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


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.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yosuke
Y
Omori
Tomohito
T
Ohtani
Yasushi
Y
Sakata
Toshiaki
T
Mano
Yasuharu
Y
Takeda
Shunsuke
S
Tamaki
Yasumasa
Y
Tsukamoto
Daisuke
D
Kamimura
Yoshihiro
Y
Aizawa
Takeshi
T
Miwa
Issei
I
Komuro
Tomoyoshi
T
Soga
Kazuhiro
K
Yamamoto
D000368:Aged; D000818:Animals; D002331:Carnitine / Q000494:pharmacology*; D000090943:Delta-5 Fatty Acid Desaturase; D019075:Electrophoresis, Capillary; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000473:pathology*; D006439:Hemodynamics; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D034741:RNA, Small Interfering; D051381:Rats; D020303:Rats, Inbred Dahl
D000090943:Delta-5 Fatty Acid Desaturase; D034741:RNA, Small Interfering; D011464:Epoprostenol; C000716847:FADS1 protein, human; D002331:Carnitine