Heart failure : advanced treatments and novel hormonal responses

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; and 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.

List of scientific papers

I. Zabarovskaja S., Gadler F., Braunschweig F., Stahlberg M., Hornsten J., Linde C., Lund L. H. Women have better long-term prognosis than men after cardiac resynchronization therapy. Europace. 2012;14(8):1148-55.
https://doi.org/10.1093/europace/eus039

II. Zabarovskaja S., Gadler F., Gabrielsen A., Linde C., Lund L. H. Identifying patients for advanced heart failure therapy by screening patients with cardiac resynchronization therapy or implantable cardioverter-defibrillator: a pilot study. Journal of Heart and Lung Transplantation. 2013;32(6):651-4.
https://doi.org/10.1016/j.healun.2013.02.008

III. Zabarovskaja S., Freda P., Williams J., Kunavarapu C., LaManca J., Mancini D., Lund L. H. Acylation of ghrelin is increased in heart failure and decreases post heart transplantation. Scandinavian Cardiovascular Journal. 2014:1-6.
https://doi.org/10.3109/14017431.2014.955052

IV. Zabarovskaja S., Hage C., Gabrielsen A., Mellbin L., Lund L. H. Copeptin in heart failure, post left ventricular assist device and post heart transplantation. [Manuscript]

V. Zabarovskaja S., Hage C., Linde C., Daubert J. C., Donal E., Gabrielsen A:, Mellbin L., Lund L. H. Adaptive cardiovascular hormones in a spectrum of heart failure phenotypes. [Manuscript]