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Diastolic heart failure: What we still don’t know

Looking for new concepts, diagnostic approaches, and the role of comorbidities

Diastolische Herzinsuffizienz: Was wir immer noch nicht wissen

Suche nach neuen Konzepten, optimierter Diagnostik und Bedeutung von Komorbiditäten

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Abstract

Heart failure with preserved ejection fraction (HFPEF) is responsible for half the disease burden of heart failure worldwide, yet there is still much we do not know about this syndrome. Its pathophysiology is classically attributed to diastolic dysfunction (thus “diastolic heart failure”), but accumulating evidence suggests that heterogeneous mechanisms contribute to HFPEF, including systolic abnormalities. Importantly, there remains no proven therapy for HFPEF. To date, clinical trials of neurohormonal blockade have failed to improve outcomes in HFPEF, despite their proven benefits in heart failure with reduced ejection fraction (HFREF). Therefore, it is still an urgent need to better understand the pathophysiology of HFPEF and identify new therapeutic targets. Such potential targets include the myocyte protein titin, intracellular calcium regulation, as well as modulation of the extracellular matrix. We also need to understand why the previous large trials have failed in HFPEF. Are we studying the right patients? How do we best diagnose this syndrome? Are we assessing the appropriate outcomes? Causes of mortality and morbidity differ between HFPEF and HFREF, and the high burden of comorbidities in HFPEF may contribute to noncardiovascular outcomes. Newer therapeutic approaches should be developed with these considerations in mind.

In conclusion, HFPEF is still an enigma. New pathophysiological concepts, improved diagnostic strategies, and a better understanding of patient factors are needed to generate new therapeutic options in the future.

Zusammenfassung

Zwar ist bei der Hälfte aller Patienten mit Herzinsuffizienzsymptomen die Ejektionsfraktion noch annähernd erhalten („heart failure with preserved ejection fraction“, HFPEF), doch diese Form der Herzinsuffizienz ist bis heute noch nicht gut ergründet. Pathophysiologisch geht man vor allem von einer Störung der diastolischen Funktion dabei aus, sodass sie auch als „diastolische Herzinsuffizienz“ bezeichnet wird. Neue Daten zeigen jedoch, dass bei HFPEF heterogene Mechanismen beteiligt sind, auch systolische Auffälligkeiten. Bis heute konnte noch keine Therapie für HFPEF etabliert werden. Klinische Studien zur Blockade der neurohumoralen Aktivierung schlugen hierbei bisher fehl, obwohl ihr Nutzen für Herzinsuffizienz mit verminderter Ejektionsfraktion („heart failure with reduced ejection fraction“, HFREF) nachgewiesen wurde. Zwar zeigen erste retrospektive Beobachtungen, dass z. B. durch renale Denervierung Blutdruck und diastolische Herzfunktion zu verbessern sind, doch es ist notwendig, neue pathophysiologische Schlüsselmechanismen zu identifizieren. Potenzielle Therapieziele könnten das myozytäre Titin und die Regulation der intrazellulären Kalzium- und extrazellulären Matrixhomöostase sein. Zusätzlich müssen wir analysieren, warum die großen klinischen HFPEF-Studien fehlschlugen: Wurden die richtigen Patienten eingeschlossen und untersucht? Sind die bisher vorgeschlagenen Diagnosekriterien spezifisch genug? Sind die in den Studien angesetzten Endpunkte adäquat? Gerade die Überlegung, dass die Ursachen für Mortalität und Morbidität von Patienten mit HFPEF und mit HFREF unterschiedlich sind, könnte der Schlüssel für die Entwicklung neuer Interventionsstrategien sein.

HFPEF ist nach wie vor ein Rätsel. Neue pathophysiologische Konzepte, Verbesserungen der diagnostischen Strategien und im Verständnis der prognostischen Faktoren sind notwendig für neue therapeutische Optionen in der Zukunft.

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Acknowledgments

Supported by a grant from the EC, FP7-Health-2010, MEDIA (261409 to C.T.) and the DFG (TR-SFB 19 to C.T.). C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore.

Conflict of interest

On behalf of all authors, the corresponding author states that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Cardiology and Pneumology, Campus Benjamin Franklin (CBF), Charité – Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany

    C. Tschöpe

  2. Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany

    C. Tschöpe

  3. DZHK (German Center for Cardiovascular Research), Berlin, Germany

    C. Tschöpe

  4. National University Health System, Singapore, Singapore

    C.S.P. Lam

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Correspondence to C. Tschöpe.

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Tschöpe, C., Lam, C. Diastolic heart failure: What we still don’t know. Herz 37, 875–879 (2012). https://doi.org/10.1007/s00059-012-3719-5

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