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Diastolic heart failure: update on mechanisms and diagnosis

Basic Sciences, Pharmacology, Genomics and Cardiovascular Pathology

This session covered the clinically relevant topic of Heart Failure with Preserved Ejection Fraction, from pathophysiological understanding to new diagnostic and therapeutic approaches. Four prestigious speakers, all experts in their field, guaranteed the excellent quality of this well-attended session.

Prof. Wolfgang Linke from Münster, Germany, spoke about the mechanisms of increased passive stiffness of the myocytes in HFpEF, largely contributing to globally reduced LV diastolic compliance in this syndrome. Linke reported evidence that changes in the isoform composition as well as in the phosphorylation status of titin, a giant protein that acts as the molecular spring of cardiomyocytes underlie elevated myocyte stiffness. Increased expression of the N2B titin isoform underlies higher titin stiffness. Reduced phosphorylation status was directly observed in biopsies from human heart samples and is in part related to reduced cGMP activity.

Prof. Adelino Leite-Moreira from Porto, Portugal, discussed the interactions between preload, afterload, and left ventricular diastolic function. In his own experiments, he demonstrated significant active relaxation of isolated mammalian and human cardiac tisse after acute stretch – corresponding to increased LV filling. In fact, this acute physiological modulation of diastolic compliance is regulated, for example by Angiotensin II or cGMP-dependent phosphorylation processes, again at the level of titin.

Prof. Grusson from Brussels, Belgium, reported on new biomarker research in HFpEF. Importantly, Prof. Grusson pointed out that due to confounding factors such as renal dysfunction, gender, and age, the diagnostic accuracy of BNP and NTproBNP in HFpEF is quite low. He reported on emerging biomarkers, such as soluble ST2 or GDF-15, which may be related to endothelial dysfunction and inflammatory processes contributing to the pathophysiology HFpEF. Galectin-3 as a new marker involved in profibrotic processes is attracting increasing attention. The aspects of added value, as well as cost effectiveness for new HFpEF biomarkers were also adressed.

Last but not least, Prof. Paulus from Amsterdam gave an overview on new diagnostic and therapeutic strategies. He discussed the emerging role of the diastolic stress test for a solid diagnosis, and the importance of comorbidities such as renal dysfunction and COPD in the disease. He specifically pointed out that recent data suggest that COPD may, though proinflammatory pathways, even accelerate the development of HFpEF. Prof. Paulus then reported data from recent larger, mostly phase II clinical trials on the treatment of HFpEF. Data on ranolazine are still too scarce to draw clinically relevant conclusions. Ivabradine might be promising and is currently being tested in a Phase II trial. MR antagonist therapy with spironolactone (Ado-DHF) induced functional and structural reverse remodeling, but failed to improve exercise capacity. Outcome data for MR antagonists are awaited from the large TOPCAT trial to be presented at AHA 2013. In RELAX, sildenafil did not improve any of the multiple outcome parameters. In contrast, in PARAMOUNT, the neprilysin inhibitor LCZ696 reduced BNP plasma levels and left atrial size, and is now being tested in an upcoming Phase III trial program. SOCRATES will be a phase II trial testing a novel guanylate cyclase stimulator in HFpEF. Prof. Paulus drew attention to the wide variability in patient characteristics in the recently published HFpEF trials.

Taken together, the lectures in this session showed that new pathophysiogical mechanisms are  described, novel diagnostic approaches are currently validated, and new therapies are tested in larger clinical trials. Fortunately, the field of HFpEF research continues to move on fast.




Diastolic heart failure: update on mechanisms and diagnosis

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.