Jakob Lundgren

sGC stimulation totally reverses hypoxia‐induced pulmonary vasoconstriction alone and combined with dual endothelin‐receptor blockade in a porcine model

Stimulation of soluble guanylate cyclase (sGC) with BAY 41‐8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)‐receptor antagonist tezosentan.

Pathophysiology and Potential Treatments of Pulmonary Hypertension due to Systolic Left Heart Failure.

Pulmonary hypertension (PH) due to left heart failure is becoming increasingly prevalent and is associated with poor outcome. The precise pathophysiological mechanisms behind PH due to left heart failure are, however, still unclear. In its early course, PH is caused by increased left ventricular filling pressures, without pulmonary vessel abnormalities. Conventional treatment for heart failure may partly reverse such passive PH by optimizing left ventricular function. However, if increased pulmonary pressures persist, endothelial damage, excessive vasoconstriction and structural changes in the pulmonary vasculature may occur. There is, at present, no recommended medical treatment for this active component of PH due to left heart failure. However, as the vascular changes in PH due to left heart failure may be similar to those in pulmonary arterial hypertension (PAH), a selected group of these patients may benefit from PAH treatment targeting the endothelin, nitric oxide or prostacyclin pathways. Such potent pulmonary vasodilators could, however, be detrimental in patients with left heart failure without pulmonary vascular pathology, as selective pulmonary vasodilatation may lead to further congestion in the pulmonary circuit, resulting in pulmonary oedema. The use of PAH therapies is therefore currently not recommended and would require the selection of suitable patients based on the underlying causes of the disease and careful monitoring of their progress. The present review focuses on the following: (i) the pathophysiology behind PH resulting from systolic left heart failure, and (ii) the current evidence for medical treatment of this condition, especially the role of PAH‐targeted therapies in systolic left heart failure.

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

Abstract 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 ESCs guidelines, ISHLTs summary statement and ISHLTs 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 ISHLTs 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.

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.

Impact of postoperative pulmonary hypertension on outcome after heart transplantation

Abstract 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

Abstract 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.

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

Abstract 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.