L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease.

Abstract

OBJECTIVES:

Prognosis of heart failure with preserved ejection fraction (HFpEF) remains poor because of unknown pathophysiology and unestablished therapeutic strategy. This study aimed to identify a potential therapeutic intervention for HFpEF through metabolomics-based analysis.

METHODS AND RESULTS:

Metabolomics with capillary electrophoresis time-of-flight mass spectrometry was performed using plasma of Dahl salt-sensitive rats fed high-salt diet, a model of hypertensive HFpEF, and showed decreased free-carnitine levels. Reassessment with enzymatic cycling method revealed the decreased plasma and left-ventricular free-carnitine levels in the HFpEF model. Urinary free-carnitine excretion was increased, and the expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was down-regulated in the left ventricle (LV) and kidney in the HFpEF model. L-Carnitine was administered to the hypertensive HFpEF model. L-Carnitine treatment restored left-ventricular free-carnitine levels, attenuated left-ventricular fibrosis and stiffening, prevented pulmonary congestion, and improved survival in the HFpEF model independent of the antihypertensive effects, accompanied with increased expression of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid, and enhanced production of arachidonic acid, a precursor of prostacyclin, and prostacyclin in the LV. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with increased FADS1/2 expression and enhanced production of arachidonic acid and prostacyclin. L-Carnitine-induced increase of arachidonic acid was canceled by knock-down of FADS1 or FADS2 in cultured cardiac fibroblasts. Serum free-carnitine levels were decreased in HFpEF patients.

CONCLUSIONS:

L-carnitine supplementation attenuates cardiac fibrosis by increasing prostacyclin production through arachidonic acid pathway, and may be a promising therapeutic option for HFpEF.

• Authors: Yosuke Omori, Tomohito Ohtani, Yasushi Sakata, Toshiaki Mano, Yasuharu Takeda, Shunsuke Tamaki, Yasumasa Tsukamoto, Daisuke Kamimura, Yoshihiro Aizawa, Takeshi Miwa, Issei Komuro, Tomoyoshi Soga, Kazuhiro Yamamoto
• Journal: Journal of hypertension (J Hypertens) Vol. 30 Issue 9 Pg. 1834-44 (Sep 2012) ISSN: 1473-5598 [Electronic] England
• PMID: 22796714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Delta-5 Fatty Acid Desaturase
• RNA, Small Interfering
• Epoprostenol
• FADS1 protein, human
• Carnitine

Topics

• Aged
• Animals
• Carnitine (pharmacology)
• Delta-5 Fatty Acid Desaturase
• Electrophoresis, Capillary
• Epoprostenol (biosynthesis)
• Female
• Fibrosis
• Heart Failure (pathology)
• Hemodynamics
• Humans
• Male
• Mass Spectrometry
• Middle Aged
• RNA, Small Interfering
• Rats
• Rats, Inbred Dahl