BACKGROUND:Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with... Show moreBACKGROUND:Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with chronic thromboembolic pulmonary hypertension. However, RV mass does not always normalize. It is unknown whether incomplete reversal of RV remodeling results from extracellular matrix expansion (diffuse interstitial fibrosis) or cellular hypertrophy, and whether residual RV remodeling relates to altered diastolic function.METHODS:We prospectively included 25 patients with chronic thromboembolic pulmonary hypertension treated with PEA. Structured follow-up measurements were performed before, and 6 and 18 months after PEA. With single beat pressure-volume loop analyses, we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV–arterial coupling (Ees/Ea), and RV end-diastolic elastance (stiffness, Eed). The extracellular volume fraction of the RV free wall was measured by cardiac magnetic resonance imaging and used to separate the myocardium into cellular and matrix volume. Circulating collagen biomarkers were analyzed to determine the contribution of collagen metabolism.RESULTS:RV mass significantly decreased from 43±15 to 27±11g/m2 (−15.9 g/m2 [95% CI, −21.4 to –10.5]; P<0.0001) 6 months after PEA but did not normalize (28±9 versus 22±6 g/m2 in healthy controls [95% CI, 2.1 to 9.8]; P<0.01). On the contrary, Eed normalized after PEA. Extracellular volume fraction in the right ventricular free wall increased after PEA from 31.0±3.8 to 33.6±3.5% (3.6% [95% CI, 1.2–6.1]; P=0.013) as a result of a larger reduction in cellular volume than in matrix volume (Pinteraction=0.0013). Levels of MMP-1 (matrix metalloproteinase-1), TIMP-1 (tissue inhibitor of metalloproteinase-1), and TGF-β (transforming growth factor-β) were elevated at baseline and remained elevated post-PEA.CONCLUSIONS:Although cellular hypertrophy regresses and diastolic stiffness normalizes after PEA, a relative increase in extracellular volume remains. Incomplete regression of diffuse RV interstitial fibrosis after PEA is accompanied by elevated levels of circulating collagen biomarkers, suggestive of active collagen turnover. Show less
Wezenbeek, J. van; Kianzad, A.; Bovenkamp, A. van de; Wessels, J.; Mouratoglou, S.A.; Braams, N.J.; ... ; Man, F.S. de 2022
Background: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and... Show moreBackground: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disorder for which no effective treatment yet exists. Pulmonary hypertension (PH) and right atrial (RA) and ventricular (RV) dysfunction are frequently observed. The question remains whether the PH with the associated RV/RA dysfunction in HFpEF are markers of disease severity. Methods: To obtain insight in the relative importance of pressure-overload and left-to-right interaction, we compared RA and RV function in 3 groups: 1. HFpEF (n=13); 2. HFpEF-PH (n=33), and; 3. pulmonary arterial hypertension (PAH) matched to pulmonary artery pressures of HFpEF-PH (PH limited to mPAP >= 30 and <= 50 mmHg) (n=47). Patients underwent right heart catheterization and cardiac magnetic resonance imaging. Results: The right ventricle in HFpEF-PH was less dilated and hypertrophied than in PAH. In addition, RV ejection fraction was more preserved (HFpEF-PH: 52 +/- 11 versus PAH: 36 +/- 12%). RV filling patterns differed: vena cava backflow during RA contraction was observed in PAH only. In HFpEF-PH, RA pressure was elevated throughout the cardiac cycle (HFpEF-PH: 10 [8-14] versus PAH: 7 [5-10] mm Hg), while RA volume was smaller, reflecting excessive RA stiffness (HFpEF-PH: 0.14 [0.10-0.17] versus PAH: 0.08 [0.06-0.11] mm Hg/mL). RA stiffness was associated with an increased eccentricity index (HFpEF-PH: 1.3 +/- 0.2 versus PAH: 1.2 +/- 0.1) and interatrial pressure gradient (9 [5 to 12] versus 2 [-2 to 5] mm Hg). Conclusions: RV/RA function was less compromised in HFpEF-PH than in PAH, despite similar pressure-overload. Increased RA pressure and stiffness in HFpEF-PH were explained by left atrial/RA-interaction. Therefore, our results indicate that increased RA pressure is not a sign of overt RV failure but rather a reflection of HFpEF-severity. Show less
Background:It is unknown if beta-blockers reduce mortality/morbidity in patients with heart failure (HF) and advanced chronic kidney disease (CKD), a population underrepresented in HF trials... Show moreBackground:It is unknown if beta-blockers reduce mortality/morbidity in patients with heart failure (HF) and advanced chronic kidney disease (CKD), a population underrepresented in HF trials.Methods:Observational cohort of HF patients with advanced CKD (estimated glomerular filtration rate <30 mL/min per 1.73 m(2)) from the Swedish Heart Failure Registry between 2001 and 2016. We first explored associations between beta-blocker use, 5-year death, and the composite of cardiovascular death/HF hospitalization among 3775 patients with HF with reduced ejection fraction (HFrEF) and advanced CKD. We compared observed hazards with those from a control cohort of 15 346 patients with HFrEF and moderate CKD (estimated glomerular filtration rate <60-30 mL/min per 1.73 m(2)), for whom beta-blocker trials demonstrate benefit. Second, we explored outcomes associated to beta-blocker among advanced CKD participants with preserved (HFpEF; N=2009) and midrange ejection fraction (HFmrEF; N=1514).Results:During a median follow-up of 1.3 years, 2012 patients had a subsequent HF hospitalization, and 2849 died in the HFrEF cohort, of which 2016 died due to cardiovascular causes. Among patients with HFrEF, beta-blocker use was associated with lower risk of death (adjusted hazard ratio 0.85 [95% CI, 0.75-0.96]) and cardiovascular mortality/HF hospitalization (0.87 [0.77-0.98]) compared with nonuse. The magnitude of the associations was similar to that observed for HFrEF patients with moderate CKD. Conversely, no significant association was observed for beta-blocker users in advanced CKD with HFpEF (death: 0.88 [0.77-1.02], cardiovascular mortality/HF hospitalization: 1.05 [0.90-1.23]) or HFmrEF (death: 0.95 [0.79-1.14], cardiovascular mortality/HF hospitalization: 1.09 [0.90-1.31]).Conclusions:In HFrEF patients with advanced CKD, the use of beta-blockers was associated with lower morbidity and mortality. Although inconclusive due to limited power, these benefits were not observed in similar patients with HFpEF or HFmrEF. Show less
Ferreira, J.P.; Verdonschot, J.; Collier, T.; Wang, P.; Pizard, A.; Bar, C.; ... ; Zannad, F. 2019
BACKGROUND: Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies.METHODS AND RESULTS: To identify... Show moreBACKGROUND: Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies.METHODS AND RESULTS: To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (> 20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the reninangiotensin- aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis.CONCLUSIONS: Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Show less
Westermann, D.; Lindner, D.; Kasner, M.; Zietsch, C.; Savvatis, K.; Escher, F.; ... ; Tschope, C. 2011
Background-The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM)... Show moreBackground-The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. Methods and Results-We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-beta. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-beta, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-beta resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction. Conclusions-Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM. (Circ Heart Fail. 2011;4:44-52.) Show less
