBRS compared to normotensives. We found a similar pattern for HRV in men, while in women HRV did not differ between phenotypes. Conclusions: In younger men and women ISH is not associated with a shift towards increased sympathetic control, while IDH and SDH in younger and all hypertensive phenotypes in older participants were associated with increased sympathetic control. This suggests that alterations in autonomic regulation could be a contributing factor to known prognostic disparities between hypertensive phenotypes.

Aims: Reflection magnitude (RM), the ratio of the amplitudes of the backward and forward central arterial pressure waves, has been shown to predict cardiovascular events. However, the association with blood pressure (BP) and hypertension is unclear. Methods: We assessed RM in 10 195 individuals of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin aged between 18 and 70 years (54.2% female) participating in the Healthy Life in an Urban Setting study. To determine RM, central arterial pressure and flow were reconstructed from finger BP. Hypertension was defined based on office-BP and medication. Associations with BP, hypertension, and hypertensive organ damage were assessed using linear regression models with correction for relevant covariates. Results: Mean RM was 62.5% (standard deviation [SD] 8.0) in men and 63.8% (SD 8.1) in women. RM was lowest in Dutch and highest in South-Asian and African participants. RM increased linearly with 1.35 (95% confidence interval [CI] 1.23–1.46) for every 10 mmHg increase in systolic BP from 120 mmHg onwards, while the relation with diastolic BP was nonlinear. RM was 2.40 (95% CI 2.04–2.76) higher in hypertensive men and 3.82 (95% CI 3.46–4.19) higher in hypertensive women compared to normotensive men and women. In hypertensive men and women with ECG-based left ventricular hypertrophy or albuminuria RM was 1.64 (95% CI 1.09–2.20) and 0.94 (95% CI 0.37–1.52) higher compared to hypertensive participants without hypertensive organ damage. Conclusion: RM is associated with BP, hypertension and hypertensive organ damage, and may in part explain disparities in hypertension associated cardiovascular risk.

Objective:Blood pressure fluctuates during diastole to create a dicrotic wave but the mechanistic origin remains poorly understood. We sought to investigate the characteristics and determinants of diastolic pressure and flow fluctuations with a focus on stiffness gradients between the central aorta and peripheral arteries. Methods:Using applanation tonometry and duplex ultrasound, pulse waveforms were recorded on the femoral artery in 592 patients (age: 55 +/- 14 years) to estimate the diastolic pressure fluctuation as a residual wave against the mono-exponential decay and the diastolic flow fluctuation as a bidirectional (forward and reverse) velocity wave. The radial, carotid, and dorsalis pedis pressures were also recorded to measure the peripheral/aortic pulse pressure (PP) and pulse wave velocity (PWV) ratios. Results:There were close resemblances between the femoral pressure and flow fluctuation waveforms. The pressure and flow fluctuations were mutually correlated in relative amplitude as indexed to the total pulse height (r = 0.63), and the former temporally followed the latter. In multivariate-adjusted models, higher peripheral/aortic PP and PWV ratios were independently associated with greater pressure and flow fluctuation indices (P < 0.001). Mediation analysis revealed that the associations of PP and PWV ratios with the pressure fluctuation index were largely mediated by the flow fluctuation index [indirect/total effect ratio: 57 (95% CI 42-80)% and 54 (30-100)%, respectively]. Conclusion:These results suggest that central-to-peripheral pulse amplification and stiffness gradients contribute to triphasic flow fluctuations and dicrotic pressure waves. Diminished or inverted stiffness gradients caused by aortic stiffening may thus reduce diastolic runoff leading to ischemic organ damage.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background Pulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA–RV interaction. Methods PAH patients with low or high end-diastolic elastance (E ed ) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying−RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure. Results With increased E ed , RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high E ed , resulting in higher vena cava backflow. Upon treatment, E ed was reduced in ~50% of the patients with high E ed , which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom E ed remained high. Conclusions In PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline E ed , diastolic stiffness remained high, despite treatment. A reduction in E ed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.

Hemodynamic instability is frequently present in critically ill patients, primarily caused by a decreased preload, contractility, and/or afterload. We hypothesized that peripheral arterial blood pressure waveforms allow to differentiate between these underlying causes. In this in-silico experimental study, a computational cardiovascular model was used to simulate hemodynamic instability by decreasing blood volume, left ventricular contractility or systemic vascular resistance, and additionally adaptive and compensatory mechanisms. From the arterial pressure waveforms, 45 features describing the morphology were discerned and a sensitivity analysis and principal component analysis were performed, to quantitatively investigate their discriminative power. During hemodynamic instability, the arterial waveform morphology changed distinctively, for example, the slope of the systolic upstroke having a sensitivity of 2.02 for reduced preload, 0.80 for reduced contractility, and -0.02 for reduced afterload. It was possible to differentiate between the three underlying causes based on the derived features, as demonstrated by the first two principal components explaining 99% of the variance in waveforms. The features with a high correlation coefficient (>0.25) to these principal components are describing the systolic up- and downstroke, and the anacrotic and dicrotic notches of the waveforms. In this study, characteristic peripheral arterial waveform morphologies were identified that allow differentiation between deficits in preload, contractility, and afterload causing hemodynamic instability. These findings are confined to an in silico simulation and warrant further experimental and clinical research in order to prove clinical usability in daily practice.