Heart failure : advanced treatments and novel hormonal responses

Detta är en avhandling från Stockholm : Karolinska Institutet, Dept of Medicine, Solna

Sammanfattning: Background Heart failure (HF) affects 2-3% of the Western population and is associated with a 1 year mortality of 20%. Despite therapeutic advances over the last decades, numerous unanswered questions remain regarding the impact of currently established therapies as well as potential new targets for therapy. Aims - to investigate 1. Long-term prognosis and the impact of gender after cardiac resynchronization therapy (CRT) 2. If systematic screening can show whether patients with CRT and/or implantable cardioverter defibrillator (ICD) are underserved by heart transplantation (HTx) and/or left ventricular assist device (LVAD) 3. If ghrelin dysregulation in HF is due to inadequate acylation of ghrelin and whether this resolves post HTx 4. If circulating copeptin (C-terminal pro-vasopressin) is elevated and predicts prognosis in HF, and if LVAD and HTx therapy are associated with reversal of activation of the vasopressin axis 5. If levels, correlations, and prognostic impact of N-terminal pro brain natriuretic peptide (NT-proBNP), mid-regional pro atrial natriuretic peptides (MR-proANP) and mid-regional pro adrenomedullin (MR-proADM) differ by HF phenotype ad 1 Long-term survival after cardiac resynchronization therapy In a single centre retrospective cohort study, data on 619 patients with CRT were collected. Overall, 1-, 5- and 10-year survivals were 91%, 63% and 39%, respectively, and female gender was the only independent predictor of survival (p=0.025). ad 2 Screening of patients with CRT In a single centre screening study of 194 patients with CRT and/or ICD, 2 (1%) had confirmed indication without contraindication for HTx and 12 (6%) had confirmed indication without contraindication for LVAD. ad 3 Acylated and unacylated ghrelin in HF and post-HTx Acylated ghrelin was lower post HTx (n=35) compared to age and gender matched HF patients (n=20) (p<0.001), but des-acyl ghrelin levels were similar. ad 4 Copeptin in HF with reduced ejection fraction (HFrEF) and post HTx and LVAD Copeptin levels were highest in patients with HFrEF (n=49), and associated with progressive lowering post LVAD (n=13) and HTx (n=22) (p <0.001). Overall, copeptin correlated with markers of congestion and in patients with HFrEF predicted risk of death, LVAD or HTx (p=0.001). ad 5 NT-proBNP, MR-proANP and MR-proADM in HFrEF, HF with preserved ejection fraction (HFpEF), post HTx and LVAD NT-proBNP and MR-proANP were higher in patients with HFrEF (n=49), than in patients with HFpEF (n=86) (p<0.001 for both), correlated with measurements of cardiac function and outcomes, whereas MR-proADM did none of the above. LVAD (n=13) and HTx (n=22) were associated with progressively decreased levels of all three biomarkers (p<0.001 for all biomarkers). Conclusions Current HF therapy improves outcomes but may be underutilized. Novel cardiovascular and/or anabolic hormones may emerge as targets for therapy. Specifically, women with CRT may have especially good prognosis; HTx and LVAD are underutilized and screening may increase the number of patients who may benefit from these treatments; ghrelin and arginine vasopressin may be involved in the pathophysiology of HF and emerge as potential novel targets; and the cardiovascular hormones BNP, ANP and ADM can characterize differences between and provide targets for potential therapy in different HF phenotypes.

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