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Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII alpha 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). Importantly, elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/Chronic hypoxic (SuHx) rat pulmonary hypertension (PH) model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricular (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance (CMR) imaging and advanced hemodynamic assessments with pressure-volume (PV) loops in patients with PAH to assess RV-pulmonary arterial (PA) coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index (VMI) were positively associated with ES while RV ejection fraction and RV-PA coupling were inversely associated with ES levels. Our animal data demonstrates that the development of PH is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared to the left ventricle (LV) and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increase early in disease development in the RV and implicate COL18A1/ES in pathologic RV dysfunction in PAH.
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BACKGROUND: Pulmonary arterial hypertension (PAH) is characterised by poor exercise tolerance. The contribution of right ventricular (RV) diastolic function to the augmentation of cardiac output during exercise is not known. This study leverages pressure-volume (P-V) loop analysis to characterise the impact of RV diastology on poor flow augmentation during exercise in PAH. METHODS: RV P-V loops were measured in 41 PAH patients at rest and during supine bike exercise. Patients were stratified by median change in cardiac index (CI) during exercise into two groups: high and low CI reserve. Indices of diastolic function (end-diastolic elastance (E ed)) and ventricular interdependence (left ventricular transmural pressure (LVTMP)) were compared at matched exercise stages. RESULTS: Compared to patients with high CI reserve, those with low reserve exhibited lower exercise stroke volume (36 versus 49â mL·m-2; p=0.0001), with higher associated exercise afterload (effective arterial elastance (E a) 1.76 versus 0.90â mmHg·mL-1; p<0.0001), RV stiffness (E ed 0.68 versus 0.26â mmHg·mL-1; p=0.003) and right-sided pressures (right atrial pressure 14 versus 8â mmHg; p=0.002). Higher right-sided pressures led to significantly lower LV filling among the low CI reserve subjects (LVTMP -4.6 versus 3.2â mmHg; p=0.0001). Interestingly, low exercise flow reserve correlated significantly with high afterload and RV stiffness, but not with RV contractility nor RV-PA coupling. CONCLUSIONS: Patients with poor exercise CI reserve exhibit poor exercise RV afterload, stiffness and right-sided filling pressures that depress LV filling and stroke work. High afterload and RV stiffness were the best correlates to low flow reserve in PAH. Exercise unmasked significant pathophysiological PAH differences unapparent at rest.
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Débito Cardíaco , Hipertensão Arterial Pulmonar , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Hipertensão Arterial Pulmonar/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Tolerância ao Exercício , Função Ventricular Direita , Teste de Esforço , Volume Sistólico , Idoso , Ventrículos do Coração/fisiopatologia , Exercício Físico/fisiologia , DiástoleRESUMO
BACKGROUND: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21-24 mmHg). METHODS: The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks. DISCUSSION: The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04797286.
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Hipertensão Pulmonar , Qualidade de Vida , Escleroderma Sistêmico , Citrato de Sildenafila , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cateterismo Cardíaco , Método Duplo-Cego , Ecocardiografia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Artéria Pulmonar , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Citrato de Sildenafila/uso terapêutico , Resultado do Tratamento , Vasodilatadores/uso terapêutico , Teste de Caminhada , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
BACKGROUND: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA. METHODS: The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death. RESULTS: We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185â 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75â 346-337â 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome. CONCLUSIONS: Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.
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Ácidos Nucleicos Livres , Insuficiência Cardíaca , Transplante de Coração , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , DNA Mitocondrial/genética , Ácidos Nucleicos Livres/genética , Estudos Longitudinais , Estudos Prospectivos , Fatores Raciais , Volume Sistólico , Biomarcadores , Rejeição de Enxerto/genética , Função Ventricular Esquerda , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/cirurgia , Transplante de Coração/efeitos adversos , Doadores de TecidosRESUMO
BACKGROUND: Detecting right heart failure post left ventricular assist device (LVAD) is challenging. Sensitive pressure-volume loop assessments of right ventricle (RV) contractility may improve our appreciation of post-LVAD RV dysfunction. METHODS: Thirteen LVAD patients and 20 reference (non-LVAD) subjects underwent comparison of echocardiographic, right heart cath hemodynamic, and pressure-volume loop-derived assessments of RV contractility using end-systolic elastance (Ees), RV afterload by effective arterial elastance (Ea), and RV-pulmonary arterial coupling (ratio of Ees/Ea). RESULTS: LVAD patients had lower RV Ees (0.20 ± 0.08 vs 0.30 ± 0.15 mm Hg/ml, p = 0.01) and lower RV Ees/Ea (0.37 ± 0.14 vs 1.20 ± 0.54, p < 0.001) versus reference subjects. Low RV Ees correlated with reduced RV septal strain, an indicator of septal contractility, in both the entire cohort (r = 0.68, p = 0.004) as well as the LVAD cohort itself (r = 0.78, p = 0.02). LVAD recipients with low RV Ees/Ea (below the median value) demonstrated more clinical heart failure (71% vs 17%, p = 0.048), driven by an inability to augment RV Ees (0.22 ± 0.11 vs 0.19 ± 0.02 mm Hg/ml, p = 0.95) to accommodate higher RV Ea (0.82 ± 0.38 vs 0.39 ± 0.08 mm Hg/ml, p = 0.002). Pulmonary artery pulsatility index (PAPi) best identified low baseline RV Ees/Ea (≤0.35) in LVAD patients ((area under the curve) AUC = 0.80); during the ramp study, change in PAPi also correlated with change in RV Ees/Ea (r = 0.58, p = 0.04). CONCLUSIONS: LVAD patients demonstrate occult intrinsic RV dysfunction. In the setting of excess RV afterload, LVAD patients lack the RV contractile reserve to maintain ventriculo-vascular coupling. Depression in RV contractility may be related to LVAD left ventricular unloading, which reduces septal contractility.
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Insuficiência Cardíaca , Coração Auxiliar , Disfunção Ventricular Direita , Humanos , Ventrículos do Coração/diagnóstico por imagem , Artéria Pulmonar , Insuficiência Cardíaca/cirurgia , Função Ventricular DireitaRESUMO
BACKGROUND: The Heartmate 3 (HM3) risk score (HM3RS) was derived and validated internally from within the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial population and provides 1- and 2-year mortality risk prediction for patients in those before HM3 left ventricular assist device (LVAD) implantation. We aimed to evaluate the HM3RS in nontrial unselected patients, including those not meeting inclusion criteria for MOMENTUM 3 trial enrollment. METHODS: Patients who underwent HM3 LVAD implant at 1 of 7 US centers between 2017 and 2021, with at least 1-year follow-up, were included in this analysis. Patients were retrospectively assessed for their eligibility for the MOMENTUM 3 trial based on study inclusion and exclusion criteria. HM3RS risk discrimination was evaluated using time-dependent receiver operating characteristic curve analysis for 1-year mortality for all patients and further stratified by MOMENTUM 3 trial eligibility. Kaplan-Meier curves were constructed using the HM3RS-based risk categories. RESULTS: Of 521 patients included in the analysis, 266 (51.1%) would have met enrollment criteria for MOMENTUM 3. The 1- and 2-year survival for the total cohort was 85% and 81%, respectively. There was no statistically significant difference in survival between those who met and did not meet enrollment criteria at 1 (87% vs 83%; p = 0.21) and 2 years postimplant (80% vs 78%; p = 0.39). For the total cohort, HM3RS predicted 1-year survival with an area under the curve (AUC) of 0.63 (95% confidence interval [CI]: 0.57-0.69, p < 0.001). HM3RS performed better in the subset of patients meeting enrollment criteria: AUC 0.69 (95% CI:0.61-0.77, p < 0.001) compared to the subset that did not: AUC 0.58 (95% CI: 0.49-0.66, p = 0.078). CONCLUSIONS: In this real-world evidence, multicenter cohort, 1- and 2-year survival after commercial HM3 LVAD implant was excellent, regardless of trial eligibility. The HM3RS provided adequate risk discrimination in "trial-like" patients, but predictive value was reduced in patients who did not meet trial criteria.
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Insuficiência Cardíaca , Coração Auxiliar , Humanos , Resultado do Tratamento , Insuficiência Cardíaca/cirurgia , Estudos Retrospectivos , Fatores de Risco , Coração Auxiliar/efeitos adversosRESUMO
BACKGROUND: Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in patients with heart failure with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. We thus sought to characterize RV myocyte contractile depression in HFrEF-PH, identify those components reflected by clinical RV indices, and uncover underlying biophysical mechanisms. METHODS: Resting, calcium-, and load-dependent mechanics were prospectively studied in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 patients with HFrEF-PH undergoing cardiac transplantation and 9 organ donor controls. RESULTS: Unsupervised machine learning using myocyte mechanical data with the highest variance yielded 2 HFrEF-PH subgroups that in turn mapped to patients with decompensated or compensated clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in decompensated clinical RV function, whereas surprisingly, many other major myocyte contractile measures including peak power and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick filament defects, myofibrillar structure was assessed by x-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in decompensated clinical RV function, but not compensated clinical RV function, as compared with controls. This corresponded to reduced myosin ATP turnover in decompensated clinical RV function myocytes, indicating less myosin in a crossbridge-ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Last, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human heart failure. CONCLUSIONS: Although there are many RV myocyte contractile deficits in HFrEF-PH, commonly used clinical indices only detect reduced isometric calcium-stimulated force, which is related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients.
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Insuficiência Cardíaca , Hipertensão Pulmonar , Disfunção Ventricular Direita , Humanos , Sarcômeros , Cálcio , Depressão , Volume Sistólico , Miócitos Cardíacos , Função Ventricular Direita/fisiologiaRESUMO
Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however, RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH. Consecutive subjects with PAH (n = 23) underwent rest and exercise right heart catheterization with multibeat pressure volume loop analysis. Pulmonary arterial blood was collected at rest and during exercise. Mass spectrometry-based targeted metabolomics were performed, and metabolic associations with hemodynamics and comprehensive measures of RV function were determined using sparse partial least squares regression. Metabolite profiles were compared with N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) measurements for accuracy in modeling ventriculo-arterial parameters. Thirteen metabolites changed in abundance with exercise, including metabolites reflecting increased arginine bioavailability, precursors of catecholamine and nucleotide synthesis, and branched-chain amino acids. Higher resting arginine bioavailability predicted more favorable exercise hemodynamics and pressure-flow relationships. Subjects with more severe PAH augmented arginine bioavailability with exercise to a greater extent than subjects with less severe PAH. We identified relationships between kynurenine pathway metabolism and impaired ventriculo-arterial coupling, worse RV diastolic function, lower RV contractility, diminished RV contractility with exercise, and RV dilation with exercise. Metabolite profiles outperformed NT-proBNP in modeling RV contractility, diastolic function, and exercise performance. Specific metabolite profiles correspond to RV functional measurements only obtainable via invasive pressure-volume loop analysis and predict RV responses to exercise. Metabolic profiling may inform discovery of RV functional biomarkers.NEW & NOTEWORTHY In this cohort of patients with pulmonary arterial hypertension (PAH), we investigate metabolomic associations with comprehensive right ventricular (RV) functional measurements derived from multibeat RV pressure-volume loop analysis. Our results show that tryptophan metabolism, particularly the kynurenine pathway, is linked to intrinsic RV function and PAH pathobiology. Findings also highlight the importance of arginine bioavailability in the cardiopulmonary system's response to exercise stress. Metabolite profiles selected via unbiased analysis outperformed N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) in predicting load-independent measures of RV function at rest and cardiopulmonary system performance under stress. Overall, this work suggests the potential for select metabolites to function as disease-specific biomarkers, offers insights into PAH pathobiology, and informs discovery of potentially targetable RV-centric pathways.
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Hipertensão Arterial Pulmonar , Disfunção Ventricular Direita , Humanos , Peptídeo Natriurético Encefálico , Função Ventricular Direita/fisiologia , Cinurenina , Hipertensão Pulmonar Primária Familiar , Biomarcadores , ArgininaRESUMO
Rationale: Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in heart failure patients with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. Objective: To determine components of myocyte contractile depression in HFrEF-PH, identify those reflected by clinical RV indices, and elucidate their underlying biophysical mechanisms. Methods and Results: Resting, calcium- and load-dependent mechanics were measured in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 HFrEF-PH patients undergoing cardiac transplantation and 9 organ-donor controls. Unsupervised machine learning using myocyte mechanical data with the highest variance yielded two HFrEF-PH subgroups that in turn mapped to patients with depressed (RVd) or compensated (RVc) clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in RVd, while surprisingly, many other major myocyte contractile measures including peak power, maximum unloaded shortening velocity, and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick-filament defects, myofibrillar structure was assessed by X-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in RVd but not RVc, as compared to controls. This corresponded to reduced myosin ATP turnover in RVd myocytes, indicating less myosin in a cross-bridge ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Lastly, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human HF. Conclusions: While there are multiple RV myocyte contractile deficits In HFrEF-PH, clinical indices primarily detect reduced isometric calcium-stimulated force related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients.
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Late right heart failure (LRHF) following left ventricular assist device (LVAD) implantation remains poorly characterized and challenging to predict. We performed a multicenter retrospective study of LRHF in 237 consecutive adult LVAD patients, in which LRHF was defined according to the 2020 Mechanical Circulatory Support Academic Research Consortium guidelines. Clinical and hemodynamic variables were assessed pre- and post-implant. Competing-risk regression and Kaplan-Meier survival analysis were used to assess outcomes. LRHF prediction was assessed using multivariable logistic and Cox proportional hazards regression. Among 237 LVAD patients, 45 (19%) developed LRHF at a median of 133 days post-LVAD. LRHF patients had more frequent heart failure hospitalizations ( p < 0.001) alongside other complications. LRHF patients did not experience reduced bridge-to-transplant rates but did suffer increased mortality (hazard ratio 1.95, 95% confidence interval [CI] 1.11-3.42; p = 0.02). Hemodynamically, LRHF patients demonstrated higher right atrial pressure, mean pulmonary arterial pressure, and pulmonary vascular resistance (PVR), but no difference in pulmonary arterial wedge pressure. History of early right heart failure, blood urea nitrogen (BUN) > 35 mg/dl at 1 month post-LVAD, and diuretic requirements at 1 month post-LVAD were each significant, independent predictors of LRHF in multivariable analysis. An LRHF prediction risk score incorporating these variables predicted LRHF with excellent discrimination (log-rank p < 0.0001). Overall, LRHF post-LVAD is more common than generally appreciated, with significant morbidity and mortality. Elevated PVR and precapillary pulmonary pressures may play a role. A risk score using early right heart failure, elevated BUN, and diuretic requirements 1 month post implant predicted the development of LRHF.
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Insuficiência Cardíaca , Coração Auxiliar , Disfunção Ventricular Direita , Adulto , Humanos , Coração Auxiliar/efeitos adversos , Estudos Retrospectivos , Insuficiência Cardíaca/complicações , Pressão Propulsora Pulmonar , Fatores de Risco , Resultado do TratamentoRESUMO
Rationale: To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival. Objectives: To describe a cohort of patients with SSc-PH and compare their characteristics and survival between the last two decades. Methods: Patients with SSc-PH prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients whose disease was diagnosed between 1999 and 2010, and cohort B included those whose disease was diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts. Measurements and Main Results: Of 504 patients with SSc-PH distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension group 1, 43 (9%) had group 2, and 151 (30%) had group 3 disease. Patients with group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis than those in cohort A (P < 0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for group 2 or 3 patients with SSc-PH, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts. Conclusions: This is the largest single-center study that compares clinical characteristics of patients with SSc-PH between the last two decades. Transplant-free survival has improved significantly for those with group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with group 2 or 3 disease continue to have dismal prognosis.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Escleroderma Sistêmico , Humanos , Hipertensão Arterial Pulmonar/terapia , Hipertensão Arterial Pulmonar/complicações , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Hipertensão Pulmonar/diagnóstico , Escleroderma Sistêmico/complicações , Hipertensão Pulmonar Primária Familiar/complicações , Sistema de RegistrosRESUMO
Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by an inability of the heart to perfuse the body without pathologic increases in filling pressure at rest or during exertion. Right heart catheterization provides direct assessment for HF, providing the most robust and direct method to evaluate the central hemodynamic abnormalities, and serves as the gold standard to confirm or refute the presence of HFpEF. This article reviews current understanding of the best practices in the performance and interpretation of hemodynamic assessment, relates important pathophysiologic concepts to clinical care, and discusses current and evidence-based applications of hemodynamics in HFpEF.
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Insuficiência Cardíaca , Cateterismo Cardíaco , Insuficiência Cardíaca/diagnóstico , Hemodinâmica , Humanos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Early right heart failure (RHF) remains a major source of morbidity and mortality after left ventricular assist device (LVAD) implantation, yet efforts to predict early RHF have proven only modestly successful. Pharmacologic unloading of the left ventricle may be a risk stratification approach allowing for assessment of right ventricular and hemodynamic reserve. METHODS: We performed a multicenter, retrospective analysis of patients who had undergone continuous-flow LVAD implantation from October 2011 to April 2020. Only those who underwent vasodilator testing with nitroprusside during their preimplant right heart catheterization were included (n = 70). Multivariable logistic regression was used to determine independent predictors of early RHF as defined by Mechanical Circulatory Support-Academic Research Consortium. RESULTS: Twenty-seven patients experienced post-LVAD early RHF (39%). Baseline clinical characteristics were similar between patients with and without RHF. Patients without RHF, however, achieved higher peak stroke volume index (SVI) (30.1 ± 8.8 vs 21.7 ± 7.4 mL/m2; p < 0.001; AUC: 0.78; optimal cut-point: 22.1 mL/m2) during nitroprusside administration. Multivariable analysis revealed that peak SVI was significantly associated with early RHF, demonstrating a 16% increase in risk of early RHF per 1 ml/m2 decrease in SVI. A follow up cohort of 10 consecutive patients from July 2020 to October 2021 resulted in all patients being categorized appropriately in regards to early RHF versus no RHF according to peak SVI. CONCLUSION: Peak SVI with nitroprusside administration was independently associated with post-LVAD early RHF while resting hemodynamics were not. Vasodilator testing may prove to be a strong risk stratification tool when assessing LVAD candidacy though additional prospective validation is needed.
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Insuficiência Cardíaca , Coração Auxiliar , Disfunção Ventricular Direita , Humanos , Estudos Retrospectivos , Nitroprussiato , Coração Auxiliar/efeitos adversos , Insuficiência Cardíaca/cirurgia , Volume Sistólico , Vasodilatadores/uso terapêuticoRESUMO
Background: Given the morbidity and mortality associated with pulmonary arterial hypertension (PAH), risk stratification approaches that guide therapeutic management have been previously employed. However, most patients remain in the intermediate-risk category despite initial therapy. Herein, we sought to determine whether echocardiographic parameters could improve the risk stratification of intermediate-risk patients. Methods: Prevalent PAH patients previously enrolled in observational studies at 3 pulmonary hypertension centers were included in this study. A validated PAH risk stratification approach was used to stratify patients into low-, intermediate-, and high-risk groups. Right ventricular echocardiographic parameters were used to further stratify intermediate-risk patients into intermediate-low- and intermediate-high-risk groups based on transplant-free survival. Results: From a total of 146 patients included in our study, 38 patients died over a median follow-up of 2.5 years. Patients with intermediate-/high-risk had worse echocardiographic parameters. Tricuspid annular plane systolic excursion (TAPSE) and the degree of tricuspid regurgitation (TR) were highly associated with survival (p < 0.01, p = 0.04, respectively) and were subsequently used to further stratify intermediate-risk patients. Among intermediate-risk patients, survival was worse for patients with TAPSE < 19 mm compared to those with TAPSE ≥ 19 mm (estimated one-year survival 74% vs. 96%, p < 0.01) and for patients with moderate/severe TR compared to those with no/trace/mild TR (estimated one-year survival 70% vs. 93%, p < 0.01). Furthermore, among intermediate-risk patients, those with both TAPSE < 19 mm and moderate/severe TR had an estimated one-year survival (56%) similar to that of high-risk patients (56%), and those with both TAPSE ≥ 19 mm and no/trace/mild TR had an estimated one-year survival (97%) similar to that of low-risk patients (95%). Conclusions: Echocardiography, a routinely performed, non-invasive imaging modality, plays a pivotal role in discriminating distinct survival phenotypes among prevalent intermediate-risk PAH patients using TAPSE and degree of TR. This can potentially help guide subsequent therapy.
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BACKGROUND: Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection. METHODS: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use. RESULTS: The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively. CONCLUSIONS: We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.
Assuntos
MicroRNA Circulante , Cardiopatias , Transplante de Coração , MicroRNAs , Anticorpos , Biomarcadores/metabolismo , Biópsia , Feminino , Rejeição de Enxerto/genética , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Echocardiography (2DE) is integral for screening and longitudinal evaluation of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc). In the present study, we sought to establish the reliability, repeatability, and reproducibility of 2DE parameters in SSc patients with and without PAH and to define the minimal detectable difference (MDD), the smallest change detected beyond measurement error. METHODS: SSc patients without known PAH and with invasively confirmed PAH on stable therapies underwent 2DE with strain at two time points. Analysis of variance (ANOVA) and coefficients of variation (CV) were calculated to assess for repeatability, reliability, and reproducibility. Intra- and inter-observer agreement were assessed using intraclass correlation. Bland-Altman analysis explored the level of agreement between evaluations. MDD was calculated using the standard error of measurement for each parameter by cohort. RESULTS: ANOVA demonstrated few significant differences between evaluations across groups. Global right ventricular longitudinal systolic strain (GRVLSS, 9.7%) and fractional area change (FAC, 21.3%) had the largest CV, while tricuspid annular plane excursion (TAPSE), S' wave, and right ventricular outflow track velocity time integral (RVOT VTI) were 0.87%, 3.2%, and 6.0%, respectively. Intra- and inter-observer agreement was excellent. MDD for TAPSE, FAC, S' wave, RVOT VTI, GRVLSS, and RVSP were 0.11 cm, 0.03%, 1.27 cm/s, 0.81 cm, 1.14%, and 6.5 mmHg, respectively. CONCLUSIONS: We demonstrate minimal measurement error in clinically important 2DE-based measures in SSc patients with and without PAH. Defining the MDD in this population has important implications for PAH screening, assessment of therapeutic response, and sample size calculations for future clinical trials.
Assuntos
Escleroderma Sistêmico , Disfunção Ventricular Direita , Ecocardiografia , Humanos , Reprodutibilidade dos Testes , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagem , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita/fisiologiaRESUMO
Rationale: Pulmonary arterial hypertension (PAH) is a rare disease characterised by limited survival despite remarkable improvements in therapy. The causes, clinical burden and outcomes of patients admitted to the intensive care unit (ICU) remain poorly characterised. The aim of this study was to describe patient characteristics, causes of ICU hospitalisation, and risk factors for ICU and 1-year mortality. Methods: Data from patients enrolled in the Johns Hopkins Pulmonary Hypertension Registry were analysed for the period between January 2010 and December 2020. Clinical, functional, haemodynamic and laboratory data were collected. Measurements and main results: 102 adult patients with 155 consecutive ICU hospitalisations were included. The leading causes for admission were right heart failure (RHF, 53.3%), infection (17.4%) and arrhythmia (11.0%). ICU mortality was 27.1%. Mortality risk factors included Na <136â mEq·mL-1 (OR: 3.10, 95% CI: 1.41-6.82), elevated pro-B-type natriuretic peptide (proBNP) (OR: 1.75, 95% CI: 1.03-2.98), hyperbilirubinaemia (OR: 1.40, 95% CI: 1.09-1.80), hyperlactaemia (OR: 1.42, 95% CI: 1.05-1.93), and need for vasopressors/inotropes (OR: 5.29, 95% CI: 2.28-12.28), mechanical ventilation (OR: 3.76, 95% CI: 1.63-8.76) and renal replacement therapy (OR: 5.57, 95% CI: 1.25-24.76). Mortality rates at 3, 6 and 12â months were 17.5%, 27.6% and 39.0%, respectively. Connective tissue disease-associated PAH has lower 1-year survival compared to idiopathic PAH (51.4% versus 79.8%, log-rank test p=0.019). Conclusions: RHF is the most common cause for ICU admission. In-hospital and 1-year mortality remain exceedingly high despite improved ICU care. Recognising specific risk factors on admission can help identifying patients at risk for poor outcomes.
RESUMO
Cardiac magnetic resonance (CMR) measures of right ventricular (RV) mass, volumes, and function have diagnostic and prognostic value in pulmonary arterial hypertension (PAH). We hypothesized that RV mass-based metrics would discriminate incident PAH as redefined by the lower mean pulmonary arterial pressure (mPAP) threshold of >20 mmHg at the Sixth World Symposium on Pulmonary Hypertension (6th WSPH). Eighty-nine subjects with suspected PAH underwent CMR imaging, including 64 subjects with systemic sclerosis (SSc). CMR metrics, including RV and left ventricular (LV) mass, were measured. All subjects underwent right heart catheterization (RHC) for assessment of hemodynamics within 48 h of CMR. Using generalized linear models, associations between CMR metrics and PAH were assessed, the best subset of CMR variables for predicting PAH were identified, and relationships between mass-based metrics, hemodynamics, and other predictive CMR metrics were examined. Fifty-nine subjects met 6th WSPH criteria for PAH. RV mass metrics, including ventricular mass index (VMI), demonstrated the greatest magnitude difference between subjects with versus without PAH. Overall and in SSc, VMI and RV mass measured by CMR were among the most predictive variables discriminating PAH at RHC, with areas under the receiver operating characteristic curve 0.86 and 0.83. respectively. VMI increased linearly with pulmonary vascular resistance and with mPAP in PAH, including in lower ranges of mPAP associated with mild PAH. VMI ≥ 0.37 yielded a positive predictive value of 90% for discriminating PAH. RV mass metrics measured by CMR, including VMI, discriminate incident, treatment-naïve PAH as defined by 6th WSPH criteria.