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

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

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1834-1844
Number of pages11
JournalJournal of Hypertension
Volume30
Issue number9
DOIs
Publication statusPublished - 2012 Sep

Fingerprint

Carnitine
Heart Diseases
Fibrosis
Heart Failure
Arachidonic Acid
Epoprostenol
Metabolomics
Heart Ventricles
Fibroblasts
Fatty Acid Desaturases
Inbred Dahl Rats
Capillary Electrophoresis
Therapeutics
Angiotensin II
Antihypertensive Agents
Cations
Mass Spectrometry
Collagen
Salts

Keywords

  • carnitine
  • diastolic heart failure
  • fibrosis
  • prostacyclin

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease. / Omori, Yosuke; Ohtani, Tomohito; Sakata, Yasushi; Mano, Toshiaki; Takeda, Yasuharu; Tamaki, Shunsuke; Tsukamoto, Yasumasa; Kamimura, Daisuke; Aizawa, Yoshihiro; Miwa, Takeshi; Komuro, Issei; Soga, Tomoyoshi; Yamamoto, Kazuhiro.

In: Journal of Hypertension, Vol. 30, No. 9, 09.2012, p. 1834-1844.

Research output: Contribution to journalArticle

Omori, Y, Ohtani, T, Sakata, Y, Mano, T, Takeda, Y, Tamaki, S, Tsukamoto, Y, Kamimura, D, Aizawa, Y, Miwa, T, Komuro, I, Soga, T & Yamamoto, K 2012, 'L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease', Journal of Hypertension, vol. 30, no. 9, pp. 1834-1844. https://doi.org/10.1097/HJH.0b013e3283569c5a
Omori, Yosuke ; Ohtani, Tomohito ; Sakata, Yasushi ; Mano, Toshiaki ; Takeda, Yasuharu ; Tamaki, Shunsuke ; Tsukamoto, Yasumasa ; Kamimura, Daisuke ; Aizawa, Yoshihiro ; Miwa, Takeshi ; Komuro, Issei ; Soga, Tomoyoshi ; Yamamoto, Kazuhiro. / L-Carnitine prevents the development of ventricular fibrosis and heart failure with preserved ejection fraction in hypertensive heart disease. In: Journal of Hypertension. 2012 ; Vol. 30, No. 9. pp. 1834-1844.
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AU - Omori, Yosuke

AU - Ohtani, Tomohito

AU - Sakata, Yasushi

AU - Mano, Toshiaki

AU - Takeda, Yasuharu

AU - Tamaki, Shunsuke

AU - Tsukamoto, Yasumasa

AU - Kamimura, Daisuke

AU - Aizawa, Yoshihiro

AU - Miwa, Takeshi

AU - Komuro, Issei

AU - Soga, Tomoyoshi

AU - Yamamoto, Kazuhiro

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N2 - 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.

AB - 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.

KW - carnitine

KW - diastolic heart failure

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