Ole Geir Solberg

Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis.

Abstract.  Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, Vermeer C, Schurgers LJ (Research Institute for Internal Medicine, University of Oslo, Oslo; University of Oslo, Oslo, Norway; and VitaK & Cardiovascular Research Institute CARIM (CV, LS), Maastricht University, Maastricht, The Netherlands) Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med 2010; 268: 483–492.

Osteoprotegerin levels predict mortality in patients with symptomatic aortic stenosis

Abstract.  Ueland T, Aukrust P, Dahl CP, Husebye T, Solberg OG, Tønnessen T, Aakhus S, Gullestad L (Oslo University Hospital Rikshospitalet; University of Oslo; Oslo University Hospital Rikshospitalet; Oslo University Hospital Ullevål; Oslo University Hospital Rikshospitalet; and Oslo University Hospital Ullevål, Oslo, Norway). Osteoprotegerin levels predict mortality in patients with symptomatic aortic stenosis. J Intern Med 2011; 270: 452–460.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12‐month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7–11 weeks after HTx or standard cyclosporine immunosuppression. Ninety‐five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm3 and 13.8 ± 28.0 mm3 [all p‐values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor‐1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus‐based CNI‐free can potentially be considered in suitable de novo HTx recipients.

Secreted Wnt Modulators in Symptomatic Aortic Stenosis

Background Valve calcification and inflammation play key roles in the development of aortic stenosis (AS). The Wnt pathways have been linked to inflammation, bone metabolism, angiogenesis, and heart valve formation. We hypothesized that soluble Wnt modulators may be dysregulated in symptomatic AS. Methods and Results We measured circulating levels (n=136) and aortic valve tissue expression (n=16) of the secreted Wnt modulators secreted frizzled related protein-3, dickkopf-1 (DKK-1), and Wnt inhibitory factor-1 (WIF-1) by enzyme immunoassay, immunostaining, and RT-PCR in patients with symptomatic, severe AS and investigated associations with echocardiographic parameters of AS and cardiac function. Finally, we assessed the prognostic value of these Wnt modulators in relation to all-cause mortality (n=35) during long-term follow-up (median 4.6 years; survivors, 4.8 years; nonsurvivors, 1.9 years) in these patients. Our main findings were: (1) serum levels of all Wnt modulators were markedly elevated in patients with symptomatic AS (mean increase 231% to 278%, P<0.001), (2) all Wnt modulators were present in calcified aortic valves but correlated poorly with systemic levels or degree of AS, (3) some modulators (ie, WIF-1) were associated with the degree of myocardial function and valvular calcification, (4) all Wnt modulators, and DKK-1 in particular, predicted long-term mortality in these patients also after adjusting for conventional predictors including NT-proBNP. Conclusions Together, these in vivo data support the involvement of Wnt signaling in the development of AS and suggest that circulating Wnt modulators should be further investigated as risk markers in larger AS populations, including patients with asymptomatic disease.

High-sensitive troponin T and N-terminal-brain-natriuretic-peptide predict outcome in symptomatic aortic stenosis.

Abstract Objectives. Aortic stenosis (AS) and atherosclerosis share similarities when it comes to risk factors and disease progression. Like in other heart diseases, we hypothesized that biomarkers like high-sensitive troponin T (hsTnT), N-terminal-pro-brain-natriuretic-peptide (NT-proBNP) and high-sensitive C-reactive protein (hsCRP) could be useful in risk stratification. Design. A total of 136 patients (57% men, mean age 74 years), referred for evaluation of AS (valve area 0.62 cm2, left ventricular ejection fraction 64%) were consecutively enrolled in the study. The relationship between hsTnT, hsCRP and NT-proBNP, different echocardiographic parameters of AS and cardiac function were investigated as well as their relation to all-cause mortality. Results. In contrast to hsCRP, hsTnT and NT-proBNP were individually correlated with prognosis. Regression analysis identified diabetes and the combination of hsTnT and NT-proBNP as significant predictors of all-cause mortality. When analyzing patients without surgery separately, only the combination of hsTnT and NT-proBNP were identified as a significant predictor of all-cause mortality in multivariable analysis. Conclusion. The combination of NT-proBNP and hsTnT came out as the strongest predictor of outcome irrespective of surgical treatment or not and could be of particular interest in risk-stratification in AS-patients. The results should be confirmed in prospective studies both in symptomatic and asymptomatic patients.

Reference interval for the index of coronary microvascular resistance

AIMS The index of microvascular resistance (IMR) is a relatively new tool that is used to assess microvascular function during routinely performed left heart catheterisations. In order to establish a reference interval for IMR, we investigated a subset of arrhythmia patients with structurally normal hearts and no or minimal coronary artery disease. METHODS AND RESULTS Physiological variables, including IMR, were measured in 20 otherwise healthy patients aged 40-60 years (10 males and 10 females) who had been referred for electrophysiological evaluation of suspected atrioventricular nodal re-entry tachycardia. IMR values were non-normally distributed with a median value of 12.6. We established a reference interval, that would be relevant to 95% of the population, of 7.3 (90% CI: 6.6-8.0) - 27.2 (90% CI: 20.8-33.7), using Box-Cox transformation and the robust Horn method. Spearmans rank correlation analysis revealed no significant relationship between IMR and several different variables. CONCLUSIONS A reference interval for IMR was established in a population of patients aged 40-60 years with structurally normal hearts, considered to be representative of the general population. IMR was not related to sex, age or any of the other variables tested, suggesting that this reference range can be applied to the general population.

Index of microvascular resistance after early conversion from calcineurin inhibitor to everolimus in heart transplantation: A sub-study to a 1-year randomized trial.

BACKGROUND Microvascular function in transplanted hearts can be evaluated by methods used in routine left heart catheterization follow-up after heart transplantation (HTx). This sub-study of a randomized study compared the effects of everolimus (EVR) and calcineurin inhibitor (CNI) treatment on microvascular function as expressed by the index of microvascular resistance (IMR) at 1 year after HTx. A secondary objective was to compare the change in IMR from 7-11 weeks to 1 year after HTx between randomized groups. METHODS There were 70 HTx recipients included and randomly assigned to combination therapy (EVR and CNI with early CNI withdrawal) vs conventional CNI treatment. Coronary physiologic assessment was performed 7-11 weeks and 1 year after HTx. A linear mixed model was used to assess the group difference at 1 year and the difference in IMR change between 7-11 weeks and 1 year after HTx. RESULTS At 1 year, there was no significant difference in IMR between the EVR group (17.5 mm Hg∙sec ± 8.9) (mean ± SD) and the CNI group (14.9 mm Hg∙sec ± 6.6, p = 0.17). The difference in IMR change between the 2 treatment arms was 1.6 mm Hg∙sec (95% confidence interval, -2.8 to 5.9; p = 0.49). Spearmans rank correlation coefficient at 1 year after HTx between IMR and maximal intimal thickness as assessed with intravascular ultrasound in the left anterior descending artery was -0.13 (p = 0.28). CONCLUSIONS In this prospective, open, randomized study comparing early CNI withdrawal with mammalian target of rapamycin inhibitors immunosuppression during the first year after HTx, early transition from CNI-based immunosuppression to EVR-based treatment did not result in differences in microvascular function as assessed by the IMR.

Impaired left ventricular filling is associated with decreased pulse oximetry values

Abstract Objectives. The aim of this study was to investigate the association between echocardiographic measures of diastolic left ventricular dysfunction and decreased arterial oxyhaemoglobin saturation measured with pulse oximetry (SpO2). Design. This is a cross-sectional population-based survey of Norwegian adults. Values obtained using echocardiography, pulse oximetry, and spirometry were included. The primary outcome was abnormal mitral Doppler inflow, defined as normal: E/A ratio 0.75–1.5 and EDT ≥ 140 ms; abnormal: E/A ratio <0.75 or >1.5 or EDT <140 ms. The associations between this outcome and possible predictors, including SpO2 ≤ 95%, were analysed using univariable and multivariable logistic regression. Results. A total of 1782 participants aged 50 years or older (54% women, mean age 67.5 years) were included in the analysis. Abnormal mitral Doppler inflow was found in 595 participants. After adjusting for age, gender, previous myocardial infarction, smoking history, dyspnoea, obesity, and decreased lung function, SpO2 ≤ 95% predicted abnormal mitral Doppler flow with an odds ratio (OR) of 1.6 [95% confidence interval (CI) 1.1–2.4]. Hypertension and BMI > =30 were also significant predictors of impaired filling, with OR of 1.7 (95% CI 1.1–2.7) OR and 1.5 (95% CI 1.2–1.9), respectively. Conclusion. Decreased SpO2 was a significant predictor of abnormal mitral Doppler flow. Diastolic dysfunction should be considered when SpO2 ≤ 95% is found.

Comparison of simplified and comprehensive methods for assessing the index of microvascular resistance in heart transplant recipients.

The objectives of the present study were to compare a simplified and a comprehensive method of estimating the index of microvascular resistance (IMR) and assess the changes from 7–11 weeks to 1 year after heart transplant (HTx).