Plasma Biomarkers for Clinical Assessment of Bone Mineral Density in Heart Transplanted Patients-A Single-Center Study at Skåne University Hospital in Lund.

We aimed to identify plasma biomarkers that predict changes in bone mineral density (BMD) and increase the understanding of impaired BMD after heart transplantation (HT). Twenty-eight adult patients were included. Data, including densitometry and 29 plasma proteins, before and 1 year after HT were analyzed. Pre-HT plasma levels of fibroblast growth factor 23 (FGF23) correlated with post-HT T score in lumbar spine, adjusted for age, gender, and BMI (1.72 [95% CI 1.33; 2.22], p = 0.011). Change (∆; post-HT-pre-HT) in plasma levels of melusin correlated to ∆T score from the lumbar spine (p = 0.028). ∆plasma levels of TR-AP, ITGB2, and Stromelysin-1 correlated to ∆T score from the femoral neck (p < 0.05). However, no correlations remained after adjustments for age, gender, and BMI. In conclusion, elevated plasma FGF23 pre-HT predicted an increase in lumbar BMD after HT. However, the results are surprising since FGF23 is known to be inversely correlated with BMD. This may partly be explained by the complex pathophysiology in this particular cohort. Due to the explorative nature of the study and the small sample size, further investigations of biochemical markers on bone metabolism in this patient population are encouraged.

Bone mineral density in pediatric heart transplanted patients: A retrospective single-center study at Skåne University Hospital in Lund 1988-2016.

BACKGROUND: Impaired bone mineral density (BMD) and osteoporosis are commonly found in patients who have undergone heart transplantation (HT), which increases the risk for bone fractures which is associated with increased morbidity and mortality in adults. However, the long-term evolution of BMD after HT in pediatric patients has not been thoroughly investigated. METHOD: Bone mineral density up to 10 years after HT was investigated in 30 patients who underwent HT at an age <20 years at Skåne University Hospital in Lund 1988-2016. RESULTS: The total observed time was 235 person-years. Before HT, 86% had low BMD for chronologic age in the lumbar spine. In lumbar spine, BMD was significantly lower than normal for chronological age before HT (p = .034), but recovered at the 4th year (p = .009). In whole body, BMD was normal at the 4th annual check-up (p = .030) and remained so throughout the follow-up period. The median T score in the lumbar spine and femoral neck 10 years after HT did not differ between the two groups based on age at HT (<20 years vs 20 years or older; p = .779 in the lumbar spine and p = .388 in the femoral neck). CONCLUSIONS: Patients who undergo HT at an age of <20 years have low BMD for chronological age already before HT, but BMD may recover completely within the first 4 years after HT. The results indicate no difference in BMD at 10 years after HT between pediatric and adult patients.

Circulating plasma microRNAs in systemic sclerosis-associated pulmonary arterial hypertension.

OBJECTIVES: SSc-associated pulmonary arterial hypertension (SSc-APAH) is a late but devastating complication of SSc. Early identification of SSc-APAH may improve survival. We examined the role of circulating miRNAs in SSc-APAH. METHODS: Using quantitative RT-PCR the abundance of mature miRNAs in plasma was determined in 85 female patients with ACA-positive lcSSc. Twenty-two of the patients had SSc-APAH. Sixty-three SSc controls without PAH were matched for disease duration. Forty-six selected miRNA plasma levels were correlated with clinical data. Longitudinal samples were analysed from 14 SSc-APAH and 27 SSc patients. RESULTS: The disease duration was 12 years for the SSc-APAH patients and 12.7 years for the SSc controls. Plasma expression levels of 11 miRNAs were lower in patients with SSc-APAH. Four miRNAs displayed higher plasma levels in SSc-APAH patients compared with SSc controls. There was significant difference between groups for miR-20a-5p and miR-203a-3p when correcting for multiple comparisons (P = 0.002 for both). Receiver operating characteristics curve showed AUC = 0.69-0.83 for miR-21-5p and miR-20a-5p or their combination. miR-20a-5p and miR-203a-3p correlated inversely with NT-pro-Brain Natriuretic Protein levels (r = -0.42 and -0.47). Mixed effect model analysis could not identify any miRNAs as predictor of PAH development. However, miR-20a-5p plasma levels were lower in the longitudinal samples of SSc-APAH patients than in the SSc controls. CONCLUSIONS: Our study links expression levels of the circulating plasma miRNAs, especially miR-20a-5p and miR-203a-3p, to the occurrence of SSc-APAH in female patients with ACA-positive lcSSc.

Right ventricular stroke work index by echocardiography in adult patients with pulmonary arterial hypertension.

BACKGROUND: In adult patients with pulmonary arterial hypertension (PAH), right ventricular (RV) failure may worsen rapidly, resulting in a poor prognosis. In this population, non-invasive assessment of RV function is challenging. RV stroke work index (RVSWI) measured by right heart catheterization (RHC) represents a promising index for RV function. The aim of the present study was to comprehensively evaluate non-invasive measures to calculate RVSWI derived by echocardiography (RVSWIECHO) using RHC (RVSWIRHC) as a reference in adult PAH patients. METHODS: Retrospectively, 54 consecutive treatment naïve patients with PAH (65 ± 13 years, 36 women) were analyzed. Echocardiography and RHC were performed within a median of 1 day [IQR 0-1 days]. RVSWIRHC was calculated as: (mean pulmonary arterial pressure (mPAP)-mean right atrial pressure (mRAP)) x stroke volume index (SVI)RHC. Four methods for RVSWIECHO were evaluated: RVSWIECHO-1 = Tricuspid regurgitant maximum pressure gradient (TRmaxPG) x SVIECHO, RVSWIECHO-2 = (TRmaxPG-mRAPECHO) x SVIECHO, RVSWIECHO-3 = TR mean gradient (TRmeanPG) x SVIECHO and RVSWIECHO-4 = (TRmeanPG-mRAPECHO) x SVIECHO. Estimation of mRAPECHO was derived from inferior vena cava diameter. RESULTS: RVSWIRHC was 1132 ± 352 mmHg*mL*m-2. In comparison with RVSWIRHC in absolute values, RVSWIECHO-1 and RVSWIECHO-2 was significantly higher (p < 0.001), whereas RVSWIECHO-4 was lower (p < 0.001). No difference was shown for RVSWIECHO-3 (p = 0.304). The strongest correlation, with RVSWIRHC, was demonstrated for RVSWIECHO-2 (r = 0.78, p < 0.001) and RVSWIECHO-1 ( r = 0.75, p < 0.001). RVSWIECHO-3 and RVSWIECHO-4 had moderate correlation (r = 0.66 and r = 0.69, p < 0.001 for all). A good agreement (ICC) was demonstrated for RVSWIECHO-3 (ICC = 0.80, 95% CI 0.64-0.88, p < 0.001), a moderate for RVSWIECHO-4 (ICC = 0.73, 95% CI 0.27-0.87, p < 0.001) and RVSWIECHO-2 (ICC = 0.55, 95% CI - 0.21-0.83, p < 0.001). A poor ICC was demonstrated for RVSWIECHO-1 (ICC = 0.45, 95% CI - 0.18-0.77, p < 0.001). Agreement of absolute values for RVSWIECHO-1 was - 772 ± 385 (- 50 ± 20%) mmHg*mL*m-2, RVSWIECHO-2 - 600 ± 339 (-41 ± 20%) mmHg*mL*m-2, RVSWIECHO-3 42 ± 286 (5 ± 25%) mmHg*mL*m-2 and for RVSWIECHO-4 214 ± 273 (23 ± 27%) mmHg*mL*m-2. CONCLUSION: The correlation with RVSWIRHC was moderate to strong for all echocardiographic measures, whereas only RVSWIECHO-3 displayed high concordance of absolute values. The results, however, suggest that RVSWIECHO-1 or RVSWIECHO-3 could be the preferable echocardiographic methods. Prospective studies are warranted to evaluate the clinical utility of such measures in relation to treatment response, risk stratification and prognosis in patients with PAH.

Plasma insulin-like growth factor binding protein 1 in pulmonary arterial hypertension.

BACKGROUND: Beside the pulmonary vasoconstriction observed in pulmonary arterial hypertension (PAH), severe proliferative and antiapoptotic cellular phenotypes result in vascular remodelling. Many recent findings indicate similarities between PAH and tumour pathology. For instance, insulin-like growth factor (IGF)-1 signalling, which is known to promote tumour development, is implicated in PAH. Higher circulating IGF binding protein (IGFBP)-1 levels are associated with worse survival in PAH. The present study aimed to investigate the relationship between plasma levels of various tumour-related biomarkers and PAH. Methods: IGFBP-1, -2 and -7, along with other tumour-related biomarkers, were measured in plasma from 48 treatment-naïve PAH patients and 16 healthy controls, using proximity extension assays. Among the PAH patients, 33 were also studied at an early treatment follow-up. Results: Plasma IGFBP-1 (p < .003), IGFBP-2 (p < .001), IGFBP-7 (p < .008), vimentin (p < .001), carbonic anhydrase 9 (p < .001), S100A11 (p < .001), human epididymis protein 4 (p < .001) and folate receptor-α (p < .004) were elevated in PAH, compared to controls. IGFBP-1 exhibited the most interesting correlations to clinical parameters and was selected for further analyses. IGFBP-1 correlated specifically to N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (r = 0.44, p < .002), mean right atrial pressure (r = 0.41, p < .004), venous oxygen saturation (r = -0.43, p < .003), cardiac index (r = -0.32, p < .03) and 6-minute walking distance (r = -0.29, p < .05). Plasma IGFBP-1 also correlated to risk scores based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) PAH guidelines (r = 0.43, p < .003) and the REVEAL model (r = 0.46, p < .001). PAH patients with supra-median baseline IGFBP-1 levels showed a trend for worse overall survival than those with infra-median levels (p = .087). IGFBP-1 was unaltered between baseline and an early treatment follow-up. However, IGFBP-1 changes, between baseline and follow-up, correlated to changes in NT-proBNP (r = 0.48, p < .006). Conclusion: Plasma IGFBP-1 levels at PAH diagnosis show moderate association to NT-proBNP and hemodynamics as well as with ESC/ERS and REVEAL risk scores.

Risk stratification in chronic thromboembolic pulmonary hypertension predicts survival.

OBJECTIVES: To investigate if the pulmonary arterial hypertension (PAH) risk assessment tool presented in the 2015 ESC/ERS guidelines is valid for patients with chronic thromboembolic pulmonary hypertension (CTEPH) when taking pulmonary endarterectomy (PEA) into account. Design. Incident CTEPH patients registered in the Swedish PAH Registry (SPAHR) between 2008 and 2016 were included. Risk stratification performed at baseline and follow-up classified the patients as low-, intermediate-, or high-risk using the proposed ESC/ERS risk algorithm. Results. There were 250 CTEPH patients with median age (interquartile range) 70 (14) years, and 53% were male. Thirty-two percent underwent PEA within 5 (6) months. In a multivariable model adjusting for age, sex, and pharmacological treatment, patients with intermediate-risk or high-risk profiles at baseline displayed an increased mortality risk (Hazard Ratio [95% confidence interval]: 1.64 [0.69-3.90] and 5.39 [2.13-13.59], respectively) compared to those with a low-risk profile, whereas PEA was associated with better survival (0.38 [0.18-0.82]). Similar impact of risk profile and PEA was seen at follow-up. Conclusion. The ESC/ERS risk assessment tool identifies CTEPH patients with reduced survival. Furthermore, PEA improves survival markedly independently of risk group and age. Take home message: The ESC/ERS risk stratification for PAH predicts survival also in CTEPH patients, even when taking PEA into account.

Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients: Design of the randomized controlled EVOLVD trial.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is characterized by diffuse thickening of the arterial intima. Statins reduce the incidence of CAV, but despite the use of statins, CAV remains one of the leading causes of long-term death after heart transplant. Inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce cholesterol levels but have not been tested in heart transplant recipients. METHODS: The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD) trial (ClinicalTrials.gov Identifier: NCT03734211) is a randomized, double-blind trial designed to test the effect of the PCSK9 inhibitor evolocumab on coronary intima thickness in heart transplant recipients. Adults who have received a cardiac transplant within the past 4-8 weeks are eligible. Exclusion criteria include an estimated glomerular filtration rate < 20 mL/min/1.73 m2 , renal replacement therapy, or contraindications to coronary angiography with intravascular ultrasound. 130 patients will be randomized (1:1) to 12-month treatment with evolocumab or matching placebo. The primary endpoint is the coronary artery intima thickness as measured by intravascular ultrasound. CONCLUSION: The EVOLVD trial is a randomized clinical trial designed to show whether treatment with the PCSK9 inhibitor evolocumab can ameliorate CAV over the first year after heart transplant.

Mild acute cellular rejection and development of cardiac allograft vasculopathy assessed by intravascular ultrasound and coronary angiography in heart transplant recipients-a SCHEDULE trial substudy.

To evaluate the association between mild acute cellular rejection (ACR) and the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Substudy of the SCHEDULE trial (n = 115), where de novo HTx recipients were randomized to (i) everolimus with early CNI elimination or (ii) CNI-based immunosuppression. Seventy-six patients (66%) were included based on matched intravascular ultrasound (IVUS) examinations at baseline and year 3 post-HTx. Biopsy-proven ACR within year 1 post-HTx was recorded and graded (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post-HTx. Median age was 53 years (45-61), and 71% were male. ACR was recorded in 67%, and patients were grouped by rejection profile: no ACR (33%), only 1R (42%), and ≥2R (25%). Median ∆MIT (maximal intimal thickness)BL-3Y was not significantly different between groups (P = 0.84). The incidence of CAV was 49% by IVUS and 26% by coronary angiography with no significant differences between groups. No correlation was found between number of 1R and ∆MITBL-3Y (r = -0.025, P = 0.83). The number of 1R was not a significant predictor of ∆MITBL-3Y (P = 0.58), and no significant interaction with treatment was found (P = 0.98). The burden of mild ACR was not associated with CAV development.

Right ventricular function parameters in pulmonary hypertension: echocardiography vs. cardiac magnetic resonance.

BACKGROUND: Right ventricular (RV) function is a major determinant of outcome in patients with pulmonary hypertension. Cardiac magnetic resonance (CMR) is gold standard to assess RV ejection fraction (RVEFCMR), however this is a crude measure. New CMR measures of RV function beyond RVEFCMR have emerged, such as RV lateral atrio-ventricular plane displacement (AVPDlat), maximum emptying velocity (S'CMR), RV fractional area change (FACCMR) and feature tracking of the RV free wall (FWSCMR). However, it is not fully elucidated if these CMR measures are in parity with the equivalent echocardiography-derived measurements: tricuspid annular plane systolic excursion (TAPSE), S'-wave velocity (S'echo), RV fractional area change (FACecho) and RV free wall strain (FWSecho). The aim of this study was to compare regional RV function parameters derived from CMR to their echocardiographic equivalents in patients with pulmonary hypertension and to RVEFCMR. METHODS: Fifty-five patients (37 women, 62 ± 15 years) evaluated for pulmonary hypertension underwent CMR and echocardiography. AVPDlat, S'CMR, FACCMR and FWSCMR from cine 4-chamber views were compared to corresponding echocardiographic measures and to RVEFCMR delineated in cine short-axis stack. RESULTS: A strong correlation was demonstrated for FAC whereas the remaining measurements showed moderate correlation. The absolute bias for S' was 2.4 ± 3.0 cm/s (relative bias 24.1 ± 28.3%), TAPSE/AVPDlat 5.5 ± 4.6 mm (33.2 ± 25.2%), FWS 4.4 ± 5.8% (20.2 ± 37.5%) and for FAC 5.1 ± 8.4% (18.5 ± 32.5%). In correlation to RVEFCMR, FACCMR and FWSecho correlated strongly, FACecho, AVPDlat, FWSCMR and TAPSE moderately, whereas S' had only a weak correlation. CONCLUSION: This study has demonstrated a moderate to strong correlation of regional CMR measurements to corresponding echocardiographic measures. However, biases and to some extent wide limits of agreement, exist between the modalities. Consequently, the equivalent measures are not interchangeable at least in patients with pulmonary hypertension. The echocardiographic parameter that showed best correlation with RVEFCMR was FWSecho. At present, FACecho and FWSecho as well as RVEFCMR are the preferred methods to assess and follow up RV function in patients with pulmonary hypertension. Future investigations of the CMR right ventricular measures, beyond RVEF, are warranted.

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.

Bone mineral density and osteoporosis in heart transplanted patients: A single-center retrospective study at Skåne University Hospital in Lund 1988-2016.

Bone mineral density (BMD) in the lumbar spine and femoral neck, the incidence of osteoporosis, and survival up to 10 years after heart transplantation (HT) were investigated in 169 patients who underwent HT at Skåne University Hospital in Lund, Sweden, 1988-2016. Within the first year post-transplantation, mean (SD) BMD decreased by 3.9% (10.1) (P < 0.001) and 9.0% (10.5) (P < 0.001) in the lumbar spine and femoral neck, respectively. The cumulative incidence of osteoporosis in the lumbar spine and femoral neck increased rapidly within the first year after HT and was detected in 17% and 13% of the patients, respectively. A higher T score before HT was a negative predictor of osteoporosis up to 10 years post-HT in the lumbar spine (HR 0.13; 95% CI 0.063-0.26; P < 0.001) and femoral neck (HR 0.54; 95% CI 0.34-0.85; P < 0.001). Moreover, only 13%, 14%, and 6% of the HT patients received calcium, vitamin D, and/or bisphosphonates before HT. In conclusion, BMD drops significantly during the first postoperative year. Optimization of BMD early among HT candidates, potentially through usage of osteoporosis preventive treatment, may be a future means to prevent osteoporosis late postoperatively.

A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension.

Aims: Guidelines recommend a goal-oriented treatment approach in pulmonary arterial hypertension (PAH). The aim is to reach a low-risk profile, as determined by a risk assessment instrument. This strategy is incompletely validated. We aimed to investigate the bearing of such risk assessment and the benefit of reaching a low-risk profile. Methods and results: Five hundred and thirty PAH patients were included. Follow-up assessments performed after a median of 4 (interquartile range 3-5) months were available for 383 subjects. Patients were classified as 'Low', 'Intermediate', or 'High risk' and the benefit of reaching the 'Low risk' group was estimated. Survival differed (P < 0.001) between the risk groups at baseline and at follow-up. Survival was similar for patients who remained in or improved to the 'Low risk' group. Survival was similar for patients who remained in or worsened to the 'Intermediate risk' or 'High risk' groups. Irrespective of follow-up risk group, survival was better (P < 0.001) for patients with a higher proportion of variables at low risk. Results were unchanged after excluding patients with idiopathic PAH >65 years at diagnosis, and when patients with idiopathic or connective tissue disease-associated PAH were analysed separately. Patients in the 'Low risk' group at follow-up exhibited a reduced mortality risk (hazard ratio 0.2, 95% confidence interval 0.1-0.4 in multivariable analysis adjusted for age, sex and PAH subset), as compared to patients in the 'Intermediate risk' or 'High risk' groups. Conclusion: These findings suggest that comprehensive risk assessments and the aim of reaching a low-risk profile are valid in PAH.

Health-related quality of life, treatment adherence and psychosocial support in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) share similar quality of life impairment. The aim of the present study was to investigate health-related quality of life (HRQoL) and its relation to the perception of treatment and psychosocial support among PAH and CTEPH patients. All adult PAH or CTEPH patients in the Swedish Pulmonary Arterial Hypertension Register were invited to participate in a national cohort survey. The survey included the EuroQol 5-dimensions (EQ-5D) instrument that measures an individual's HRQoL; the Beliefs about Medicines Questionnaire-Specific Scale that assesses the perception of PAH-specific treatment; the Mastery scale that evaluates the feeling of control and ability to cope with the disease; and the Social Network and Support Scale that maps the social support network. Of the 440 invited patients, 74% responded. Mean age was 66 ± 14 years, 58% were female and 69% diagnosed with PAH. Patients with PAH were younger, more often female and had a lower EQ-5D index (0.67 ± 0.29 vs. 0.73 ± 0.25, p = 0.050) than patients with CTEPH. Patients with a low EQ-5D index had more concerns about treatment ( p = 0.004), lower coping ability ( p < 0.001), less emotional support ( p = 0.003) and less accessible social network ( p = 0.002). In conclusion, patients with an impaired HRQoL also reported negative effects on their social support network, ability to handle stressors and concerns about treatment.

Impact of age and comorbidity on risk stratification in idiopathic pulmonary arterial hypertension.

Recent reports from worldwide pulmonary hypertension registries show a new demographic picture for patients with idiopathic pulmonary arterial hypertension (IPAH), with an increasing prevalence among the elderly.We aimed to investigate the effects of age and comorbidity on risk stratification and outcome of patients with incident IPAH.The study population (n=264) was categorised into four age groups: 18-45, 46-64, 65-74 and ≥75 years. Individual risk profiles were determined according to a risk assessment instrument, based on the European Society of Cardiology and the European Respiratory Society guidelines. The change in risk group from baseline to follow-up (median 5 months) and survival were compared across age groups. In the two youngest age groups, a significant number of patients improved (18-45 years, Z= -4.613, p<0.001; 46-64 years, Z= -2.125, p=0.034), but no significant improvement was found in the older patient groups. 5-year survival was highest in patients aged 18-45 years (88%), while the survival rates were 63%, 56% and 36% for patients in the groups 46-64, 65-74 and ≥75 years, respectively (p<0.001). Ischaemic heart disease and kidney dysfunction independently predicted survival.These findings highlight the importance of age and specific comorbidities as prognostic markers of outcome in addition to established risk assessment algorithms.

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.

Acute cellular rejection later than one year after heart transplantation: A single-center retrospective study at Skåne University Hospital in Lund 1988-2010.

Routine endomyocardial biopsy (EMB) to detect acute cellular rejection (ACR) late (>1 year) after heart transplantation (HT) remains debated. To gain knowledge on late ACR and thereby approach this issue, we studied the incidence, predictors, and outcome of late ACR. 815 late EMBs from 183 patients transplanted 1988-2010 were retrospectively reviewed until June 30, 2012. Only 4.4% of the routine and 17.6% of the additional clinically indicated late EMBs showed ACR ≥ grade 2. With time post-HT, there was a clear trend toward fewer ACRs, a lower incidence of ACR per patient per year, and a deceleration in the decrease in the proportion of patients free from ACR. Sex-mismatching and first-year ACR were associated with an increased risk of late ACR, which also was associated with worse outcome. Although rare, when compared to our previous study on first-year EMBs, it appears as if late more often than early ACR remains undetected and that also late and not only early ACR influences outcome. Extended EMB surveillance >1 year post-HT therefore still seems reasonable in "high-risk" patients, as also suggested in the International Society for Heart and Lung Transplantation guidelines. These should include, but not be limited to, the two risk groups above.