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Waon therapy attenuates cardiac hypertrophy and promotes myocardial capillary growth in hypertensive rats: a comparative study with fluvastatin

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Abstract

Cardiac hypertrophy and fibrosis in heart failure with preserved ejection fraction are associated with a pro-inflammatory state and reduced NO bioavailability. Effects on myocardial structural and molecular alterations were compared between Waon therapy (WT; repeated dry sauna therapy) and statin in hypertensive rats. Seven-week-old Dahl salt-sensitive rats were assigned to 4 groups: low-salt (LS) diet, high-salt (HS) diet, HS diet with oral fluvastatin (FL; 10 mg/kg/day for 4 weeks) starting from the age of 9 weeks, and HS diet with WT treatment in a far-infrared dry sauna (39 °C for 15 min followed by 34 °C for 20 min once daily for 4 weeks). HS rats developed left ventricular (LV) hypertrophy with preserved LV systolic function. WT reduced LV wall thickness and myocyte cross-sectional area along with decreased levels of myocardial ANP and BNP mRNA expression compared with HS rats. Reduction in LV fibrosis and increase in capillary density in WT animals were accompanied by reductions in myocardial levels of TGF-β1, MMP2, p22phox and gp91phox mRNA expression, and increases in myocardial levels of VEGF and HSP90 mRNA and phosphorylated eNOS protein. These effects were comparable between WT and FL animals. WT improves structural and molecular alterations in salt-induced hypertensive rats similarly to fluvastatin.

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References

  1. Setoguchi M, Hashimoto Y, Sasaoka T, Ashikaga T, Isobe M (2015) Risk factors for rehospitalization in heart failure with preserved ejection fraction compared with reduced ejection fraction. Heart Vessels 30:595–603

    Article  PubMed  Google Scholar 

  2. Kalogeropoulos A, Georgiopoulou V, Psaty BM, Rodondi N, Smith AL, Harrison DG, Liu Y, Hoffmann U, Bauer DC, Newman AB, Kritchevsky SB, Harris TB, Butler J, Health ABC Study Investigators (2010) Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol 55:2129–2137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss HP, Tschöpe C (2011) Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail 4:44–52

    Article  PubMed  Google Scholar 

  4. Lam CS, Brutsaert DL (2012) Endothelial dysfunction: a pathophysiologic factor in heart failure with preserved ejection fraction. J Am Coll Cardiol 60:1787–1789

    Article  PubMed  Google Scholar 

  5. Paulus WJ, Tschöpe C (2013) A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 62:263–271

    Article  PubMed  Google Scholar 

  6. Tschöpe C, Bock CT, Kasner M, Noutsias M, Westermann D, Schwimmbeck PL, Pauschinger M, Poller WC, Kühl U, Kandolf R, Schultheiss HP (2005) High prevalence of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction. Circulation 111:879–886

    Article  PubMed  Google Scholar 

  7. Schulz E, Jansen T, Wenzel P, Daiber A, Münzel T (2008) Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. Antioxid Redox Signal 10:1115–1126

    Article  CAS  PubMed  Google Scholar 

  8. Calderone A, Thaik CM, Takahashi N, Chang DL, Colucci WS (1998) Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest 101:812–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222

    Article  CAS  PubMed  Google Scholar 

  10. Marcus ML, Wilson RF, White CW (1987) Methods of measurement of myocardial blood flow in patients: a critical review. Circulation 76:245–253

    Article  CAS  PubMed  Google Scholar 

  11. Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y, Akazawa H, Tateno K, Kayama Y, Harada M, Shimizu I, Asahara T, Hamada H, Tomita S, Molkentin JD, Zou Y, Komuro I (2007) p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446:444–448

    Article  CAS  PubMed  Google Scholar 

  12. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K (2000) The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6:1004–1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Laufs U, Liao JK (1998) Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 273:24266–24271

    Article  CAS  PubMed  Google Scholar 

  14. Hasegawa H, Yamamoto R, Takano H, Mizukami M, Asakawa M, Nagai T, Komuro I (2003) 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats. J Mol Cell Cardiol 35:953–960

    Article  CAS  PubMed  Google Scholar 

  15. Lee TM, Lin MS, Chou TF, Tsai CH, Chang NC (2005) Effect of pravastatin on development of left ventricular hypertrophy in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 289:H220–H227

    Article  CAS  PubMed  Google Scholar 

  16. Loch D, Levick S, Hoey A, Brown L (2006) Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats. J Cardiovasc Pharmacol 47:396–404

    CAS  PubMed  Google Scholar 

  17. Tousoulis D, Antoniades C, Vassiliadou C, Toutouza M, Pitsavos C, Tentolouris C, Trikas A, Stefanadis C (2005) Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure. Eur J Heart Fail 7:1126–1132

    Article  CAS  PubMed  Google Scholar 

  18. Warita S, Kawasaki M, Tanaka R, Ono K, Kojima T, Hirose T, Iwama M, Watanabe T, Nishigaki K, Takemura G, Noda T, Watanabe S, Minatoguchi S (2012) Effects of pitavastatin on cardiac structure and function and on prevention of atrial fibrillation in elderly hypertensive patients: a prospective study of 2-years’ follow-up. Circ J 76:2755–2762

    Article  CAS  PubMed  Google Scholar 

  19. Fukuta H, Sane DC, Brucks S, Little WC (2005) Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation 112:357–363

    Article  CAS  PubMed  Google Scholar 

  20. Investigators GISSI-HF (2008) Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 372:1231–1239

    Article  Google Scholar 

  21. Kihara T, Biro S, Imamura M, Yoshifuku S, Takasaki K, Ikeda Y, Otuji Y, Minagoe S, Toyama Y, Tei C (2002) Repeated sauna treatment improves vascular endothelial and cardiac function in patients with chronic heart failure. J Am Coll Cardiol 39:754–759

    Article  PubMed  Google Scholar 

  22. Ohori T, Nozawa T, Ihori H, Shida T, Sobajima M, Matsuki A, Yasumura S, Inoue H (2012) Effect of repeated sauna treatment on exercise tolerance and endothelial function in patients with chronic heart failure. Am J Cardiol 109:100–104

    Article  CAS  PubMed  Google Scholar 

  23. Ikeda Y, Biro S, Kamogawa Y, Yoshifuku S, Eto H, Orihara K, Kihara T, Tei C (2001) Repeated thermal therapy upregulates arterial endothelial nitric oxide synthase expression in Syrian golden hamsters. Jpn Circ J 65:434–438

    Article  CAS  PubMed  Google Scholar 

  24. Sobajima M, Nozawa T, Shida T, Ohori T, Suzuki T, Matsuki A, Inoue H (2011) Repeated sauna therapy attenuates ventricular remodeling after myocardial infarction in rats by increasing coronary vascularity of noninfarcted myocardium. Am J Physiol Heart Circ Physiol 301:H548–H554

    Article  CAS  PubMed  Google Scholar 

  25. Fujita S, Ikeda Y, Miyata M, Shinsato T, Kubozono T, Kuwahata S, Hamada N, Miyauchi T, Yamaguchi T, Torii H, Hamasaki S, Tei C (2011) Effect of Waon therapy on oxidative stress in chronic heart failure. Circ J 75:348–356

    Article  CAS  PubMed  Google Scholar 

  26. Shida T, Nozawa T, Sobajima M, Ihori H, Matsuki A, Inoue H (2014) Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature. Heart Vessels 29:532–541

    Article  PubMed  Google Scholar 

  27. Tei C, Horikiri Y, Park JC, Jeong JW, Chang KS, Toyama Y, Tanaka N (1995) Acute hemodynamic improvement by thermal vasodilation in congestive heart failure. Circulation 91:2582–2590

    Article  CAS  PubMed  Google Scholar 

  28. Hayashidani S, Tsutsui H, Shiomi T, Suematsu N, Kinugawa S, Ide T, Wen J, Takeshita A (2002) Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 105:868–873

    Article  CAS  PubMed  Google Scholar 

  29. Oi S, Haneda T, Osaki J, Kashiwagi Y, Nakamura Y, Kawabe J, Kikuchi K (1999) Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells. Eur J Pharmacol 376:139–148

    Article  CAS  PubMed  Google Scholar 

  30. Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, Kitakaze M, Liao JK (2001) Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 108:1429–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee TM, Chou TF, Tsai CH (2002) Association of pravastatin and left ventricular mass in hypercholesterolemic patients: role of 8-iso-prostaglandin f2alpha formation. J Cardiovasc Pharmacol 40:868–874

    Article  CAS  PubMed  Google Scholar 

  32. Westermann D, Riad A, Richter U, Jäger S, Savvatis K, Schuchardt M, Bergmann N, Tölle M, Nagorsen D, Gotthardt M, Schultheiss HP, Tschöpe C (2009) Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure. Basic Res Cardiol 104:499–509

    Article  CAS  PubMed  Google Scholar 

  33. Akasaki Y, Miyata M, Eto H, Shirasawa T, Hamada N, Ikeda Y, Biro S, Otsuji Y, Tei C (2006) Repeated thermal therapy up-regulates endothelial nitric oxide synthase and augments angiogenesis in a mouse model of hindlimb ischemia. Circ J 70:463–470

    Article  CAS  PubMed  Google Scholar 

  34. Miyauchi T, Miyata M, Ikeda Y, Akasaki Y, Hamada N, Shirasawa T, Furusho Y, Tei C (2012) Waon therapy upregulates Hsp90 and leads to angiogenesis through the Akt-endothelial nitric oxide synthase pathway in mouse hindlimb ischemia. Circ J 76:1712–1721

    Article  CAS  PubMed  Google Scholar 

  35. Kimura Y, Izumiya Y, Hanatani S, Yamamoto E, Kusaka H, Tokitsu T, Takashio S, Sakamoto K, Tsujita K, Tanaka T, Yamamuro M, Kojima S, Tayama S, Kaikita K, Hokimoto S, Ogawa H (2014) High serum levels of thrombospondin-2 correlate with poor prognosis of patients with heart failure with preserved ejection fraction. Heart Vessels. doi:10.1007/s00380-014-0571-y

    PubMed Central  Google Scholar 

  36. Ichihara S, Noda A, Nagata K, Obata K, Xu J, Ichihara G, Oikawa S, Kawanishi S, Yamada Y, Yokota M (2006) Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure. Cardiovasc Res 69:726–735

    Article  CAS  PubMed  Google Scholar 

  37. Chang SA, Kim YJ, Lee HW, Kim DH, Kim HK, Chang HJ, Sohn DW, Oh BH, Park YB (2009) Effect of rosuvastatin on cardiac remodeling, function, and progression to heart failure in hypertensive heart with established left ventricular hypertrophy. Hypertension 54:591–597

    Article  CAS  PubMed  Google Scholar 

  38. Rupérez M, Rodrigues-Díez R, Blanco-Colio LM, Sánchez-López E, Rodríguez-Vita J, Esteban V, Carvajal G, Plaza JJ, Egido J, Ruiz-Ortega M (2007) HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways. Hypertension 50:377–383

    Article  PubMed  Google Scholar 

  39. Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Nishizawa T, Noda A, Izawa H, Nagata K, Murohara T, Yokota M (2006) Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol 47:770–779

    Article  CAS  PubMed  Google Scholar 

  40. Nicoletti A, Michel JB (1999) Cardiac fibrosis and inflammation: interaction with hemodynamic and hormonal factors. Cardiovasc Res 41:532–543

    Article  CAS  PubMed  Google Scholar 

  41. Ruetten H, Dimmeler S, Gehring D, Ihling C, Zeiher AM (2005) Concentric left ventricular remodeling in endothelial nitric oxide synthase knockout mice by chronic pressure overload. Cardiovasc Res 66:444–453

    Article  CAS  PubMed  Google Scholar 

  42. Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, Spiekermann S, Hilfiker-Kleiner D, Templin C, Kotlarz D, Mueller M, Fuchs M, Hornig B, Haller H, Drexler H (2004) Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 110:1933–1939

    Article  CAS  PubMed  Google Scholar 

  43. Ramasubbu K, Estep J, White DL, Deswal A, Mann DL (2008) Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol 51:415–426

    Article  CAS  PubMed  Google Scholar 

  44. Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rütten H, Fichtlscherer S, Martin H, Zeiher AM (2001) HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 108:391–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kimura H, Esumi H (2003) Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis. Acta Biochim Pol 50:49–59

    CAS  PubMed  Google Scholar 

  46. Doi R, Masuyama T, Yamamoto K, Doiaa Y, Mano T, Sakata Y, Onoaaa K, Kuzuya T, Hirota S, Koyama T, Miwa T, Hori M (2000) Development of different phenotypes of hypertensive heart failure: systolic versus diastolic failure in Dahl salt-sensitive rats. J Hypertens 18:111–120

    Article  CAS  PubMed  Google Scholar 

  47. Klotz S, Hay I, Zhang G, Maurer M, Wang J, Burkhoff D (2006) Development of heart failure in chronic hypertensive Dahl rats: focus on heart failure with preserved ejection fraction. Hypertension 47:901–911

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Hiroyuki Ihori.

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Ihori, H., Nozawa, T., Sobajima, M. et al. Waon therapy attenuates cardiac hypertrophy and promotes myocardial capillary growth in hypertensive rats: a comparative study with fluvastatin. Heart Vessels 31, 1361–1369 (2016). https://doi.org/10.1007/s00380-015-0779-5

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  • DOI: https://doi.org/10.1007/s00380-015-0779-5

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