Validation of cause of death classification after heart transplantation and cause-specific life expectancy compared to the general population.

BACKGROUND: Post heart-transplant survival has increased, but information is lacking on specific causes of death and life expectancy. We aimed to assess cause-specific loss of life-years compared to the general population, evaluate classification for cause of death after heart transplantation, and assess validity of cause of death data from the International Society of Heart and Lung Transplant (ISHLT) registry. METHODS: In this single center study, we included 239 heart recipients transplanted between 1988 and 2019 in Lund, Sweden (n = 239, 50% of the transplanted population where the cause of death was available). Two cardiologists retrospectively assigned causes of death according to a published classification (CLASS) in the 91 recipients who died during follow-up. Life expectancy was compared to data from the general population. RESULTS: Compared to the average Swedish population, life expectancy for heart transplant recipients was 20 years shorter (IQR 12.9-27.2). The largest number of life-years lost were for deaths due to acute (49 years) and chronic rejection (27 years). Primary graft dysfunction (24 years) accounted for 24% of deaths, followed by malignancy (20 years) and infection (17 years), each accounting for ∼20% of deaths. Use of CLASS revealed moderate inter-rater agreement (56%) and moderate agreement with the ISHLT registry (62%). CONCLUSIONS: Survival after heart transplantation was 20 years lower than in the general population. In the young, more life-years were lost due to acute graft rejection, whereas chronic graft rejection and primary graft failure were more important causes of death in older patients. Agreement was moderate between CLASS and the ISHLT registry classifications.

Elevated plasma tyrosine kinases VEGF-D and HER4 in heart failure patients decrease after heart transplantation in association with improved haemodynamics.

Receptor tyrosine kinases (RTKs) are implicated in cardiovascular growth and remodelling. We aimed to identify the plasma levels of RTKs and related proteins and their association with haemodynamic alterations in heart failure (HF) and related pulmonary hypertension (PH) following heart transplantation (HT). Using proximity extension assay, 28 RTKs and related proteins were analysed in plasma from 20 healthy controls and 26 HF patients before and 1-year after HT. In end-stage HF, out of 28 RTKs, plasma vascular endothelial growth factor-D (VEGF-D) and human epidermal growth factor-4 (HER4) were elevated compared to controls (p < 0.001), but decreased (p < 0.0001) and normalised after HT. Following HT, plasma changes (Δ) of VEGF-D correlated with Δmean pulmonary artery pressure (rs = 0.65, p = 0.00049), Δpulmonary artery wedge pressure (rs = 0.72, p < 0.0001), Δpulmonary arterial compliance (PAC) (rs = - 0.52, p = 0.0083) and Δpulmonary vascular resistance (PVR) (rs = 0.58, p = 0.0032). ΔHER4 correlated with Δmean right atrial pressure (rs = 0.51, p = 0.012), ΔNT-proBNP (rs = 0.48, p = 0.016) and Δcardiac index (rs = - 0.56, p = 0.0044). In HF patients following HT, normalisation of VEGF-D reflected reversal of passive pulmonary congestion and restored PAC and PVR; whereas the normalisation of HER4 reflected decreased volume overload and improved cardiac function. The precise function of these proteins, their potential clinical use and pathophysiological relation in HF and related PH remain to be elucidated.

Elevated plasma endocan and BOC in heart failure patients decrease after heart transplantation in association with improved hemodynamics.

BACKGROUND: The prevalence of heart failure (HF) is rising with ageing population and constitutes a major health problem globally. A common complication of HF is pulmonary hypertension (PH) which negatively impacts survival. A pathophysiological association between HF and PH with tumorigenic processes has been suggested. We aimed to identify the plasma levels of, and the association between tumour-related proteins and hemodynamic improvements in patients with HF and PH due to left heart disease (LHD) before and 1-year after heart transplantation (HT). METHODS: Forty-eight tumour-related proteins were measured with proximity extension assay in plasma from 20 controls and 26 HF patients before and 1-year after HT. Patients' hemodynamics were measured with right heart catheterization. RESULTS: Out of 48 proteins, specifically, plasma levels of endocan and brother of CDO (BOC) were elevated in end-stage HF patients compared to controls (p < 0.001), but decreased after HT (p < 0.01), towards controls' levels. The decrease of endocan levels after HT correlated with improved mean pulmonary arterial pressure (rs = 0.80, p < 0.0001), pulmonary arterial wedge pressure (rs = 0.63, p = 0.0012), and pulmonary vascular resistance (rs = 0.70, p < 0.001). The decrease and normalization of BOC after HT correlated with decreased mean right atrial pressure (rs = 0.61 p = 0.0015) and NT-proBNP (rs = 0.57, p = 0.0022), as well as increased cardiac index (rs = - 0.51, p = 0.0086) and left-ventricular stroke work index (rs = - 0.57, p = 0.0039). CONCLUSION: Our results suggest that (i) plasma endocan in HF may reflect the state of pulmonary vascular congestion and PH-LHD, whereas (ii) plasma BOC may reflect the cardiac function and the hemodynamic overload in HF. The exact role of these proteins and their clinical applicability as biomarkers in HF and PH-LHD ought to be investigated in larger cohorts.

Alterations in plasma L-arginine and methylarginines in heart failure and after heart transplantation.

OBJECTIVE: Endothelial function, including the nitric oxide (NO)-pathway, has previously been extensively investigated in heart failure (HF). In contrast, studies are lacking on the NO pathway after heart transplantation (HT). We therefore investigated substances in the NO pathway prior to and after HT in relation to hemodynamic parameters. DESIGN: 12 patients (median age 50.0 yrs, 2 females), heart transplanted between June 2012 and February 2014, evaluated at our hemodynamic lab, at rest, prior to HT, as well as four weeks and six months after HT were included. All patients had normal left ventricular function post-operatively and none had post-operative pulmonary hypertension or acute cellular rejection requiring therapy at the evaluations. Plasma concentrations of ADMA, SDMA, L-Arginine, L-Ornithine and L-Citrulline were analyzed at each evaluation. RESULTS: In comparison to controls, the plasma L-Arginine concentration was low and ADMA high in HF patients, resulting in low L-Arginine/ADMA-ratio pre-HT. Already four weeks after HT L-Arginine was normalized whereas ADMA remained high. Consequently the L-Arginine/ADMA-ratio improved, but did not normalize. The biomarkers remained unchanged at the six-month evaluation and the L-Arginine/ADMA-ratio correlated inversely to pulmonary vascular resistance (PVR) six months post-HT. CONCLUSIONS: Plasma L-Arginine concentrations normalize after HT. However, as ADMA is unchanged, the L-Arginine/ADMA-ratio remained low and correlated inversely to PVR. Together these findings suggest that (i) the L-Arginine/ADMA-ratio may be an indicator of pulmonary vascular tone after HT, and that (ii) NO-dependent endothelial function is partly restored after HT. Considering the good postoperative outcome, the biomarker levels may be considered "normal" after HT.

Plasma L-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction.

Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from L-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, L-arginine, L-ornithine, and L-citrulline were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma levels of ADMA and SDMA were higher, whereas L-arginine and L-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of L-arginine than patients with LVSD (p < 0.05). L-Arginine correlated to 6 min walking distance (6MWD) (r s = 0.58, p = 0.006) and L-arginine/ADMA correlated to WHO functional class (r s = -0.46, p = 0.043) in PAH. In conclusion, L-arginine levels were significantly lower in treatment naïve PAH patients compared to patients with LVSD. Furthermore, L-arginine correlated with 6MWD in PAH. L-arginine may provide useful information in differentiating PAH from LVSD.

Impact of postoperative pulmonary hypertension on outcome after heart transplantation.

OBJECTIVES: We wanted to investigate the effects of postoperative pulmonary hypertension (PHpostop: mean pulmonary artery pressure [MPAP] ≥ 25 mmHg), diastolic pressure gradient (DPG), pulmonary vascular resistance (PVR), and repeated hemodynamic measurements on long-term survival after heart transplantation (HT). DESIGN: Eighty-nine patients who underwent HT at Skåne University Hospital in Lund in the period 1988-2010 and who were evaluated with right-heart-catheterization at rest, prior to HT and repeatedly during the first postoperative year, were grouped based on their MPAP, DPG, and PVR. RESULTS: One year after HT, survival was lower in patients with PHpostop than in those without, in patients with DPG ≥7 mmHg than in those with DPG <7 mmHg, and in patients with PVR >3 WU than in those with PVR ≤3 WU. Moreover, compared to patients with no PHpostop or with PHpostop at one evaluation during the first year after HT, PHpostop at repeated evaluations was associated with higher mortality (hazard ratio 3.4, 95% CI 1.4-8.0). There was no significant difference in acute cellular rejection between patients with and without PHpostop, but postoperative kidney function was worse in patients with repeated PHpostop. CONCLUSIONS: When defined according to present guidelines, PH one year after HT may emerge as a prognostic marker for long-term outcome after HT. Moreover, PHpostop at repeated evaluations during the first year after HT had stronger prognostic value than PHpostop at a single examination, illustrating a means of identifying a high-risk population. However, confirmation in larger multi-center studies is warranted.

Angiogenic and inflammatory biomarkers in the differentiation of pulmonary hypertension.

OBJECTIVES: Pulmonary hypertension (PH) is a serious condition where diagnosis often is delayed due to unspecific symptoms. New methods to diagnose and differentiate PH earlier would therefore be of great value. The aim of this study was therefore to evaluate the relationship between circulating angiogenic and inflammatory biomarkers and various hemodynamic variables in relation to different causes of PH. DESIGN: Plasma samples from 63 patients at diagnosis were extracted from Lund Cardio Pulmonary Register, separated into pulmonary arterial hypertension (PAH, n = 22), chronic thromboembolic pulmonary hypertension (CTEPH, n = 15) and left heart disease (LHD) with (n = 21) and without (n = 5) PH. Blood samples from eight control subjects devoid of PH were additionally evaluated. Plasma concentrations of angiogenic (PlGF, Tie2, VEGF-A, VEGF-D, bFGF, sFlt-1) and inflammatory (IL-6, IL-8, TNF-α) biomarkers were analysed and related to hemodynamic variables. RESULTS: SFlt-1 (p < .004) and VEGF-A (p < .035) were higher in all PH groups compared to controls. TNF-α (p < .030) were elevated in PAH patients in relation to the other PH groups as well as controls. Likewise, plasma VEGF-D (p < .008) were elevated in LHD with PH compared to the other groups with PH and controls. In PAH, higher sFlt-1 concentrations correlated to a worse state of hemodynamics. CONCLUSIONS: Our findings indicate that sFlt-1 and VEGF-A may be future tools when discriminating PH from non-PH. Moreover, TNF-α may differentiate PAH and VEGF- D may differentiate LHD with PH, from the other groups with PH, as well as controls. SFlt-1 may furthermore play a role as a future marker of disease severity.

Preoperative pulmonary hypertension and its impact on survival after heart transplantation.

OBJECTIVES: Pulmonary hypertension (PH) due to left heart disease may impair outcome after heart transplantation (HT). To evaluate to what extent previous, and present, haemodynamic criteria discriminate the impact of pre-operative-PH on survival, we characterized the PH in our HT-patients according to ESC's guidelines, ISHLT's summary statement and ISHLT's relative contraindications and criteria for early risk of death after HT. DESIGN: Records from the 215 HT-patients in Lund during 1988-2010 were reviewed. Subsequent analysis included adults (n = 94) evaluated with right-heart-catheterization at our lab, at rest before HT. End of follow-up was 30th of June 2012. RESULTS: Survival (mean, n) did not differ (p = ns) for the 94 HT-patients; without (13.0 years, n = 28) or with (13.9 years, n = 66) PH, passive (13.8 years, n = 50) or reactive (12.2 years, n = 13) post-capillary-PH, "modified" passive (13.1 years, n = 40), mixed (16.6 years, n = 23), "modified" reactive (12.6 years, n = 7) or non-reactive (12.2 years, n = 8) post-capillary-PH; or for ISHLT's relative contraindications (12.0 years, n = 22) or increased risk of right-heart-failure and early death (16.5 years, n = 23) after HT. CONCLUSIONS: As previous and present haemodynamic criteria did not sufficiently discriminate the impact of pre-operative-PH for survival after HT at our centre, larger multi-centre studies are encouraged to redefine criteria that may influence outcome.

Extracellular Vesicle-Associated TWEAK Contributes to Vascular Inflammation and Remodeling During Acute Cellular Rejection.

Acute cellular rejection (ACR) is a leading cause of graft loss and death after heart transplantation despite effective immunosuppressive therapies. The identification of factors that impair graft vascular barrier function or promote immune cell recruitment during ACR could provide new therapeutic opportunities for the treatment of patients who receive transplants. In 2 ACR cohorts, we found the extracellular vesicle-associated cytokine TWEAK to be elevated during ACR. Vesicular TWEAK promoted expression of proinflammatory genes and the release of chemoattractant cytokines from human cardiac endothelial cells. We conclude that vesicular TWEAK is a novel target with potential therapeutic implications in ACR.

Association between central haemodynamics and renal function in advanced heart failure: a nationwide study from Sweden.

AIMS: Renal dysfunction in patients with heart failure (HF) has traditionally been attributed to declining cardiac output and renal hypoperfusion. However, other central haemodynamic aberrations may contribute to impaired kidney function. This study assessed the relationship between invasive central haemodynamic measurements from right-heart catheterizations and measured glomerular filtration rate (mGFR) in advanced HF. METHODS AND RESULTS: All patients referred for heart transplantation work-up in Sweden between 1988 and 2019 were identified through the Scandiatransplant organ-exchange organization database. Invasive haemodynamic variables and mGFR were retrieved retrospectively. A total of 1001 subjects (49 ± 13 years; 24% female) were eligible for the study. Analysis of covariance adjusted for age, sex, and centre revealed that higher right atrial pressure (RAP) displayed the strongest relationship with impaired GFR [ß coefficient -0.59; 95% confidence interval (CI) -0.69 to -0.48; P < 0.001], followed by lower mean arterial pressure (MAP) (ß coefficient 0.29; 95% CI 0.14-0.37; P < 0.001), and finally reduced cardiac index (ß coefficient 3.51; 95% CI 2.14-4.84; P < 0.003). A combination of high RAP and low MAP was associated with markedly worse mGFR than any other RAP/MAP profile, and high renal perfusion pressure (RPP, MAP minus RAP) was associated with superior renal function irrespective of the degree of cardiac output. CONCLUSIONS: In patients with advanced HF, high RAP contributed more to impaired GFR than low MAP. A higher RPP was more closely related to GFR than was high cardiac index.

Elevated plasma sRAGE and IGFBP7 in heart failure decrease after heart transplantation in association with haemodynamics.

AIMS: Metabolic derangement is implicated in the pathophysiology of heart failure (HF) and pulmonary hypertension (PH). We aimed to identify the dynamics of metabolic plasma proteins linked to end-stage HF and associated PH in relation to haemodynamics, before and after heart transplantation (HT). METHODS AND RESULTS: Twenty-one metabolic plasma proteins were analysed with proximity extension assay in 20 controls and 26 patients before and 1 year after HT. Right heart catheterizations were performed in the HF patients pre-operatively and 1 year after HT. Plasma levels of soluble receptor for advanced glycation end products (sRAGE) and insulin-like growth factor-binding protein 7 (IGFBP7) were higher in HF patients compared with controls (P < 0.0001) and decreased after HT (P < 0.0001), matching controls' levels. The decrease in sRAGE after HT correlated with improved mean pulmonary arterial pressure (rs = 0.7; P < 0.0001), pulmonary arterial wedge pressure (rs = 0.73; P < 0.0001), pulmonary vascular resistance (rs = 0.65; P = 0.00062), and pulmonary arterial compliance (rs = -0.52; P = 0.0074). The change in plasma IGFBP7 after HT correlated with improved mean right atrial pressure (rs = 0.71; P = 0.00011) and N-terminal pro-brain natriuretic peptide (rs = 0.71; P < 0.0001). CONCLUSIONS: Our results indicate that plasma sRAGE may reflect passive pulmonary vascular congestion and the 'mechanical' state of the pulmonary vasculature in HF patients with or without related PH. Furthermore, sRAGE and IGFBP7 may provide additional insight into the pathophysiological mechanisms in HF and associated PH. Their potential clinical and therapeutic relevance in HF and associated PH need further investigation.

Prolargin and matrix metalloproteinase-2 in heart failure after heart transplantation and their association with haemodynamics.

AIMS: Remodelling of the extracellular matrix (ECM) is a key mechanism involved in the development and progression of heart failure (HF) but also functional in associated pulmonary hypertension (PH). Our aim was to identify plasma ECM proteins associated to end-stage HF and secondary PH in relation to haemodynamics, before and after heart transplantation (HT). METHODS AND RESULTS: Twenty ECM plasma proteins were analysed with proximity extension assay in 20 controls and 26 HF patients pre-HT and 1 year post-HT. Right heart catherization haemodynamics were assessed in the patients during the preoperative evaluation and at the 1 year follow-up post-HT. Plasma levels of prolargin and matrix metalloproteinase-2 (MMP-2) were elevated (P < 0.0001) in HF patients compared with controls and decreased (P < 0.0001) post-HT towards controls' levels. The decrease in prolargin post-HT correlated with improved mean right atrial pressure (rs = 0.63; P = 0.00091), stroke volume index (rs = -0.73; P < 0.0001), cardiac index (rs = -0.64; P = 0.00057), left ventricular stroke work index (rs = -0.49; P = 0.015), and N-terminal pro brain natriuretic peptide (rs = 0.7; P < 0.0001). The decrease in MMP-2 post-HT correlated with improved mean pulmonary artery pressure (rs = 0.58; P = 0.0025), mean right atrial pressure (rs = 0.56; P = 0.0046), pulmonary artery wedge pressure (rs = 0.48; P = 0.016), and N-terminal pro brain natriuretic peptide (rs = 0.56; P = 0.0029). CONCLUSIONS: The normalization pattern in HF patients of plasma prolargin and MMP-2 post-HT towards controls' levels and their associations with improved haemodynamics indicate that prolargin and MMP-2 may reflect, in part, the aberrant ECM remodelling involved in the pathophysiology of HF and associated PH. Their potential clinical use as biomarkers or targets for future therapy in HF and related PH remains to be investigated.

[Pulmonary hypertension due to left heart disease - not to be confused with pulmonary arterial hypertension]. / Olika tillstånd av pulmonell hypertension ska inte förväxlas - PAH-läkemedel bör inte användas vid pulmonell hypertension på basen av vänstersidig hjärtsjukdom.

Pulmonary hypertension is a common consequence of left heart disease, associated with poor prognosis. The pulmonary hypertension in left heart disease is initially caused by a passive congestion of the pulmonary circuit but may, if longstanding, result in endothelial dysfunction and excessive vasoconstriction. In some cases pulmonary vascular remodeling occur, further complicating the condition and worsening the prognosis. It has been debated whether these patients may benefit from pulmonary vasodilators presently used in pulmonary arterial hypertension. Several randomized controlled trials have been performed on this subject, the vast majority being negative. As maintenance therapy may be harmful, they should be avoided outside clinical trials.

Plasma receptor tyrosine kinase RET in pulmonary arterial hypertension diagnosis and differentiation.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a serious disease exhibiting unspecific symptoms, as a result of which diagnosis is often delayed and prognosis is poor. The underlying pathophysiology includes vasoconstriction and remodelling of small pulmonary arteries. As receptor tyrosine kinases (RTKs) and their ligands have been shown to promote PAH remodelling, our aim was to evaluate if their plasma levels may be utilised to differentiate between various causes of pulmonary hypertension. METHODS: 28 biomarkers involved in RTK signalling were measured using proximity extension assays in venous plasma from patients with PAH (n=48), chronic thromboembolic pulmonary hypertension (CTEPH) (n=20), pulmonary hypertension due to diastolic (n=33) or systolic (n=36) heart failure and heart failure patients without pulmonary hypertension (n=15), as well as healthy controls (n=20). RESULTS: Plasma proto-oncogene tyrosine-protein kinase receptor Ret (RET) was decreased (p<0.04) in PAH compared with all disease groups and controls. RET generated a sensitivity of 64.6% and a specificity of 81.6% for detecting PAH from other disease groups. PAH and the other pulmonary hypertension groups showed elevated plasma tyrosine-protein kinase MER (p<0.01), vascular endothelial growth factor (VEGF)-A (p<0.02), VEGF-D (p<0.01), placental growth factor (p<0.01), amphiregulin (p<0.02), hepatocyte growth factor (p<0.01) and transforming growth factor-α (p<0.05) and decreased VEGF receptor-2 (p<0.04) and epidermal growth factor receptor (p<0.01) levels compared with controls. CONCLUSION: Plasma RET differentiates patients with PAH from those with CTEPH, systolic or diastolic heart failure with or without pulmonary hypertension as well as healthy controls. Future studies would be of value to determine the clinical usefulness of RET as a biomarker and its link to PAH pathophysiology.

Profiling of the plasma proteome across different stages of human heart failure.

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.

[Pulmonary hypertension ­ a common condition in left heart disease]. / Pulmonell hypertension vanligt vid vänstersidig hjärtsjukdom - Kunskapsläget är dåligt ­ fler kliniska studier behövs.

Pulmonary hypertension (PH) is a serious complication to left heart disease (LHD), affecting a majority of the patients during the course of the disease. Initially, PH-LHD is caused by passive congestion of the pulmonary vessels due to increased left atrial pressures, a condition that is currently denoted as isolated post-capillary PH (Icp-PH). In the majority of patients the increased atrial pressure is a result of elevated left ventricular filling pressures. Furthermore, chronically elevated filling pressures may yield endothelial damage, resulting in structural and functional alterations in the pre-capillary bed with further elevation in pulmonary pressures as well as elevated vascular resistance, defined as combined precapillary and postcapillary PH (Cpc-PH). With previous definitions of PH-LHD it has been difficult to differentiate between the subgroups, so a new classification was presented in the 2015 PH guidelines. Despite PH-LHD being common and serious, specific therapies are lacking for the pulmonary component. Instead, treatments focus on optimizing the underlying cause of PH-LHD and involve medical as well as surgical therapies. In the present review we presents, based on the new guidelines, current knowledge on pathophysiological and pathobiological mechanisms, epidemiology, investigation and treatment of PH-LHD.

Hemodynamic Characteristics Including Pulmonary Hypertension at Rest and During Exercise Before and After Heart Transplantation.

BACKGROUND: Little is known about the hemodynamic response to exercise in heart failure patients at various ages before and after heart transplantation (HT). This information is important because postoperative hemodynamics may be a predictor of survival. To investigate the hemodynamic response to HT and exercise, we grouped our patients based on preoperative age and examined their hemodynamics at rest and during exercise before and after HT. METHODS AND RESULTS: Ninety-four patients were evaluated at rest prior to HT with right heart catheterization at our laboratory. Of these patients, 32 were evaluated during slight supine exercise before and 1 year after HT. Postoperative evaluations were performed at rest 1 week after HT and at rest and during exercise at 4 weeks, 3 months, 6 months, and 1 year after HT. The exercise patients were divided into 2 groups based on preoperative age of ≤50 or >50 years. There were no age-dependent differences in the preoperative hemodynamic exercise responses. Hemodynamics markedly improved at rest and during exercise at 1 and 4 weeks, respectively, after HT; however, pulmonary and, in particular, ventricular filling pressures remained high during exercise at 1 year after HT, resulting in normalized pulmonary vascular resistance response but deranged total pulmonary vascular resistance response. CONCLUSIONS: Our findings suggest that, (1) in patients with heart failure age ≤50 or >50 years may not affect the hemodynamic response to exercise to the same extent as in healthy persons, and (2) total pulmonary vascular resistance may be more adequate than pulmonary vascular resistance for evaluating the exercise response after HT.