EDITORIAL (SEE BERTONI ET AL., P. 2791)

Diabetic

t has been over 30 years since Rubler et 60% in well-controlled type 2 diabetic pa- and induce myocardial inflammation al. (1) described four diabetic patients tients. Therefore, it is not surprising that through stimulation of poly(ADP-ribose) I with congestive (CHF), in this issue of Care, Bertoni et al. polymerase-1; yet poly(ADP-ribose) normal coronary arteries, and no other (9) have documented that the diagnosis of polymerase-1 inhibition prevents and re- etiologies for CHF and proposed that it idiopathic cardiomyopathy is more com- verses these effects (19). Lipotoxicity due was due to diabetic cardiomyopathy. mon in the diabetic patient. to the elevation of free fatty acids (FFAs) Eight years ago, I reviewed the evidence While these studies of diastolic dys- associated with and/or in- for diabetic cardiomyopathy as a unique function were performed in diabetic pa- sulin resistance may also be a factor be- entity unassociated with coronary artery tients with a normal left ventricular mass, cause FFAs and their oxidation products disease and concluded that diabetic car- left ventricular is more prev- may be directly toxic to the myocardium diomyopathy was a distinct entity charac- alent in type 2 diabetic patients and con- and contribute to the development of di- terized by diastolic dysfunction, which tributes to ventricular dysfunction. In the abetic cardiomyopathy (20). was rarely clinically apparent unless asso- Framingham Heart study, diabetic Since diabetic cardiomyopathy is ciated with (when it was women had a left ventricular mass 10% now known to have a high prevalence in likely to become clinically apparent) greater than that of their nondiabetic the asymptomatic type 2 diabetic patient, and/or with myocardial (when it peers; and in the Tayside Study, left ven- screening for its presence at the earliest was likely to present with severe clinical tricular hypertrophy was present in 32% stage of development would be appropri- manifestations) (2). At that time the evi- of normotensive type 2 diabetic subjects ate in order to prevent the progression to dence also suggested that diastolic dys- who were not utilizing ACE inhibitors and CHF. The most sensitive test for that is a function was due to myocellular had no known (10, standard echocardiogram with pulsed- hypertrophy and myocardial fibrosis, and 11). Unlike myocardial fibrosis, which is wave Doppler examinations during the at the cellular level there were defects in likely due to hyperglycemia, left ventric- second stage of the Valsalva maneuver calcium transportation, myocardial con- ular hypertrophy is most likely related to (7,8). However, the cost of this screening tractile protein collagen formation, and the resistance syndrome (12). is prohibitive, and a less expensive pre- fatty acid metabolism (2). Since then we The high prevalence of diastolic dys- screening method needs to be devised. have learned that diabetic cardiomyopa- function is due to myocardial fibrosis, and Fortunately, detection of microalbumin- thy is not a rare condition but instead a in the Strong Heart Study, the extent and uria, which should be performed annu- very common one, and that its etiology is frequency of diastolic dysfunction was di- ally in all diabetic patients, is an adequate largely due to hyperglycemia with con- rectly proportional to the HbA1c level prescreening test. The Strong Heart Study tributions from the (13,14). The most likely reason for this (21) showed that the degree of diastolic syndrome that cause left ventricular intimate association is the accumulation dysfunction was proportional to the level hypertrophy. of advanced glycosylation end products of microalbuminuria, even after adjusting Left ventricular diastolic dysfunction (AGEs) in the myocardium (15). In ani- for age, sex, BMI, systolic blood pressure, is characterized by impairment in early mal studies the presence of diabetes re- duration of diabetes, left ventricular mass, diastolic filling, prolongation of isovolu- sults in increased myocardial AGE and presence of coronary artery disease. metric relaxation, and increased atrial fill- receptor expression, increased cross- Furthermore, the Heart Outcomes Pre- ing, and these characteristics have even linking of collagen, and myocardial fibro- vention Evaluation (HOPE) (22) study been documented in young type 1 dia- sis. With lysis of the collagen cross-links, showed that the presence of microalbu- betic patients (3). Older studies (4–6) of there was a decrease in myocardial fibro- minuria was associated with significant well-controlled type 2 diabetic subjects sis and an improvement in diastolic dys- risk for CHF. Because microalbuminuria showed that 30% had diastolic dysfunc- function (16). Intracellular myocardial is a marker of endothelial dysfunction in tion. However, this prevalence was based also alters calcium homeostasis, the glomerulus, which is an arteriole, it is on standard testing, in leading to myocardial dysfunction, which logical to postulate that endothelial dys- which mild and early diastolic dysfunc- can be reversed with an aminoguanidine- function in the myocardium leads to in- tion is not detectable in approximately induced reduction in glycosylation (17). creased ventricular scarring and stiffness one-third of subjects. When more rigor- In animal studies, activation of protein ki- (2). Therefore, the presence or develop- ous Doppler methods are used, early and nase C (PKC)-␤ activity by hyperglycemia ment of microalbuminuria warrants the mild diastolic dysfunction can be diag- has resulted in myocardial necrosis and cost of echocardiography with pulsed- nosed. Using these methods in Olmstead fibrosis and ventricular dysfunction, wave Doppler evaluation, even in the County, Minnesota, 52% of diabetic sub- which again improved with the inhibition asymptomatic diabetic patient. jects were shown to have diastolic dys- of PKC-␤ (18). Hyperglycemia also in- Documentation of diastolic dysfunc- function (7). Using similarly sensitive creases the myocardial content of free rad- tion should result in the initiation of ther- methods, Porier et al. (8) showed the icals and oxidants, which decrease nitric apy to prevent advancement to heart prevalence of diastolic dysfunction to be oxide levels, worsen endothelial function, failure. Achievement of glycemic control,

DIABETES CARE, VOLUME 26, NUMBER 10, OCTOBER 2003 2949 Editorial preferably with agents that reduce insulin 20th St., Birmingham, AL 35294-3407. E-mail: good DT, Gorlin R, Shimabukuro S: Rela- resistance, is essential. In the future, the [email protected]. tion among left ventricular mass, insulin D.S.H.B. has served as a consultant for and re- resistance, and blood pressure in nono- availability of agents that prevent or re- ceived honoraria from Abbott Laboratories and verse glycosylation and cross-linking of bese subjects. J Clin Endocrinol Metab 83: GlaxoSmithKline Pharmaceuticals. 4284–4288, 1998 collagen or decrease lipotoxicity or its ef- © 2003 by the American Diabetes Association. 13. Shehadeh A, Regan TJ: Cardiac conse- fects will be helpful. At the present time, ␤ quences of diabetes mellitus. Clin Cardiol we know that -blockers and thiazo- ●●●●●●●●●●●●●●●●●●●●●●● 18:301–305, 1995 lidinediones shift the metabolism of the References 14. Devereux RB, Roman MJ, Paranicas M, myocardium from the use of FFAs to that 1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral O’Grady MJ, Lee ET, Welty TK, Fabsitz of (23,24). In addition, thiazo- T, Branwood AW, Grishman A: New type RR, Robbins D, Rhoades ER, Howard BV: lidinediones have been shown in animals of cardiomyopathy associated with dia- Impact of diabetes on cardiac structure to decrease myocardial FFA content and betic glomerulosclerosis. Am J Cardiol 30: and function: the Strong Heart Study. Cir- their toxic metabolites and improve ven- 595–602, 1972 culation 101:2271–2276, 2000 tricular function (25). The initial defini- 2. Bell DSH: Diabetic cardiomyopathy: a 15. Bauters C, Lamblin N, McFadden EP, Van tive therapy should be the use of ACE unique entity or a complication of coro- Bell E, Millaire A, DeGroote P: Influence naryarterydisease?DiabetesCare18:708– of diabetes mellitus on heart failure risk inhibitors, which decrease left ventricular 714, 1995 and outcome. Cardiovasc Diabetol 2:1–16, hypertrophy and myocardial fibrosis, 3. Schannwell CM, Schneppenheim M, Per- 2003 prevent myocardial remodeling, improve ings S, Plehn G, Strauer BE: Left ventric- 16. Candido R, Forbes JM, Thomas MC, Thal- endothelial function, and lower insulin ular diastolic dysfunction as an early las V, Dean RG, Burns WC, Tikellis C, resistance (26). Because the new diagnos- manifestation of diabetic cardiomyopa- Ritchie RH, Twigg SM, Cooper ME, Bur- tic criteria for heart failure regard the thy. Cardiology 98:33–39, 2002 rell LM: A breaker of advanced glyca- presence of diabetes as stage 1 heart fail- 4. Di Bonito P, Cuomo S, Moio N, Sibilio G, tion end products attenuates diabetes- ure, even the addition of a ␤-blocker at Sabatini D, Quattrin S, Capaldo B: Dia- induced myocardial structural changes. this early stage to prevent or reverse any stolic dysfunction in patients with non- Circ Res 92:785–792, 2003 present myocardial remodeling is appro- insulin-dependent diabetes mellitus of 17. Ziegelhoffer A, Ravingerova T, Styk J, Se- short duration. Diabet Med 13:321–324, bokova J, Waczulikova I, Breier A, Dzurba priate (27). Use of a third-generation ␤ 1996 A, Volkovova K, Carsky J, Turecky L: -blocker such as carvedilol, which 5. Beljic T, Miric M: Improved metabolic Mechanisms that may be involved in cal- through its ␣1 blockade has the advan- control does not reverse left ventricular cium tolerance of the diabetic heart. Mol tages of vasodilatation and lowering of in- filling abnormalities in newly diagnosed Cell Biochem 176:191–198, 1997 sulin resistance in addition to its proven non-insulin-dependent diabetes patients. 18. Wakasaki H, Koya D, Schoen FJ, Jirousek efficacy in heart failure, provides a dis- Acta Diabetol 31:147–150, 1994 MR, Ways DK, Hoit BD, Walsh RA, King tinct advantage in the diabetic patient 6. Nicolino A, Longobardi G, Furgi G, Rossi GL: Targeted overexpression of protein (28). Either spironolactone or eplerenone M, Zoccolillo N, Ferrara N, Rengo F: Left kinase C beta2 isoform in myocardium because of antifibrotic effects in the myo- ventricular diastolic filling in diabetes causes cardiomyopathy. Proc Natl Acad Sci cardium, also seem to be a logical therapy, mellitus with and without hypertension. USA94:9320–9325, 1997 Am J Hypertens 8:382–389, 1995 19. Szabo C: PARP as a drug target for the but they are unproven in diabetic cardio- 7. Redfield MM, Jcobsen SJ, Burnett JC, Ma- therapy of diabetic cardiovascular dys- myopathy (29). honey DW, Bailey KR, Rodeheffer RJ: Bur- function. Drug News Perspect 15:197– Therefore, the prevalence of diabetic den of systolic and diastolic ventricular 205, 2002 cardiomyopathy in the type 2 diabetic pa- dysfunction in the community. JAMA 20. Young ME, McNulty P, Taegtmeyer H: tient is higher than was previously be- 289:194–202, 2003 Adaptation and maladaptation of the lieved, and diabetic cardiomyopathy is due 8. Poirier P, Bogaty P, Garneau C, Marois L, heart in diabetes. Part II. Potential mech- to diastolic dysfunction caused by myo- Dumesnil JG: Diastolic dysfunction in anisms. Circulation 105:1861–1870, 2002 cardial fibrosis, which occurs in response normotensive men with well-controlled 21. Liu JE, Robbins DC, Palmieri V, Bella JN, to hyperglycemia. A definitive diagnosis : importance of maneuvers Roman MJ, Fabsitz R, Howard BV, Welty of diabetic cardiomyopathy can be made in echocardiographic screening for pre- TK, Lee ET, Devereux RB: Association of clinical diabetic cardiomyopathy. Diabe- albuminuria with systolic and diastolic by echocardiographic techniques, and tes Care 24:5–10, 2001 left ventricular dysfunction in type 2 dia- echocardiographic screening for asymp- 9. Bertoni AG, Tsai A, Kasper EK, Francati betes: the Strong Heart Study. J Am Coll tomatic diabetic cardiomyopathy should FL: Diabetes and idiopathic cardiomyop- Cardiol 42:2022–2028, 2003 be performed in all asymptomatic dia- athy: a nationwide case-control study. Di- 22. Arnold JM, Yusuf S, Young J, Mathew J, betic subjects with microalbuminuria. abetes Care 26:2791–2795, 2003 Johnstone D, Avezum A, Lonn E, Pogue J, Identification of diabetic cardiomyopathy 10. Galderisi M, Anderson KM, Wilson PW, Bosch J, HOPE Investigators: Prevention should result in the initiation of therapies Levy D: Echocardiographic evidence for of heart failure in patients in the Heart to prevent the progression of diabetic car- the existence of a distinct diabetic car- Outcome Prevention Evaluation (HOPE) diomyopathy to CHF. diomyopathy (the Framingham Heart study. Circulation 107:1284–1290, 2003 Study). Am J Cardiol 68:85–89, 1991 23. Bell DSH: Use of beta blockers in patients 11. Struthers AD, Morris AD: Screening for with diabetes. Endocrinologist 13:116– DAVID S.H. BELL, MB, FACE and treating left-ventricular abnormalities 123, 2003 From the University of Alabama School of Medicine, in diabetes mellitus: a new way of reduc- 24. Nuttila P, Hallsten K, Kirsi A, Virtanen F, Birmingham, Alabama. ing cardiac deaths. Lancet 359:1430– Lonnqvst F, Vitcari J, Ronnemaa T, Knutti Address correspondence to David S.H. Bell, MB, 1432, 2002 J: Rosiglitazone but not metformin en- FACE, Faculty Office Tower, Room 702, 510 South 12. Phillips RA, Krakoff LR, Dunaif A, Fine- hances insulin stimulated glucose uptake

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in patients with type 2 diabetes (Ab- grani MP, Feldman AM, Francis GS, Ga- diol 38:2101–2113, 2001 stract). Diabetes 51 (Suppl. 2):A142, 2002 niats TG, Goldstein S, Gregoratos G, 28. Bell DSH: Treatment of heart failure in 25. Zhou Y-T, Graburn P, Karim A, Shima- Jessup ML, Noble RJ, Packer M, Silver patients with diabetes: clinical update. bukuro M, Higa M, Baeters D, Orci L, Un- MA, Stevenson LW, Gibbons RJ, Antman Ethn Dis 12:S1–S8, 2002 ger H: Lipotoxic heart disease in obese EM, Alpert JS, Faxon DP, Fuster V, Jacobs 29. Hagashi M, Tsutamoto T, Wada A, Tsut- rats: implications for human obesity. AK, Hiratzka LF, Russell RO, Smith SC Jr, sui T, Ishii C, Ohno K, Fuji M, Tanigachi Proc Natl Acad SciUSA97:1784–1789, American College of Cardiology/Ameri- A, Hamatani T, Nozato Y, Kataoka K, 2000 can Heart Association: ACC/AHA guide- Morigami N, Ohnishi M, Kinoshita M, 26. Kambara N, Holycross BJ, Wung P, lines for the evaluation and management Horie M: Immediate administration of Schanbacher B, Ghosh S, McCune SA, of chronic heart failure in the adult: exec- mineraldocorticoid receptor antagonist Bauer JA, Kwiatowski P: Combined ef- utive summary: a report of the American spironolactone prevents post-infarct left fects of low-dose oral spironolactone and College of Cardiology/American Heart ventricular remodeling associated with captopril therapy in a rat model of spon- Association Task Force on Practice suppression of a marker of myocardial taneous hypertension and heart failure. Guidelines (Committee to Revise 1995 collagen synthesis in patients with first J Cardiovasc Pharmacol 41:830–837, 2003 Guidelines for the Evaluation and Man- anterior acute . Cir- 27. Hunt SA Baker DN, Chin MH, Cinque- agement of Heart Failure). J Am Coll Car- culation 107:2559–2565, 2003

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