In recent years, several post-interventional analyses of large-scale randomized controlled clinical trials have given us a new concept regarding the risk management of hypertension and cardiovascular diseases. The beneficial effects of intensive treatments were extended even after the interventions ended. This phenomenon is known as “metabolic memory” or “legacy effect”, and we recognized its clinical significance. A certain level of evidence in human and animal studies employing organ transplantation techniques has indicated that this type of “memory” resides in each organ and could be transferrable, erasable, and rewritable, which is similar to neuronal and immune “memory”. In this review, we define this memory as “organ memory” and summarize the current picture and future direction of this concept. “Organ memory” can be observed in many clinical settings, including in the control of hypertension, diabetes mellitus, and dyslipidemia. Several intensive treatments were demonstrated to have the potential to rewrite “organ memory”, leading to the curability of targeted diseases. “Organ memory” is the engraved phenotype of altered organ responsiveness acquired by a time-dependent accumulation of organ stress responses. Not only is the epigenetic change of key genes involved in the formation of “organ memory” but the alteration of multiple factors, including low molecular weight energy metabolites, immune mediators, and tissue structures, is involved as well. These factors intercommunicate during every stress response and carry out incessant remodeling in a certain direction in a spiral fashion through positive feedback mechanisms. Future studies should be directed toward the identification of the core unit of “organ memory” and its manipulation.
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Colditz GA, Bonita R, Stampfer MJ, Willett WC, Rosner B, Speizer FE, et al. Cigarette smoking and risk of stroke in middle-aged women. N Engl J Med. 1988;318:937–41.
Rosenberg L, Kaufman DW, Helmrich SP, Shapiro S. The risk of myocardial infarction after quitting smoking in men under 55 years of age. N Engl J Med. 1985;313:1511–4.
Meguro S, Kabeya Y, Tanaka K, Kawai T, Tomita M, Katsuki T, et al. Past obesity as well as present body weight status is a risk factor for diabetic nephropathy. Int J Endocrinol. 2013;2013:590569.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.
The Diabetes Control and Complications Trial Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342:381–9.
Zoungas S, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, et al. ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371:1392–406.
Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. Long-term follow-up of the west of scotland coronary prevention study. N Engl J Med. 2007;357:1477–86.
Strandberg TE, Pyorala K, Cook TJ, Wilhelmsen L, Faergeman O, Thorgeirsson G. et al. Mortality and incidence of cancer during 10-year follow-up of the scandinavian simvastatin survival study (4S). Lancet. 2004;364:771–7.
Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ. et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–53.
Cushman WC, Evans GW, Byington RP, Goff DC,Jr, Grimm RH,Jr, Cutler JA. et al. The ACCORD Study Group Effects of intensive Blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.
Buckley LF, Dixon DL, Wohlford GF 4th, Wijesinghe DS, Baker WL, Van Tassell BW. Effect of intensive blood pressure control in patients with type 2 diabetes mellitus over 9 years of follow-up: a subgroup analysis of high-risk ACCORDION trial participants. Diabetes Obes Metab. 2018;20:1499–502.
Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N. et al. Trial of Preventing Hypertension (TROPHY) Study Investigators Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354:1685–97.
Harrap SB, Van der Merwe WM, Griffin SA, Macpherson F, Lever AF. Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term. Hypertension. 1990;16:603–14.
Wu JN, Berecek KH. Prevention of genetic hypertension by early treatment of spontaneously hypertensive rats with the angiotensin converting enzyme inhibitor captopril. Hypertension. 1993;22:139–46.
Nakaya H, Sasamura H, Hayashi M, Saruta T. Temporary treatment of prepubescent rats with angiotensin inhibitors suppresses the development of hypertensive nephrosclerosis. J Am Soc Nephrol. 2001;12:659–66.
Togashi N, Maeda T, Yoshida H, Koyama M, Tanaka M, Furuhashi M, et al. Angiotensin ii receptor activation in youth triggers persistent insulin resistance and hypertension--a legacy effect? Hypertens Res. 2012;35:334–40.
Geleijnse JM, Hofman A, Witteman JC, Hazebroek AA, Valkenburg HA, Grobbee DE. Long-term effects of neonatal sodium restriction on blood pressure. Hypertension. 1997;29:913–7.
Oguchi H, Sasamura H, Shinoda K, Morita S, Kono H, Nakagawa K, et al. Renal arteriolar injury by salt intake contributes to salt memory for the development of hypertension. Hypertension. 2014;64:784–91.
Itoh H, Kurihara I, Miyashita K, Tanaka M. Clinical significance of “cardiometabolic memory”: a systematic review of randomized controlled trials. Hypertens Res. 2017;40:526–34.
Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008;359:1565–76.
Bosch J, Lonn E, Pogue J, Arnold JM, Dagenais GR, Yusuf S. HOPE/HOPE-TOO Study Investigators Long-term effects of ramipril on cardiovascular events and on diabetes: results of the hope study extension. Circulation. 2005;112:1339–46.
Buch P, Rasmussen S, Abildstrom SZ, Køber L, Carlsen J, Torp-Pedersen C. TRACE investigators The long-term impact of the angiotensin-converting enzyme inhibitor trandolapril on mortality and hospital admissions in patients with left ventricular dysfunction after a myocardial infarction: follow-up to 12 years. Eur Heart J. 2005;26:145–52.
Strandgaard S, Hansen U. Hypertension in renal allograft recipients may be conveyed by cadaveric kidneys from donors with subarachnoid haemorrhage. BMJ. 1986;292:1041–4.
Curtis JJ, Luke RG, Dustan HP, Kashgarian M, Whelchel JD, Jones P, et al. Remission of essential hypertension after renal transplantation. N Engl J Med. 1983;309:1009–15.
Khush KK, Menza R, Nguyen J, Zaroff JG, Goldstein BA. Donor predictors of allograft use and recipient outcomes after heart transplantation. Circ Heart Fail. 2013;6:300–9.
Fridell JA, Mangus RS, Taber TE, Goble ML, Milgrom ML, Good J, et al. Growth of a nation part i: impact of organ donor obesity on whole-organ pancreas transplantation. Clin Transplant. 2011;25:E225–32.
Bianchi G, Fox U, Di Francesco GF, Giovanetti AM, Pagetti D. Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med. 1974;47:435–48.
Rapp JP, Knudsen KD, Iwai J, Dahl LK. Genetic control of blood pressure and corticosteroid production in rats. Circ Res. 1973;1:139–49.
Cho I, Yamanishi S, Cox L, Methé BA, Zavadil J, Li K, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature. 2012;488:621–6.
Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158:705–21.
Lee JL. Reconsolidation: maintaining memory relevance. Trends Neurosci. 2009;32:413–20.
Almeida-Correa S, Amaral OB. Memory labilization in reconsolidation and extinction--evidence for a common plasticity system? J Physiol Paris. 2014;108:292–306.
Hayashi K, Hishikawa A, Itoh H. DNA damage and epigenetic changes in kidney diseases - focused on transcription factors in podocytes. Curr Hypertens Rev. 2016;12:105–11.
Hayashi K, Sasamura H, Ishiguro K, Sakamaki Y, Azegami T, Itoh H. Regression of glomerulosclerosis in response to transient treatment with angiotensin ii blockers is attenuated by blockade of matrix metalloproteinase-2. Kidney Int. 2010;78:69–78.
Ishiguro K, Hayashi K, Sasamura H, Sakamaki Y, Itoh H. “Pulse” treatment with high-dose angiotensin blocker reverses renal arteriolar hypertrophy and regresses hypertension. Hypertension. 2009;53:83–9.
Hayashi K, Sasamura H, Nakamura M, Sakamaki Y, Azegami T, Oguchi H, et al. Renin-angiotensin blockade resets podocyte epigenome through kruppel-like factor 4 and attenuates proteinuria. Kidney Int. 2015;88:745–53.
Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344:630–4.
Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, et al. Restoring systemic gdf11 levels reverses age-related dysfunction in mouse skeletal muscle. Science. 2014;344:649–52.
Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med. 1998;339:69–75.
Sasamura H, Nakaya H, Julius S, Tomotsugu N, Sato Y, Takahashi F. et al. STAR CAST investigators Feasibility of regression of hypertension using contemporary antihypertensive agents. Am J Hypertens. 2013;26:1381–8.
Angeli D, Ferrell JE Jr, Sontag ED. Detection of multistability, bifurcations, and hysteresis in a large class of biological positive-feedback systems. Proc Natl Acad Sci USA. 2004;101:1822–7.
Xiong W, Ferrell JE. A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision. Nature. 2003;426:460–5.
Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988;318:1315–21.
Levenson JM, Sweatt JD. Epigenetic mechanisms in memory formation. Nat Rev Neurosci. 2005;6:108–18.
Somanna NK, Valente AJ, Krenz M, McDonald KS, Higashi Y, Noda M, et al. Histone deacetyltransferase inhibitors Trichostatin A and Mocetinostat differentially regulate MMP9, IL-18 and RECK expression, and attenuate Angiotensin II-induced cardiac fibroblast migration and proliferation. Hypertens Res. 2016;39:709–16.
Hayashi K, Itoh H. Transcription factors and epigenetic modulation: its therapeutic implication in chronic kidney disease. Arch Immunol Ther Exp (Warsz). 2015;63:193–6.
Hayashi K, Sasamura H, Nakamura M, Azegami T, Oguchi H, Sakamaki Y, et al. Klf4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. J Clin Invest. 2014;124:2523–37.
Hervouet E, Vallette FM, Cartron PF. Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics. 2009;4:487–99.
Accili D, Arden KC. Foxos at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117:421–6.
Nakae J, Cao Y, Hakuno F, Takemori H, Kawano Y, Sekioka R, et al. Novel repressor regulates insulin sensitivity through interaction with foxo1. EMBO J. 2012;31:2275–95.
Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30:52–60.
Katada S, Imhof A, Sassone-Corsi P. Connecting threads: epigenetics and metabolism. Cell. 2012;148:24–8.
Hasegawa K, Wakino S, Simic P, Sakamaki Y, Minakuchi H, Fujimura K, et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med. 2013;19:1496–504.
Kraus D, Yang Q, Kong D, Banks AS, Zhang L, Rodgers JT, et al. Nicotinamide n-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014;508:258–62.
Ulanovskaya OA, Zuhl AM, Cravatt BF. Nnmt promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol. 2013;9:300–6.
El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205:2409–17.
Miao F, Chen Z, Genuth S, Paterson A, Zhang L, Wu X. et al. DCCT/EDIC Research Group Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes. Diabetes. 2014;63:1748–62.
We express sincere gratitude to Dr. Masami Tanaka (Keio University) for helpful contributions to this article.