Ventricular-arterial Uncoupling Research Articles

Relationship of interleukin-16 with different phenogroups in acute heart failure with preserved ejection fraction.

Interleukin-16 (IL-16) has been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (HFpEF). We sought to elucidate whether IL-16 has a distinct impact on pathophysiology and prognosis across different subphenotypes of acute HFpEF. We analysed 211 patients enrolled in a prospective multicentre registry of acute decompensated HFpEF for whom serum IL-16 levels after stabilization were available (53% female, median age 81 [interquartile range 75-85] years). We divided this sub-cohort into four phenogroups using our established clustering algorithm. The study endpoint was all-cause death. Patients were subclassified into phenogroup 1 ('rhythm trouble' [n=69]), phenogroup 2 ('ventricular-arterial uncoupling' [n=49]), phenogroup 3 ('low output and systemic congestion' [n=41]), and phenogroup 4 ('systemic failure' [n=52]). After a median follow-up of 640days, 38 patients had died. Among the four phenogroups, phenogroup 2 had the highest IL-16 level. The IL-16 level showed significant associations with indices of cardiac hypertrophy, diastolic dysfunction, and congestion only in phenogroup 2. Furthermore, the IL-16 level had a significant predictive value for all-cause death only in phenogroup 2 (C-statistic 0.750, 95% confidence interval 0.606-0.863, P=0.017), while there was no association between the IL-16 level and the endpoint in the other phenogroups. Our results indicated that the serum IL-16 level had a significant association with indices that reflect the pathophysiology and prognosis of HFpEF in a specific phenogroup in acute HFpEF.

Pathophysiological insights into machine-learning-based subphenotypes of acute heart failure with preserved ejection fraction: a biomarker analysis of PURSUIT-HFpEF registry

Abstract Background Our understanding of heart failure with preserved ejection fraction (HFpEF) has evolved from mere left ventricular diastolic dysfunction to a multiorgan disease. Purpose This study aimed to investigate the heterogeneous pathophysiology of the several phenotypes of HFpEF with multiple biomarker data. Methods This study is a post-hoc analysis of the PURSUIT-HFpEF study (N=1,231), an ongoing, prospective, multi-referral center, observational study of acute decompensated HFpEF [UMIN000021831]. In this registry, there is a pre-defined sub-cohort in which we perform multi-biomarker tests (N=212). We applied the machine-learning-based clustering model that we have previously established to the sub-cohort and classified them into 4 phenotypes: phenotype 1 labeled as "rhythm trouble" (n=69), phenotype 2 "ventricular-arterial uncoupling" (n=49), phenotype 3 "low output and systemic congestion" (n=41), and phenotype 4 "systemic failure" (n=53). Characteristics of biomarker tests in each phenotype were evaluated. Results The phenotype 2 characterized by hypertension and cardiac hypertrophy showed the highest value of N-terminal pro-brain natriuretic peptide (NT-proBNP), IL-16, high-sensitive C-reactive protein (CRP), tumor necrosis factor (TNF)-α, growth differentiation factor (GDF)-15, troponin T, and cystatin C, whereas the phenotype 1 presented the lowest value of these markers. The phenotype 3 showed the second highest value of GDF-15 and cystatin C. The phenotype 4 presented a low NT-proBNP value and a relatively high GDF-15. Conclusions The specific characteristics of biomarkers in each phenotype confirmed the validity of the machine learning model-based classification. The contribution of inflammation to the pathogenesis considerably differed in different HFpEF phenotypes. Systemic inflammation substantially contributes to the pathophysiology of the classical HFpEF phenotype with cardiac hypertrophy.

The Role of Right Ventriculo-Arterial Coupling in Symptoms Presentation of Patients with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. The hallmark of HCM is myocardial fibrosis which contributes to heart failure, arrhythmias, and sudden cardiac death (SCD). To identify the factors implicated in heart failure symptoms and functional capacity of patients with HCM. In this cohort study, 43 patients with HCM were recruited. According to functional capacity and symptoms presentation, patients were categorized according to New York Heart Association (NYHA) classification, and echocardiographic measurements of left ventricle systolic and diastolic function were conducted. The echocardiographic assessment of right ventriculo-arterial coupling (RVAC) was made by calculating the tricuspid annular peak systolic tissue Doppler velocity (TASV)/estimated RV systolic pressure (RVSP) ratio. Almost half (51%) of our study population present symptoms of heart failure and were categorized as the symptomatic group-NYHA 2 or higher. Maximum LVOT gradient, RVSP, and the ratio of E/e' were higher in the symptomatic group compared with the asymptomatic group. TASV was lower in the symptomatic group compared with the asymptomatic group (11 ± 1 cm/s vs. 13 ± 2 cm/s, p = 0.04). However, there was no difference in other potentially influential factors, such as heart rate or systemic blood pressure. The SCD risk score does not differ between the two studied groups. The RVAC (estimated with the TASV/RVSP ratio) was lower in the symptomatic group compared with the asymptomatic group (0.32 ± 0.09 vs. 0.46 ± 0.11, p < 0.001). A low RVAC (as estimated with TASV/RVSP ratio) value could represent an echocardiographic marker of right ventricular-arterial uncoupling in patients with HCM and impaired functional status.

Pathophysiology of the right ventricle in health and disease: an update.

The contribution of the right ventricle (RV) to cardiac output is negligible in normal resting conditions when pressures in the pulmonary circulation are low. However, the RV becomes relevant in healthy subjects during exercise and definitely so in patients with increased pulmonary artery pressures both at rest and during exercise. The adaptation of RV function to loading rests basically on an increased contractility. This is assessed by RV end-systolic elastance (Ees) to match afterload assessed by arterial elastance (Ea). The system has reserve as the Ees/Ea ratio or its imaging surrogate ejection fraction has to decrease by more than half, before the RV undergoes an increase in dimensions with eventual increase in filling pressures and systemic congestion. RV-arterial uncoupling is accompanied by an increase in diastolic elastance. Measurements of RV systolic function but also of diastolic function predict outcome in any cause pulmonary hypertension and heart failure with or without preserved left ventricular ejection fraction. Pathobiological changes in the overloaded RV include a combination of myocardial fibre hypertrophy, fibrosis and capillary rarefaction, a titin phosphorylation-related displacement of myofibril tension-length relationships to higher pressures, a metabolic shift from mitochondrial free fatty acid oxidation to cytoplasmic glycolysis, toxic lipid accumulation, and activation of apoptotic and inflammatory signalling pathways. Treatment of RV failure rests on the relief of excessive loading.

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.

Right ventricular-arterial uncoupling as an independent prognostic factor in acute heart failure with preserved ejection fraction accompanied with coronary artery disease.

Right ventricular (RV)-arterial uncoupling is a powerful independent predictor of prognosis in heart failure with preserved ejection fraction (HFpEF). Coronary artery disease (CAD) can contribute to the pathophysiological characteristics of HFpEF. This study aimed to evaluate the prognostic value of RV-arterial uncoupling in acute HFpEF patients with CAD. This prospective study included 250 consecutive acute HFpEF patients with CAD. Patients were divided into RV-arterial uncoupling and coupling groups by the optimal cutoff value, based on a receiver operating characteristic curve of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP). The primary endpoint was a composite of all-cause death, recurrent ischemic events, and HF hospitalizations. TAPSE/PASP ≤0.43 provided good accuracy in identifying patients with RV-arterial uncoupling (area under the curve, 0.731; sensitivity, 61.4%; and specificity, 76.6%). Of the 250 patients, 150 and 100 patients could be grouped into the RV-arterial coupling (TAPSE/PASP >0.43) and uncoupling (TAPSE/PASP ≤0.43) groups, respectively. Revascularization strategies were slightly different between groups; the RV-arterial uncoupling group had a lower rate of complete revascularization (37.0% [37/100] vs . 52.7% [79/150], P <0.001) and a higher rate of no revascularization (18.0% [18/100] vs . 4.7% [7/150], P <0.001) compared to the RV-arterial coupling group. The cohort with TAPSE/PASP ≤0.43 had a significantly worse prognosis than the cohort with TAPSE/PASP >0.43. Multivariate Cox analysis showed TAPSE/PASP ≤0.43 as an independent associated factor for the primary endpoint, all-cause death, and recurrent HF hospitalization (hazard ratios [HR]: 2.21, 95% confidence interval [CI]: 1.44-3.39, P <0.001; HR: 3.32, 95% CI: 1.30-8.47, P = 0.012; and HR: 1.93, 95% CI: 1.10-3.37, P = 0.021, respectively), but not for recurrent ischemic events (HR: 1.48, 95% CI: 0.75-2.90, P = 0.257). RV-arterial uncoupling, based on TAPSE/PASP, is independently associated with adverse outcomes in acute HFpEF patients with CAD.

Time to reconsider the perception and management of hypertensive heart disease.

Time to reconsider the perception and management of hypertensive heart disease.

PS-BPC05-10: DIASTOLIC DYSFUNCTION, HYPERTROPHY AND HYPERTENSION VENTRICULAR-ARTERIAL UNCOUPLING TREATMENT

Objective: the aim of this study was to evaluate the effects of hypertension ventricular-arterial uncoupling treatment on left ventricular hypertrophy and diastolic dysfunction regression. Design and method: observational prospective study, consecutive hypertension patients. Left ventricle mass index measured by Devereux 2D echocardiography method and diastolic function by conventional and tissue Doppler following the Guidelines from Echocardiography from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Left ventricular end systolic elastance (Ees) was measured by Guarracino calculator, the effective arterial elastance (Ea) and ventricular-arterial coupling (VAC) measured by Sunagawa et al single beat method adapted by Chen et al in human ventricles. The sample was analyzed in quartiles (Q) according to VAC (Q1 worst VAC to Q4 best VAC). Follow-up 2 years. Results: 288 patients, mean age 56.3 + 12.5 years and 168 patients (58.3%) males. VAC increased from 0.303 + 0.07 to 0.54 + 0.25 (p &lt; 0.005) in Q1 mainly due to a reduction in Ees from 5.25 + 2.3 to 3.68 + 0.25 mm Hg/ml (p &lt; 0.01) while Ea increased from 1.5 + 0.53 to 1.64 + 0.56 mm Hg/ml (p = NS); on the other side VAC was reduced from 0.87 + 0.15 to 0.68 + 0.26 (p &lt; 0.05) in Q 4 with an increase in Ees from 2.28 + 0.6 to 2.67 + 1.07 mm Hg/ml (p = NS) and a reduction of Ea from 1.94 + 0.41 to 1.69 + 0.67 mm Hg/ml (p = NS) (Figure). The frequency of LVH was reduced from 31.9% to 10.8% in Q1 (p &lt; 0.025) while moved from 14.7 to 17.9% (p = NS) in Q2, 22.9% to 13.9% (p = NS) in Q3 and 11.3 % to 23.7% (p = NS) in Q4. The frequency of normal diastolic function increased from 75% to 94.6% (p &lt; 0.01) in Q1, from 78.7% to 100% in Q2 (p &lt; 0.005), from 87.1% to 100% (p &lt; 0.025) in Q3 and from 88.7% to 100% (0,025) in Q4. Conclusions: 1) patients with the worst ventricular-arterial uncoupling (Q1) are the most VAC benefited from hypertension treatment; 2) regression of left ventricular hypertrophy was observed only in the group of patients with the worst ventricular-arterial uncoupling (Q1); 3) improvement in diastolic function was demonstrated in all Q of ventricular-arterial coupling. This study shows that achieving an optimal mechanical efficiency measured as ventricular-arterial coupling by hypertension treatment is essential for left ventricular hypertrophy and diastolic dysfunction regression.

USING NOVEL CARDIOVASCULAR MAGNETIC RESONANCE 4D FLOW HEMODYNAMIC IMAGING TO INVESTIGATING VENTRICULAR AORTIC COUPLING

<h3>Introduction</h3> Ventricular-aortic-coupling (VAC) is a mechanism of growing interest in heart disease and aging. It has been postulated that aortic stiffness could lead to progressive systolic and indirectly diastolic dysfunction. VAC is important to understand the interaction of cardiac contractility and compliance with the arterial system. Studies have reported anesthetic dose and rate of infusion are associated with ventricular-arterial uncoupling. This can be confounded further in patients with severe hemodynamic disorders such as septic shock, however, the relationship between the ventricular and arterial systems is still not fully understood. With 4D-flow cardiovascular magnetic resonance (CMR) imaging, the images of the thoracic cavity can be acquired in a single acquisition. Our goal was to investigate the relationship between intraventricular and aortic hemodynamics in a healthy population, using modern measures of 4D-Flow analysis and myocardial deformation. <h3>Methods</h3> 40 healthy participants were recruited to undergo a 3-Tesla CMR scan. A 4D-flow acquisition of the thoracic cavity was acquired and blood flow in the left ventricle were assessed for direct flow (blood that enters and leaves the ventricle during one heartbeat) and retained inflow (blood that enters the LV during diastole but is not ejected during the same cardiac cycle). From the same acquisition, 4D-pulse wave velocity (PWV) was calculated of the aorta. Systolic and diastolic ventricular function were assessed by peak systolic global longitudinal strain (GLS) and early diastolic strain rate from standard function cines. <h3>Results</h3> Participants (62.5% male) were aged from 21 to 63 years. Mean aortic PWV was 6.1±1.4m/s, LV direct flow fraction was 44.8±12.0% and retained inflow fraction was 25.6±6.3%. GLS was -17.1±2.0% and diastolic strain rate was 0.94±0.24/s. Increasing age was related to three parameters: Increase in aortic PWV (r=0.415, p=0.001), decrease in retained inflow (r=-0.575, p=0.001) and in early diastolic strain rate (r=-0.637, p<0.001). There was no association between systolic measures of GLS and direct flow fraction with age. When comparing flow results to ventricular strain, both a high aortic PWV (β=0.615, p=0.017) and reduced direct flow fraction (β=-0.06, p=0.048) were independently correlated with attenuated GLS, even when accounting for age. Diastolic strain rate was also independently linked to a high aortic PWV indicating aortic stiffness (β=0.024, p=0.001), and there was a correlation with the retained inflow fraction (r=0.408, p=0.031), however this was not significant when accounting for age. <h3>Conclusion</h3> Advanced measures of 4D-flow have shown that aortic pulse wave velocity as a measure of aortic stiffness and intraventricular hemodynamics are associated with reduced diastolic and systolic left ventricular deformation in a healthy control population. These modern quantitative measures should now be implemented in patient cohorts to investigate the role of VAC in cardiovascular disease, and how it may be impacted in an anesthetic setting.

Ventricular-Arterial Uncoupling and Hypertension Mediated Diastolic Dysfunction.

The increase in the pulsatile component of left ventricle afterload is suspected to cause a mismatch between the left ventricle (LV) and the vascular tree. Todemonstrate that ventricular-arterial uncoupling is frequently present in the development of LV hypertrophy (H) and diastolic dysfunction (DD) in hypertension (HBP). Observational study, HBP patients with ejection fraction >54%. Conventional 2D echocardiography and tissue Doppler performed following imaging guidelines. LV end systolic elastance (Ees), the effective arterial elastance (Ea), and ventricular-arterial coupling (VAC) measured by Chen single beat method. 288 patients, mean age 56.3±12.5 years and 168 patients (58.3%) males. Mean LV mass index was 87.2±20.4 grs/m2 and frequency of LVH 20.1% (58 patients). The mean VAC was 0.54±9.23. LV Stroke volume, stroke work and systolic stress were 46.2±10.3 cc/m2, 91.4±22.2 g-min/m2, and 57±14.6 dynes/cm2 in quartile 1, and 33.5±6.6 cc/m2, 65.5±15.2 g-min/m2, and 77.8±17.1 dynes/cm2, in quartile 4, respectively (p<0.001). Peripheral resistance index was 3349±1072 and 4410±1143 dynes*s/cm-5/m2 quartiles 1 vs. 4 (p<0.005). The frequency of LVH was 31.9% in quartile 1 and 11.3% in quartile 4 (p<0.005) and LVH or DD was 37.5% and 12.7%, respectively (p<0.001). Stroke volume and stroke work were significantly increased while systolic stress and peripheral resistance index were significantly reduced in patients with worst VAC. Ventricular-arterial uncoupling is mostly caused by an increase in Ees rather than by an elevation of Ea. LVH or DD are more frequent in the worst cases of ventricular-arterial uncoupling.

Minimal subphenotyping model for acute heart failure with preserved ejection fraction.

AimsApplication of the latent class analysis to acute heart failure with preserved ejection fraction (HFpEF) showed that the heterogeneous acute HFpEF patients can be classified into four distinct phenotypes with different clinical outcomes. This model‐based clustering required a total of 32 variables to be included. However, this large number of variables will impair the clinical application of this classification algorithm. This study aimed to identify the minimal number of variables for the development of optimal subphenotyping model.Methods and resultsThis study is a post hoc analysis of the PURSUIT‐HFpEF study (N = 1095), a prospective, multi‐referral centre, observational study of acute HFpEF [UMIN000021831]. We previously applied the latent class analysis to the PURSUIT‐HFpEF dataset and established the full 32‐variable model for subphenotyping. In this study, we used the Cohen's kappa statistic to investigate the minimal number of discriminatory variables needed to accurately classify the phenogroups in comparison with the full 32‐variable model. Cohen's kappa statistic of the top‐X number of discriminatory variables compared with the full 32‐variable derivation model showed that the models with ≥16 discriminatory variables showed kappa value of >0.8, suggesting that the minimal number of discriminatory variables for the optimal phenotyping model was 16. The 16‐variable model consists of C‐reactive protein, creatinine, gamma‐glutamyl transferase, brain natriuretic peptide, white blood cells, systolic blood pressure, fasting blood sugar, triglyceride, clinical scenario classification, infection‐triggered acute decompensated HF, estimated glomerular filtration rate, platelets, neutrophils, GWTG‐HF (Get With The Guidelines‐Heart Failure) risk score, chronic kidney disease, and CONUT (Controlling Nutritional Status) score. Characteristics and clinical outcomes of the four phenotypes subclassified by the minimal 16‐variable model were consistent with those by the full 32‐variable model. The four phenotypes were labelled based on their characteristics as ‘rhythm trouble’, ‘ventricular‐arterial uncoupling’, ‘low output and systemic congestion’, and ‘systemic failure’, respectively.ConclusionsThe phenotyping model with top 16 variables showed almost perfect agreement with the full 32‐variable model. The minimal model may enhance the future clinical application of this clustering algorithm.

Hypertension and Ventricular-Arterial Uncoupling in Collegiate American Football Athletes.

BackgroundVentricular–arterial (VA) coupling is defined as the ratio between arterial elastance (EA) and left ventricular elastance (ELV). VA uncoupling, as occurs in hypertensive heart disease, is associated with adverse outcomes. This study sought to determine the relationship between American football (AF)–associated hypertension and VA uncoupling.Methods and ResultsThis was a multicenter, longitudinal, and repeated measures observational study of collegiate AF athletes across 3 years of AF participation. Of 200 freshman athletes initially enrolled, 142 (67 Black [47%]/75 White [53%], 58 linemen [41%]/84 nonlinemen [59%]) were prospectively studied with echocardiography and applanation tonometry. Primary echocardiographic VA coupling outcome measures were EA/ELV and ΔEA/ELV, with increased EA/ELV indicating VA uncoupling. Adjusting for race and player position, AF athletes demonstrated increased EA/ELV (mean [95% CI]Δ, 0.10 [0.04–0.15]; P=0.001) and systolic blood pressure (SBP) (mean [95% CI]Δ, 11.4 [8.3–14.5] mm Hg, P<0.001) over their collegiate AF careers. In combination with longitudinal VA uncoupling, hypertension prevalence (including both stage 1 and 2) increased from 54% at baseline to 77% (44% stage 2) at the end of the study period (P<0.001). In multivariable mixed‐effects linear regression analysis, higher SBP (β=0.021, P=0.02), lower E′ (β=−0.010, P=0.03), and worse global longitudinal strain (β=0.036, P<0.001) were associated with higher EA/ELV. Increased SBP (ΔSBP, β=0.029, P=0.02) and worsened global longitudinal strain (Δglobal longitudinal strain, β=0.045, P<0.001) also predicted increased ΔEA/ELV.ConclusionsVA uncoupling is associated with pathologically increased SBP and subclinical impairments in left ventricular systolic function in collegiate AF athletes, indicating a key mechanism underlying maladaptive cardiovascular phenotypes observed in this population. Future studies analyzing whether targeted clinical interventions improve VA coupling and health outcomes are warranted.

Optimizing left ventricular-arterial coupling during the initial resuscitation in septic shock \u2013 a pilot prospective randomized study

BackgroundLeft ventricular-arterial coupling (VAC), defined as the ratio of effective arterial elastance (Ea) to left ventricular end-systolic elastance (Ees), has been extensively described as a key determinant of cardiovascular work efficacy. Previous studies indicated that left ventricular-arterial uncoupling was associated with worse tissue perfusion and increased mortality in shock patients. Therefore, this study aims to investigate whether a resuscitation algorithm based on optimizing left VAC during the initial resuscitation can improve prognosis in patients with septic shock.MethodsThis pilot study was conducted in an intensive care unit (ICU) of a tertiary teaching hospital in China. A total of 83 septic shock patients with left ventricular-arterial uncoupling (i.e., the Ea/Ees ratio ≥ 1.36) were randomly assigned to receive usual care (usual care group, n = 42) or an algorithm-based resuscitation that attempt to reduce the Ea/Ees ratio to 1 within the first 6 h after randomization (VAC-optimized group, n = 41). The left VAC was evaluated by transthoracic echocardiography every 2 h during the study period. The primary endpoint was 28-days mortality. The secondary endpoints included lactate clearance rate, length of ICU stay, and duration of invasive mechanical ventilation (IMV).ResultsEighty-two patients (98.8%) completed the study and were included in the final analysis. The Ea/Ees ratio was reduced in both groups, and the decrease in Ea/Ees ratio in the VAC-optimized group was significantly greater than that in the usual care group [median (interquartile range), 0.39 (0.26, 0.45) vs. 0.1 (0.06, 0.22); P < 0.001]. Compared with the usual care group, the VAC-optimized group likely exhibited the potential to reduce the 28-days mortality (33% vs. 50%; log-rank hazard ratio = 0.526, 95% confidence interval: 0.268 to 1.033). Moreover, the VAC-optimized group had a higher lactate clearance rate than the usual care group [27.7 (11.9, 45.7) % vs. 18.3 (− 5.7, 32.1) %; P = 0.038]. No significant difference was observed in terms of the length of ICU stay or duration of IMV.ConclusionsDuring the initial resuscitation of septic shock, optimizing left ventricular-arterial coupling was associated with improved lactate clearance, while likely having a beneficial effect on prognosis.Trial registrationChinese Clinical Trial Registry, ChiCTR1900024031. Registered 23 June 2019 - Retrospectively registered.

Unmasking right ventricular-arterial uncoupling during fluid challenge in pulmonary hypertension

Patients with pulmonary hypertension (PH) frequently show preserved right ventricular (RV) function at rest. However, volume challenge may uncover pending RV dysfunction. We aimed to assess the physiological and prognostic impact of RV-pulmonary arterial (RV-PA) uncoupling during volume challenge in patients with precapillary PH. We prospectively assessed 32 patients with PH (pulmonary arterial hypertension, n=27; inoperable chronic thromboembolic disease, n=5) and 4 controls using invasive pressure-volume (PV) catheterization. PV loops were recorded during preload reduction (balloon occlusion of inferior vena cava; baseline) and acute volume loading (200ml saline in 20s). Contractility (multi-beat end-systolic elastance [Ees]), arterial elastance (Ea), and RV-PA coupling (Ees/Ea) were obtained at baseline and at maximum volume loading (MVL). Median [interquartile range] time to MVL was 19 [18-22] s. Ees/Ea significantly declined from baseline (0.89 [0.69-1.23]) to MVL (0.16 [0.12-0.34]; p<0.001) in patients with PH but remained stable in controls (baseline: 1.08 [0.94-1.80]; MVL: 1.01 [0.80-2.49]; p=0.715). The same pattern was observed for Ees, while Ea remained unchanged. The percent decline of RV-PA coupling (ΔEes/Ea) during fluid challenge was significantly associated with pulmonary resting hemodynamics, RV ejection fraction (RVEF), and RV end-diastolic volume. Kaplan-Meier analysis revealed that patients with PH who had a smaller ΔEes/Ea (<-65%) had a significantly better prognosis (log-rank p=0.0389). In multivariate Cox regression analysis, clinical worsening was predicted by ΔEes/Ea (hazard ratio: 0.96 [95% confidence interval: 0.93-1.00]) and RVEF (hazard ratio: 0.95 [95% confidence interval: 0.92-0.98]). Assessment of PV loops during fluid challenge uncovers exhausted RV coupling reserve with severely reduced contractility in PH. RV-PA uncoupling during volume challenge can be predicted by pulmonary resting hemodynamics and RVEF. RV-PA uncoupling during fluid challenge and RVEF (as a noninvasive correlate) are predictors of clinical worsening. URL: https://www.clinicaltrials.gov. Unique identifier: NCT03403868 (January 19, 2018).

Prognostic value of right ventricular native T1 mapping in pulmonary arterial hypertension

BackgroundRight ventricular function is an important prognostic marker for pulmonary arterial hypertension. Native T1 mapping using cardiovascular magnetic resonance imaging can characterize the myocardium, but accumulating evidence indicates that T1 values of the septum or ventricular insertion points do not have predictive potential in pulmonary arterial hypertension. We aimed to elucidate whether native T1 values of the right ventricular free wall (RVT1) can predict poor outcomes in patients with pulmonary arterial hypertension.MethodsThis retrospective study included 30 patients with pulmonary arterial hypertension (median age, 45 years; mean pulmonary artery pressure, 41±13 mmHg) and 16 healthy controls (median age, 43 years) who underwent native T1 mapping. RVT1 was obtained from the inferior right ventricular free wall during end systole.ResultsPatients with pulmonary arterial hypertension had significantly higher native RVT1 than did controls (1384±74 vs. 1217±57 ms, p<0.001). Compared with T1 values of the septum or ventricular insertion points, RVT1 correlated better with the effective right ventricular elastance index (R = −0.53, p = 0.003), ventricular-arterial uncoupling (R = 0.46, p = 0.013), and serum brain natriuretic peptide levels (R = 0.65, p<0.001). Moreover, the baseline RVT1 was an accurate predictor of the reduced right ventricular ejection fraction at the 12-month follow-up (delta -3%). RVT1 was independently associated with composite events of death or hospitalization from any cause (hazard ratio = 1.02, p = 0.002).ConclusionsRVT1 was predictive of right ventricular performance and outcomes in patients with pulmonary arterial hypertension. Thus, native T1 mapping in the right ventricular free wall may be an effective prognostic method for pulmonary arterial hypertension.

Right ventricular dysfunction and right ventricular-arterial uncoupling at admission increase the in-hospital mortality in patients with COVID-19 disease.

BackgroundCoronavirus disease 2019 (COVID‐19) frequently involves cardiovascular manifestations such as right ventricular (RV) dysfunction and alterations in pulmonary hemodynamics. We evaluated the application of the critical care ultrasonography ORACLE protocol to identify the most frequent alterations and their influence on adverse outcomes, especially those involving the RV (dilatation and dysfunction).MethodsThis cross‐sectional study included 204 adult patients with confirmed COVID‐19 admitted at three centers. Echocardiography and lung ultrasound images were acquired on admission using the ORACLE ultrasonography algorithm.ResultsTwo‐hundred and four consecutive patients were evaluated: 22 (11.9%) demonstrated a fractional shortening of < 35%; 33 (17.1%) a tricuspid annular plane systolic excursion (TAPSE) of < 17 mm; 26 (13.5%) a tricuspid peak systolic S wave tissue Doppler velocity of < 9.5 cm/sec; 69 (37.5%) a RV basal diameter of > 41 mm; 119 (58.3%) a pulmonary artery systolic pressure (PASP) of > 35 mm Hg; and 14 (11%) a TAPSE/PASP ratio of < .31. The in‐hospital mortality rate was 37.6% (n = 71). Multiple logistic regression modeling showed that PASP > 35 mm Hg, RV FS of < 35%, TAPSE < 17 mm, RV S wave < 9.5, and TAPSE/PASP ratio < .31 mm/mm Hg were associated with this outcome. PASP and the TAPSE/PASP ratio had the lowest feasibility of being obtained among the investigators (62.2%).ConclusionThe presence of RV dysfunction, pulmonary hypertension, and alteration of the RV–arterial coupling conveys an increased risk of in‐hospital mortality in patients presenting with COVID‐19 upon admission; therefore, searching for these alterations should be routine. These parameters can be obtained quickly and safely with the ORACLE protocol.

Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload

BackgroundWe previously reported that upregulated AMP deaminase (AMPD) contributes to diastolic ventricular dysfunction via depletion of the adenine nucleotide pool in a rat model of type 2 diabetes (T2DM), Otsuka Long-Evans-Tokushima Fatty rats (OLETF). Meanwhile, AMPD promotes the formation of substrates of xanthine oxidoreductase (XOR), which produces ROS as a byproduct. Here, we tested the hypothesis that a functional link between upregulated AMPD and XOR is involved in ventricular dysfunction in T2DM rats. Methods and resultsPressure-volume loop analysis revealed that pressure overloading by phenylephrine infusion induced severer left ventricular diastolic dysfunction (tau: 14.7 ± 0.8 vs 12.5 ± 0.7 msec, left ventricular end-diastolic pressure: 18.3 ± 1.5 vs 12.2 ± 1.3 mmHg, p < 0.05) and ventricular-arterial uncoupling in OLETF than in LETO, non-diabetic rats, though the baseline parameters were comparable in the two groups. While the pressure overload did not affect AMPD activity, it increased XOR activity both in OLETF and LETO, with OLETF showing significantly higher XOR activity than that in LETO (347.2 ± 17.9 vs 243.2 ± 6.1 μg/min/mg). Under the condition of pressure overload, myocardial ATP level was lower, and levels of xanthine and uric acid were higher in OLETF than in LETO. Addition of exogenous inosine, a product of AMP deamination, to the heart homogenates augmented XOR activity. OLETF showed 68% higher tissue ROS levels and 47% reduction in mitochondrial state 3 respiration compared with those in LETO. Overexpression of AMPD3 in H9c2 cells elevated levels of hypoxanthine and ROS and reduced the level of ATP. Inhibition of XOR suppressed the production of tissue ROS and mitochondrial dysfunction and improved ventricular function under the condition of pressure overload in OLETF. ConclusionsThe results suggest that increases in the activity of XOR and the formation of XOR substrates by upregulated AMPD contribute to ROS-mediated diastolic ventricular dysfunction at the time of increased cardiac workload in diabetic hearts.

Right ventricular-arterial uncoupling independently predicts survival in COVID-19 ARDS

AimTo investigate the prevalence and prognostic impact of right heart failure and right ventricular-arterial uncoupling in Corona Virus Infectious Disease 2019 (COVID-19) complicated by an Acute Respiratory Distress Syndrome (ARDS).MethodsNinety-four consecutive patients (mean age 64 years) admitted for acute respiratory failure on COVID-19 were enrolled. Coupling of right ventricular function to the pulmonary circulation was evaluated by a comprehensive trans-thoracic echocardiography with focus on the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratioResultsThe majority of patients needed ventilatory support, which was noninvasive in 22 and invasive in 37. There were 25 deaths, all in the invasively ventilated patients. Survivors were younger (62 ± 13 vs. 68 ± 12 years, p = 0.033), less often overweight or usual smokers, had lower NT-proBNP and interleukin-6, and higher arterial partial pressure of oxygen (PaO2)/fraction of inspired O2 (FIO2) ratio (270 ± 104 vs. 117 ± 57 mmHg, p < 0.001). In the non-survivors, PASP was increased (42 ± 12 vs. 30 ± 7 mmHg, p < 0.001), while TAPSE was decreased (19 ± 4 vs. 25 ± 4 mm, p < 0.001). Accordingly, the TAPSE/PASP ratio was lower than in the survivors (0.51 ± 0.22 vs. 0.89 ± 0.29 mm/mmHg, p < 0.001). At univariate/multivariable analysis, the TAPSE/PASP (HR: 0.026; 95%CI 0.01–0.579; p: 0.019) and PaO2/FIO2 (HR: 0.988; 95%CI 0.988–0.998; p: 0.018) ratios were the only independent predictors of mortality, with ROC-determined cutoff values of 159 mmHg and 0.635 mm/mmHg, respectively.ConclusionsCOVID-19 ARDS is associated with clinically relevant uncoupling of right ventricular function from the pulmonary circulation; bedside echocardiography of TAPSE/PASP adds to the prognostic relevance of PaO2/FIO2 in ARDS on COVID-19.

THE IMPACT OF AMERICAN-STYLE FOOTBALL PARTICIPATION ON VENTRICULAR-ARTERIAL COUPLING

American-style football (ASF) participation is associated with reduced diastolic function, arterial stiffening, and hypertension. While these maladaptive physiologic changes suggest the presence of ventricular-arterial (V-A) uncoupling, a validated measure of cardiovascular (CV) inefficiency, the