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Pregledni Ëlanak / Review article
DijabetiËka kardiomiopatija
Diabetic cardiomyopathy
Jasna »erkez Habek*, Jozica ikiÊ
KliniËka bolnica “Sveti Duh”, Zagreb, Hrvatska
Sveti Duh University Hospital, Zagreb, Croatia
SAÆETAK: DijabetiËka kardiomiopatija, koronarna bo-
SUMMARY: Diabetic cardiomyopathy, coronary heart di-
lest srca (KBS) i autonomna neuropatija su bolesti koje sease (CHD) and autonomic neuropathy are the disea- poveÊavaju morbiditet i mortalitet pacijenta sa πeÊernom ses that increase morbidity and mortality in patients with bolesti. DijabetiËku kardiomiopatiju definiraju asimpto- diabetes mellitus. Diabetic cardiomyopathy is characteri- matske, progresivne promjene u strukturi, a potom i funk- zed by asymptomatic, progressive changes in the struc- ciji miokarda koje dovode do njegovog remodeliranja, a ture, and also in the myocardial function that lead to myo- nisu vezane uz KBS, arterijsku hipertenziju ili valvularnu cardial remodeling, and are not related to CHD, hyper-tension or valvular pathology. The etiology of these chan- patologiju. Etiologija navedenih promjena je multifaktor- ges is multifactorial and is the consequence of metabolic ska i posljedica je metaboliËkog disbalansa koji je vezan imbalance that is primarily related to long-term hypergly- prvenstveno uz dugotrajnu hiperglikemiju. Naæalost, dija- cemia. Unfortunately, diabetic cardiomyopathy, despite its betiËka kardiomiopatija usprkos svog znaËaja ostaje Ëe- significance often remains an unrecognized complication sto neprepoznata komplikacija viπegodiπnjeg dijabetesa of diabetes that patients suffer from for several years that koja znaËajno poveÊava smrtnost. KliniËka slika moæe however, greatly increases mortality. The clinical symp- varirati od subkliniËke ventrikularne disfunkcije, do razvi- toms may vary from subclinical ventricular dysfunction to jene kliniËke slike srËanog zatajivanja. Bolesnici s razvi- advanced clinical symptoms of heart failure. Patients jenom dijabetiËkom kardiomiopatijom imaju dva do pet with advanced diabetic cardiomyopathy have two to five puta veÊi rizik od srËanog zatajivanja. Ehokardiografija je time higher risk of heart failure. Echocardiography is the standard u otkivanju kardiomiopatije, u poËetnoj fazi bo- standard in detecting cardiomyopathies, in the initial sta- lesti nalazi se oπteÊenje dijastoliËke funkcije razliËitog ge of the disease there is an impairment of the diastolic stupnja, a tek u terminalnoj fazi kardiomiopatije se verifi- function of a different degree, and the reduction of systo- cira i smanjenje sistoliËke funkcije lijeve klijetke. Rjee se lic left ventricular function is verified only in the end-stage dijagnoza postavlja uporabom magnetske rezonance, a of cardiomyopathy. Rarely, the diagnosis is made by u istraæivanjima su i novi biomarkeri koji bi olakaπli dijag- using magnetic resonance imaging, and reserchers havefound new biomarkers that would facilitate the diagnos- nostiku u asimptiomatskih bolesnika. LijeËenje dijabetiË- tics in asymptomatic patients. The treatment of diabetic ke kardiomiopatije podrazumijeva promjene u æivotnom cardiomyopathy involves changes in lifestyle, better gly- stilu, bolju regulaciju glikemije, lipidnog profila i arterijske cemic control, lipid profile and hypertension accompa- hipertenzije i redovitu fiziËku aktivnost, a terapija srËanog nied by regular physical activity, whereas the therapy of zatajivanja se ne razlikuje se od bolesnika bez dijabete- heart failure does not differ from the therapy administe- sa. Naæalost, strukturalne i morfoloπke promjene miokar- red to the patients without diabetes. Unfortunately, the da zapoËinju veÊ u pre-dijabetiËkoj fazi, stoga se oËekuje myocardial structural and morphological changes start da Êe nova istraæivanja indentificirati biomarkere koji already in the pre-diabetic stage, therefore, the new trials mogu detektirati asimptomatske bolesnike uz pronalazak are expected to identify biomarkers that can detect asym- strategije koja bi navedene promjene uËinila reverzibilni- ptomatic patients thereby finding a strategy that would KLJU»NE RIJE»I: dijabetiËka kardimiopatija, zatajiva-
KEYWORDS: diabetic cardiomyopathy, heart failure,
nje srca, Ëimbenici rizika, patofizioloπki mehanizmi, pre- risk factors, pathophysiological mechanisms, prevention.
CITATION: Cardiol Croat. 2013;8(12):456-464.
Introduction
U svijetu viπe od 194 milijuna ljudi boluje od πeÊerne bolesti, There are more than 194 million of people worldwide that a Svjetska zdravstvena organizacija procjenjuje da Êe u svi- suffer from diabetes mellitus, and the World Health Orga- jetu do 2025. godine broj oboljelih porasti na 350 milijuna, nization estimates that by the year 2025 the number of the odnosno udvostruËit Êe se broj oboljelih u odnosu na 2000.
diseased will increase to 350 million, that is, the number of godinu1. Dobro je poznata Ëinjenica da pacijenti s dijabete- the diseased will double compared to the year 2000 at an som imaju uËestalije od opÊe populacije znaËajne ateroskle- international level1. It is well known that patients with dia- rotske promjene na epikardijalnim koronarnim arterijama uz betes mellitus more commonly have significant atheroscle- poremeÊaj mikrocirkulacije uz moguÊi razvoj autonomne rotic changes in the epicardial coronary arteries compared Cardiologia CROATICA
disfunkcije, πto sve pridonosi njihovom poveÊanom pobolu i to the general population with the microcirculatory disorder naæalost smrtnosti2. Navedena stanja se rijetko javljaju izoli- accompanied by a potential development of autonomic dys- rano, veÊ se obiËno preklapaju i meusobno potenciraju3.
function, where all of this unfortunately contributes to their Ipak, poznato je da dijabetiËari i u odsustvu navedne patolo- increased morbidity and mortality2. These conditions rarely gije imaju veÊi rizik za zatajivanje srca. occur separately, but they usually overlap and are mutuallypotentiated3. Anyway, it is known that diabetic patients are Joπ je 1954. godine Lundbeak definirao dijabetiËku kardio- at an increased risk for heart failure (HF) even in the absen- miopatiju kao bolest miokarda uzrokovanu dijabetesom, ali neovisno o vaskularnoj patologiji4, a kasnije se u definiciju In 1954 Lundbeak defined diabetic cardiomyopathy as myo- dodaje da je bolest neovisna i o valvularnim greπkama i cardial disease caused by diabetes mellitus, but indepen- arterijskoj hipertenziji5. Danas se u literaturi joπ naziva i ne- dent of vascular pathology4, and later the definition is added ishemijska dijabetiËka kardiomiopatija. Kroz literaturu se by the fact that the disease is also independent of valvular prate Ëlanci u kojima se dijabetiËka kardiomiopatija tretira defects and hypertension5. Today, it is also referred to as kao mit6. ZahvaljujuÊi brojnim kliniËkim i eksperimentalnim non-ischemic diabetic cardiomyopathy in the literature.
studijama koje su dokazale funkcionalne, morfoloπke i bio- Through the literature the articles are followed which treat kemijske promjene u miokardu7 s posljediËnom disfunkcijom the diabetic cardiomyopathy as a myth6. Owing to numerous lijeve klijetke, podjednako kod pacijenta s tipom 1 i 2 dijabe- clinical and experimental studies that have proven functio- tesa, teπko je postojanje entiteta ignorirati, posebice πto se nal, morphological and biochemical changes in the myocar- neinvazivnim dijagnostiËkim metodama u svakodnevnoj kli- dium7 with consequential left ventricular dysfunction, both in niËkoj praksi mogu dijagnosticirati pacijenti s dijabetiËkom patients with type 1 and type 2 of diabetes, it is difficult to ig- kardiomiopatijom. Pravovremena dijagnostika uz medika- nore the existence of the entity, especially as the non-inva- mentoznu terapiju potpomognutu promjenama u stilu æivota, sive diagnostic methods in daily clinical practice are used to mogu osigurati bolesnicima znaËajno bolju kvalitetu æivota i diagnose patients with diabetic cardiomyopathy. Timely dia-gnosis with medical therapy assisted by changes in lifestyle, odgodu nastanka simptoma zatajivanja miokarda. can provide patients an improved quality of life and delay ofthe occurrence of myocardial infarction symptoms. Epidemiologija
Epidemiology
Prevalencija dijabetiËke kardiomiopatije nije poznata zbognedostatka velike studije u razliËitim populacijama dijabe- The prevalence of diabetic cardiomyopathy is not known tiËara8. Meutim, dobro je istraæena povezanost dijabetesa i due to the lack of a large study in different populations of srËanog zatajivanja. Framinghamska studija dokazuje da je diabetic patients8. However, the link between diabetes and rizik od zatajivanja srca veÊi 2,4 puta u muπkaraca i Ëak 5 HF has been well studied. The Framingham study proves puta u æena9, ali neovisno o postojanju koronarne bolesti that the risk of HF is 2.4 times higher in men and even five srca (KBS) i arterijske hipertenzije. Dodatnim iskljuËenjem iz times in woman9, but regardless of the presence of coronary analize svih bolesnika s od ranije poznatom koronarnom i heart disease (CHD) and hypertension. If we additionally reumatskom bolesti srca, tada rizik za razvoj zatajivanja exclude all patients with previously known coronary and srca raste na 3.8 kod muπkaraca i 5,5 kod æena s dijabete- rheumatic heart disease from the analysis, then the risk of som. I brojne druge studije navode sliËne rezultate10. Nove developing HF increases to 3.8 in men and 5.5 in women studije potvruju hipotezu da osobe s dijebetesom i loπom with diabetes mellitus. Numerous other studies report simi-lar results as well10. New studies support the hypothesis that regulacijom glikemije imaju znaËajno veÊi rizik za razvoj kar- persons with diabetes and poor glycemic control are at si- diomiopatije11. Tako je kohortna studija na 31.1997 pacijen- gnificantly higher risk for developing cardiomyopathy11.
ta, koji su predominatno imali dijabetes tipa 2, dokazala da Thus, the cohort study involving 31.1997 patients, who pre- za svaki 1% porasta HbA1c raste rizik od zatajivanja srca za dominantly had type 2 diabetes, demonstrated that for every 8%11. Neke studije ukazuju da i osobe s inzulinskom rezi- 1% increase in HbA1c the risk of HF increases by 8%11.
stencijom, bez kriterija za dijagnozu dijabetesa, takoer ima- Some studies suggest that people with insulin resistance, ju poveÊani rizik od zatajivanja srca12. Prevalencija dijasto- with no criteria for diagnosis of diabetes are also at a higher liËke disfunkcije kod dijabetiËara varira od 30-60%13. Ne- risk for HF12. The prevalence of diastolic dysfunction in dia- davna prospektivna studija kod bolesnika sa πeÊernom bole- betic patients ranges from 30-60%13. A recent prospective sti tipa 1 koja je trajala najmanje 10 godina, daje rezultate o study in patients with type 1 diabetes which lasted at least prevalenciji disfunkcije miokarda u 14,5% i srËanog zatajiva- 10 years gives results on the prevalence of myocardial dys- nja 3,7% nakon sedmogodiπnjeg praÊenja14. function in 14.5% and HF in 3.7% after a seven-year follow-up14. Kod dijabetiËara tipa 2 se moæe u 80% bolesnika oËekavatipojava dijastoliËke disfunkcije, a bolesnici s loπijom regu- In type 2 diabetic patients, the occurrence of diastolic dys- lacijom glikemije i duljim trajanjem bolesti imaju teæi stupanj function can be expected in 80% of patients, while the pa- dijastoliËke disfunkcije15. Osim hiperglikemije, najspominja- tients with poorer glycemic control and longer duration of the niji Ëimbenici rizika za razvoj zatajivanja srca kod dijabeti- disease tend to have a more severe degree of diastolic dys- Ëara su: starija æivotna dob16, trajanje dijabetesa, inzulinska function15. In addition to hyperglycemia, the most often men- terapija, KBS, periferna arterijska bolest, poviπenje kreatini- tioned risk factors for the development of HF in diabetic na u serumu i mikroalbuminurija17. Poznato je i da nakon re- patients are: older age16, duration of diabetes, insulin thera- vaskularazcije miokarda angioplastikom ili ugradnom pre- py, CHD, peripheral arterial disease, elevation of serum cre- mosnica je ËeπÊa kardijalna dekompenzacija kod dijabeti- atinine and microalbuminuria17. It is known that after myo- Ëara. Vrijedi i obrnuta statistika, u OPTIMIZE HF registru cardial revascularazation by angioplasty or stent implanta-tion, the cardiac decompensation is more common in dia- 42% hospitaliziranih zbog popuπtanja srca su bili dijabe- betic patients. The completely different statistics applies, in OPTIMIZE HF registry 42% of hospitalized patients werediabetic patients due to HF18.
Cardiologia CROATICA
Patofiziologija
Pathophysiology
eÊerna bolest dovodi do strukturnih i funkcijskih abnormal- Diabetes mellitus leads to structural and functional abnor- nosti u koronarnoj mikrocirkulaciji koje uzrokuju smanjenje malities in the coronary microcirculation causing a reduction protoka krvi kroz tkivo miokarda, iako ne nalazimo znaËajnih of blood flow through the myocardial tissue, although we find patomorfoloπki promjena na epikardijalnim arterijama. Kli- no significant pathomorphological changes in the epicardial niËke i eksperimentalne studije su dokazale da dijabetes arteries. Clinical and experimental studies have shown that uzrokuje hipertrofiju miokarda, apoptozu i nekrozu miocita, diabetes causes myocardial hyperthrophy, apoptosis and remodelaciju matriksa, poveÊava intersticijsko tkivo te dovo- necrosis of myocytes, matrix remodeling, increases intersti-tial tissue and leads to the activation of sympathicus and in- di do aktivacija simpatikusa i poveÊava renalnu absorpciju The pathogenesis of diabetic cardiomyopathy is complex Patogeneza dijabetiËke kardiomiopatije je sloæena i postoji and there are several mechanisms which explain the above nekoliko mehanizama pomoÊu kojih se objaπnjava navede- mentioned situation. Metabolic imbalance as hyperglyce- no stanje. MetaboliËki disbalans kao hiperglikemija20, hiper- mia20, hyperlipidemia, hyperinsulinemia, defect of stimula- lipidemija, hiperinzulinemija, defekt stimulacije glikolize i ok- tion of glycolysis and glucose oxidation21 lead to structural sidacije glukoze21 dovode u stanicama miokarda do struktu- and functional changes in myocardial cells. The described ralnih i funkcionalnih promjena. Opisane promjene uzrokuju changes cause damage and decay of myocytes by increa- oπteÊenje i odumiranje miocita poveÊanim oksidativnim stre- sed oxidative stress, development of undesired interstitial som, razvojem neæeljene intersticijske fibroze, poremeÊaji- fibrosis, disorders in the transport of electrolytes and loss of ma u transportu elektrolita i gubitak homeostaze. »ini se da homeostasis. It seems that hyperglycemia induces maladap- hiperglikemija inducira maladaptivne mehanizme koji oπtete tive mechanisms that damage myocardial metabolism and metabolizam miokarda i funkciju miofibrila πto rezultira pro- function of myofibrils resulting in changes in the cytoskele- mjenama u citoskeletu i poviπenoj neurohumoralnoj aktivno- ton and elevated neurohumoral activity. The consequence sti. Posljedica navedenih mehanizama je neæeljena remod- of these mechanisms is the undesirable myocardial remo- elacija miokarda koja vodi u circulus vitiosus gdje zatajivan- deling that leads to the vicious circle where HF increases in- je srca poveÊava inzulinsku rezistenciju i obratno11. Ipak, sulin resistance and vice versa11. However, using non-inva-sive diagnostic methods show that the fibrosis is the most neinvazivnim dijagnostiËkim metodama fibroza se izdvaja responsible for the development of diabetic cardiomyopathy, kao najznaËajnija za razvoj dijabetiËke kardiomiopatije, jer because in diabetics type 1 and type 2 the amount of colla- kod dijabetiËara i tipa 1 i 2 nalazi se poveÊana koliËina kola- gen in the myocardium is increased, which leads to the dia- gena u miokardu koji dovodi u poËetku do dijastoliËke dis- stolic dysfunction at the beginning. Severe fibrosis of the funkcije. Izrazita fibroza miokarda moæe biti perivaskularna, myocardium can be perivascular, interstitial or combined.
intersticijska ili kombinirana. Progresijom bolesti dolazi do Disease progression leads to reduction of the number of redukcije broja miocita koji bivaju zamijenjeni vezivnim myocytes, which are replaced by connective tissue22,23. The elevated level of free fatty acids24 is also considered one Poviπena razina slobodnih masnih kiselina24 se takoer of the major factors that contribute to the development of the smatra jednim od glavnih Ëimbenika koji doprinosi razvoju diabetic cardiomyopathy by increasing peripheral insulin dijabetiËke kardiomiopatije poveÊanjem periferne inzulinske resistance thereby inducing apoptosis of myocytes25. The rezistencije i time pokreÊe apoptozu miocita25. PoveÊana increased concentration of circulating free fatty acids, as koncentracija cirkulirajuÊih slobodnih masnih kiselina, kao i well as intercellular ones, leads to the accumulation of po- onih intercelularnih, dovodi do nakupljanja potencijalno tok- tentially toxic metabolites during their degradation and to the siËnih metabolita prilikom njihove razgradnje i do smanjenja reduction of the oxidation of glucose which is considered to oksidacije glukoze πto se smatra jednim od vaænijih uzroka be one of the most important causes of the development of razvoja dijabetiËke kardiomiopatije. Teæini kliniËke slike do- diabetic cardiomyopathy. The severity of the clinical mani- prinosi i razvoj autonomne disfunkcije uz sniæenje varijabil- festations is contributed by the development of autonomicdysfunction with a reduction in heart rate variability and nosti srËanog ritma i tahikardije26 te razvoj endotelne dis- tachycardia26 and development of endothelial dysfunction funkcije uz smanjenje protoka kroz koronarne arterije. Na- with a reduction of blood flow through the coronary arteries.
dalje, intersticijsko gomilanje glikoproteina, spori ulazak kal- Furthermore, interstitial accumulation of glycoproteins, a cija u sarkoplazmatski retikulum27, slabo oslobaanje du- slow entry of calcium into sarcoplasmatic reticulum27, a poor πikovog oksida iz endotela koronarnih arterija28 Ëesto se release of nitric oxide from the endothelium of coronary opisuju kao moguÊi uzroci razvoja dijabetiËke kardiomiopati- arteries28 are often described as the potential causes of the Kod pacijenta s DM tip 2 postoji jasna poveznica izmeu re- In patients with type 2 DM there is a clear link between glycemic gulacije glikemije i razine faktora rasta IGF-I (engl. Insulin-li- control and the insulin-like growth factor (IGF-I). Poorer ke growth factor). Loπija regulacija glikemije dovodi do sni- glycemic control leads to lower concentrations of IGF-I con- æenja koncentracije IGF-I u plazmi. Eksperimentalnim mod- centrations in plasma. Experimental models have proved that elima je dokazano da IGF-I smanjuje apoptozu miocita i IGF-I reduces myocyte apoptosis and improves myocardial poboljπava funkciju miokarda viπestrukim uËincima29. Zbog function with multiple effects29. Secretion of IGF, interleukin, luËenja IGF, interleukina, citokina i ostalih pro-inflamatornih cytokines and other pro-inflammatory agents cause the ex- agenasa, dolazi do ekspresije mikro RNA (MiRNA), pose- pression of micro RNA (MiRNA), especially mi R-155 and mi bice mi R-155 i mi R-223, koji imaju anti-inflamatornu i kar- R-223, which have anti-inflammatory and cardioprotective dioprotektivnu funkciju30. MiRNA su male molekule, do 22 function30. MiRNA are small molecules, up to 22 nucleotides, nukleotida, koje moduliraju gensku ekspesiju i Ëine se upra- which modulate gene expression and seem to be the key vo kljuËno i obeÊavajuÊe mjesto moguÊeg lijeËenja kardio- and promising site for potential treatment of cardiovascular vaskularne i πeÊerne bolesti31. S obzirom da je njihova razi- and diabetic disease31. Since their level has been altered in na promijenjena kod bolesnika s dijabetiËkim srcem, smatra- patients with diabetic heart, they are considered to be a Cardiologia CROATICA
ju se dobrim biomarkerom za kardiovaskularnu bolest, a ra- good biomarker for cardiovascular disease, and the different zliËita ekspresija specifiËnih MiRNA u cirkulaciji se moæe ko- expression of specific MiRNA in the circulation can be used ristiti za dijagnostiku razliËitih stupnjava dijabetiËke kardio- for diagnostics of various degrees of diabetic cardiomyopa- Navedeno objaπnjava kako lijeËenjem metaboliËkih poreme- The above explains that the treatment of metabolic disor- Êaja poboljπavamo i funkciju miocita, naæalost opisane funk- ders leads to the improvement of the function of myocytes.
cijske promjene lijeve klijetke se javljaju i kod pacijenata s Unfortunately, the described functional changes to the left ventricle occur even in patients with good glycemic control32.
Dijagnostika dijabetiËke kardiomiopatije
Diagnostics of diabetic cardiomyopathy
Prepoznavanje dijabetiËke kardiomiopatije u ranoj fazi bole- Identifying diabetic cardiomyopathy at an early stage of the sti i dalje ostaje izazov. Ehokardiografija je za sada najËeπ- disease remains a challenge. Echocardiography is currently Êe koriπtena metoda. U najrajnijoj fazi bolesti primjeÊuje se the most widely used method. In the earliest stage of the di- poveÊanje gustoÊe miokarda ili abnormalnosti u funkciji sease we can notice an increase in the myocardial density subendokarda upotrebom strain i strain rate funkcije. Tkiv- or abnormalities in the subendocardial function by using the nim Dopplerom se mogu uoËiti najranije abnormalnosti u strain and strain rate function. Tissue Doppler imaging may dijastoliËkom protoku, a kako bolest progredira biljeæi se pa- show the earliest abnormalities in diastolic flow, and as the toloπki zapis pulsnim dopplerom transvalvularnog mitralnog disease progresses, it can be record an abnormal record by protoka i protoka u pluÊnim venama, πto je najËeπÊa tehni- pulse-Doppler ultrasound of transvalvular mitral flow and ka za dokazivanje dijastoliËke disfunkcije. Progresijom stup- pulmonary venous flow, which is the most common techni- nja kardiomiopatije dolazi do iscrpljenja inotropne rezerve u que for proving diastolic dysfunction. The progression of the fiziËkom naporu, a u uznapredovaloj fazi hipotetske “kardio- cardiomyopathy stage leads to exhaustion of inotropic reser- miopatske kaskade” nalaze se regionalni, a kasnije i global- ve in physical strain, and at an advanced stage of the hypo- ni ispadi kontraktilnosti i u mirovanju33. Kod bolesnika s re- thetical “cardiomyopathic cascade” there are regional and duciranom sistoliËkim funkcijom nalazimo ekscentriËnu, za later global contractile deficits even at rest33. In patients with razliku od bolesnika s dijastoliËkom disfunkcijom koji imaju reduced systolic function we have recorded an eccentric myocardial hypertrophy, unlike the patients with diastolic dys- U dijastoliËkom zatajivanju srca lijeva klijetka poprima oso- function who have concentric myocardial hypertrophy.34 bitosti neelastiËne πupljine, tako da dio volumena krvi u pro- In diastolic HF, the left ventricle takes on characteristics of todijastoli utjeËe brzinom koju odreuje gradijent tlaka iz- inelastic cavity, so that a part of the blood volumen in proto- meu volumnog optereÊenja i brzine kojom se klijetka relak- diastole affects the speed determined by the pressure gra- sira. U mezo- i teledijastoliji dolazi do punjenja lijeve klijetke dient between the volume load and the velocity at which the uz znatan porast tlaka u lijevom atriju i u pluÊnim venama, ventricle relaxes. Filling of the left ventricle occurs in the me- πto moæe dovesti do kongestije pluÊa i Ëak do edema plu- so-and tele-diastole with a significant increase in pressure in Êa35. PoveÊanje tlaka u lijevoj pretklijetki je kompenzacijski the left atrium and pulmonary veins, which can lead to con- mehanizam jer omoguÊuje uËinkovitije punjenje lijeve kli- gestion of the lungs and even to pulmonary edema35. In- jetke. S progresijom bolesti moæe se oËekivati pojava si- creasing the pressure in the left atrium is a compensatory stoliËke disfunkcije, a poznato je da svi pacijenti kod kojih je mechanism because it allows more efficient filling of the left verificiran razliËiti stupanj sistoliËke disfunkcije imaju veÊ ventricle. As the disease progresses, we can expect the oc- sigurno oπteÊenu i dijastoliËku funkciju lijeve klijetke36. »ini currence of systolic dysfunction, and it is known that all pa- se da ne postoji bolest koja bi samo dovela do sistoliËkog tients known to have a different degree of systolic dysfunc- kongestivnog zatajivanja miokarda, a uz oËuvanu dijasto- tion certainly have an impaired diastolic function of the left ventricle as well36. It seems that there is no disease that Dijagnoza dijabetiËke kardiomiopatije veÊ u pretkliniËkoj fazi would only lead to systolic congestive myocardial failure bolesti moæe se dokazati i magnetskom rezonacom koja je visoko selektivni alat za otkrivanje hipertofije lijevog ven- The diagnosis of diabetic cardiomyopathy already at precli- trikula, promjene njegove geometrije ili poremeÊaja u kon- nical stage of the disease can be proved by magnetic reso- traktilnosti, a daje informaciju o stupnju kardiomiopatije i nance imaging, which is a highly selective tool for the detec- moguÊoj aritmiji. Takoer je dobra metoda za dijagnosticira- tion of left ventricular hypotrophy, a change in its geometry nje dijastoliËke disfunkcije kao i steatoze miokarda37. Ako se or disorder in contractility, and provides the information tijekom snimanja magentskom rezonancom koriste i razliËiti about the degree of cardiomyopathy and potential arrhyth- radionuklidi i pozitronska emisijska tomografija (PET) mogu mia. It is also a good method for diagnosing diastolic dys- se otkriti i metoboliËke abnormalnosti, πto omoguÊuje dija- function as well as myocardial steatosis37. If different radio- gnozu dijabetiËke kardiomiopatije u najranijoj fazi bolesti. nuclides and positron emission tomography (PET) are used Postoje i seroloπki biomarkeri koji olakπavaju dijagnostiku i during the magnetic resonance imaging, we can also detect procjenu teæine kardiomiopatije, to su dobro poznati: HbA1c, metabolic abnormalities, which enables the diagnosis of dia- NT-proBNP i troponin. Vrijednost NT-proBNP-a iznad 90 betic cardiomyopathy in the earliest stage of the disease. pg/mL u dijabetiËkih bolesnika s visokom pozitivnom predik- There are serological biomarkers that facilitate the diagno- tivnom vrijednoπÊu od 96% detektira dijastoliËku disfunkciju sis and assessment of severity of cardiomyopathy, these lijeve klijetke dokazanu ehokardiografijom. Kardijalni tropo- are the following which are well known: HbA1c, NT-proBNP nini (I, T, N) se otpuπtaju u cirkulaciju kod oπteÊenja miokar- and troponin. The value of NT-proBNP above 90 pg/mL in da bilo zbog ishemije ili upale, a uloga poviπenih troponina diabetic patients with a highly positive predictive value of kod dijabetiËke kardiomiopatije joπ nije posve jasna. Povi- 96% detects the diastolic dysfunction of the left ventricle πena koncentracija matriks metaloproteinaze (MMP), pose- proven by echocardiography. Cardiac troponins (I, T, N) are Cardiologia CROATICA
bice tipa 9 (MMP9) i sniæena koncentracija tkivnog inhibito- released into the circulation in case of myocardial damage ra metaloproteinaza (TIMP) su dobri indikatori fibroze mio- either due to ischemia or inflammation, and the role of ele- karda38. Metaloproteze sudjeluju u razgradnji ekstracelular- vated troponin levels in diabetic cardiomyopathy is not yet nog matriksa i dovode so promjeni u ekspresiji nekoliko mi- entirely clear. An increased concentration of matrix metallo- kro RNA (Mi RNA) πto za posljedicu ima kontraktilnu dis- proteinase (MMP), especially type 9 (MMP9), and a decrea- funkciju miokarda. Kao prediktor dijabetiËke kardiomiopatije sed concentration of tissue inhibitor of metalloproteinases se moæe koristiti i poviπena koncentracija enzima beta-N (TIMPs) are good indicators of myocardial fibrosis38. Meta- acetilglukozamina (0-GlcNAc)39. ToËno kliniËko znaËanje na- loproteases participate in the degradation of extracellular vedenih novih biomolekula u dijagnosti dijabetiËke kardio- matrix and lead to a change in the expression of a number miopatije bit Êe poznato nakon rezultata istraæivanja koja su of micro RNA (Mi RNA) which results in myocardial contrac-tile dysfunction. An elevated concentration of the enzymes beta-N-acetylglucosamine (0-GlcNAc) can also be used as Koronarografija je Ëesto potrebna u terminaloj fazi dijabetiË- a predictor of diabetic cardiomyopathy.39 A proper clinical meaning of the mentioned new biomolecules in diagnosticsof diabetic cardiomyopathy will be known after the publica- KliniËka slika dijabetiËke kardiomiopatije
tion of the findings of the trials that are in progress. Coronary angiography is often required in end-stage of dia- Oteæana relaksacija i smanjena rastegljivost miokarda dovo- de do znaËajnog poveÊanja tlaka punjenja veÊ pri malompoveÊanju volumena punjenja, πto se u testu optereÊenjem Clinical manifestations of diabetic
prezentira kao rano nastala zaduha i sistoliËki porast arterij- cardiomyopathy
skog tlaka. Uznapredovala dijastoliËka disfunkcija dovodivremenom do pluÊne kongestije koja se kliniËki oËituje into- Impaired relaxation and reduced myocardial extensibility lead lerancijom napora, progresivnom i paroksizmalnom noÊnom to a significant increase in filling pressure even at the time of dispnejom, ortopnejom, kaπljem i kroniËnim umorom u ka- a small increase in filling volume, which in the stress test is snijoj fazi bolesti. DijastoliËko zatajivanje iznosi oko 50% presented as an early dyspnoa and an increase in systolic svih srËanih zatajivanja. U fizikalnom statusu Ëuju se krepi- blood pressure. Advanced diastolic dysfunction eventually tacije na pluÊima sve do pluÊnog edema, vide se oteËene leads to pulmonary congestion, which is clinically manife- potkoljenice, poveÊana jetra, nabrekle vene vrata i ostali sted as intolerance of exertion, progressive and paroxysmal znakovi globalnog srËanog zatajivanja.
nocturnal dyspnea, orthopnea, cough and chronic fatigue inthe later stages of the disease. Diastolic HF is about 50% of Diferencijalna dijagnoza dispneje posebno je teπka kod sta- all HFs. In the physical status we can hear lung crepitations rijih i pretilih pacijenata, naroËito ako se kliniËkim pregledom including the pulmonary edema, and we can see the swollen ne nalazi znakova kongestije. Tada je potrebno ehokardio- legs, enlarged liver, swollen neck veins and other signs of grafski iskljuËiti poËetno dijastoliËko zatajivanje srca. Bo- lesnici s razvijenom kardijalnom dekompenzacijom imaju lo- Differential diagnosis of dyspnea is particularly difficult in el- πiju prognozu bez obzira na njihovu istisnu frakciju, odnosno derly and obese patients, especially if the clinical examina- o tipu zatajivanja. Godiπnja smrtnost kod dijastoliËkog zata- tion finds no signs of congestion. In such a case it is neces- jivanja srca iznosi oko 8%, a ako se radi o sistoliËkom-dijas- sary to use the echocardiography to exclude the initial dias- toliËkom zatajivanju tada godiπnja smrtnost iznosi 19%40. tolic HF. The patients with developed HF have a worse prog-nosis, regardless of their ejection fraction or a type of the LijeËenje dijabetiËke kardiomiopatije
failure. Annual mortality in diastolic HF is about 8%, and if asystolic-diastolic failure is concerned, the annual mortality LijeËenje dijabetiËke kardiomiopatije ukljuËuje promjene æi- votnog stila, bolju kontrolu glikemije i lipodograma, lijeËenjekoegzistirajuÊe hipertenzije, kao i lijeËenje srËanog zatajiva- The treatment of diabetic cardiomyopathy
nja. LijeËenje srËanog zatajivanja kod bolesnika s dijabetiËkom The treatment of diabetic cardiomyopathy includes lifestyle kardiomiopatijom se ne razlikuje od lijeËenja ne-dijabetiËkog changes, better glycemic and lipodogram control, the treat- popuπtanja miokarda, a definirano je Smjernicama Europ- ment of coexisting hypertension, as well as the treatment ofHF. skog kradioloπkog druπtva za lijeËenje akutnog i kroniËnogsrËanog zatajivanja iz 2012. godine41. Naglaπeno je da za The treatment of HF in patients with diabetic cardiomyopa- sada nema lijeËenja koje bi sa sigurnoπÊu moglo smanjiti thy is no different from the treatment of non-diabetic HF, and mortalitet i morbiditet bolesnika s dijastoliËkim zatajivanjem is defined in the European Society of Cardiology Guidelines srca. Diuretici se koriste za kontrolu natrija i retencije vode i for the diagnosis and treatment of acute and chronic heartfailure 201241. It has been emphasized that there is no treat- kako bi se olakπali simptomi zaduhe i edema. Koriste se ment that could safely reduce mortality and morbidity in pa- diuretici Henijeve petlje (furosemid, torasemid, bumetanid) i tients with diastolic HF. Diuretics are used to control sodium tiazidski diuretici (hidroklortiazid i indapamid), a kod nekih and water retention, and to mitigate the symptoms of dysp- bolesnika i diuretici kojim πtede kalij (spironolakton, eple- nea and edema. Henle’s loop diuretics (furosemide, torse- renon, amilorid i triamteren). Prepoznata je vaænost ade- mide, bumetanide) and thiazide diuretics (hydrochlorothia- kvatnog lijeËenja hipertenzije, ishemije miokarda, kao i ade- zide and indapamide) are used while potassium-sparing diu- kvatne regulacije ventrikularnog odgovora kod bolesnika s retics such as (spironolactone, eplerenone, amiloride and fibrilacijom atrija. ObeshrabrujuÊi su rezultati tri velike studi- triamterene) are used in some patients. The importance of je na kandesartanu42 (CHARM), perindoprilu43 (PEP-CHF) i adequate treatment of hypertension, myocardial ischemia, irbesatanu44 (I-Preserve) koje nisu dokazale smanjenje smrt- as well as adequate control of ventricular response in pa- nosti u hospitaliziranih bolesnika s dijastoliËkim zatajivanjem tients with atrial fibrillation has been identified. The findings of three large studies on candesartan42 (CHARM), perindo- Cardiologia CROATICA
LijeËenje srËanog zatajivanja uz oπteÊenu sistoliËku funkci- pril43 (PEP-CHF) and irbesatan44 (I-Preserve) that have not ju lijeve klijetke provodi se s ciljem olakaπavanja simptoma, proved the reduction in mortality of hospitalized patients poboljπanja kvalitete æivota i poveÊanja funkcijskog kapa- citeta. Za to su nuæni lijekovi iz tri velike neuro-humoralne The treatment of HF with the impaired left ventricular systo- skupine: inhibitori angiotenzin konvertirajuÊeg enzima (ACE lic function is conducted with the aim to reduce the symp- inhibitori), blokatori angiotenzinskih receptora (ARB) i anta- toms, improve quality of life and increase functional capaci- gonsti receptora mineralokortikoida. Diuretska terapija sma- ty. This requires drugs from the three major neuro-humoral njuje simptome i znakove kongestije. SOLVD i SAVE studi- groups: angiotensin-converting enzyme (ACE) inhibitors, je dokazale su da je dobrobit lijeËenja ACE inhibitorima jed- angiotensin receptor blockers (ARB), and mineralocorticoid naka kod bolesnika s i bez dijabetesa45.
receptor agonists. Diuretic therapy reduces symptoms and LijeËenje beta-blokatorima znaËajno poveÊava preæivljenje signs of congestion. SOLVD and SAVE studies have de- bolesnika sa srËanim popuπtanjem, neovisno imaju li dija- monstrated that the benefit of the treatment by ACE inhi- betes ili nemaju, bez razlike u redukciji rizika. Tri su kljuËne bitors is equal in patients with and without diabetes45.
studije dokazale doprinos bisoprolola46 (CIBIS II), metapro- The treatment with beta-blockers significantly increases the lola47 (MERIT-HF) i karvediolola48 (COPERNICUS) u sma- survival of patients with HF, regardless of whether they have njenju smrtnosti. U svakoj studiji biljeæi se smanjenje morta- diabetes or not with no difference in reduction in risk. Three liteta oko 34% i smanjenje hospitalizacija od 28-36% zbog key studies have proved the benefit of bisoprolol46 (CIBIS II), zatajivanja srca tijekom godine dana. Viπe od 90% bolesni- metaprolol47 (MERIT-HF) and carvediolol48 (COPERNICUS) ka u navedenim studijama uz beta-blokator su bili na terapi- in reduction of mortality. Each study reports on a reduction in mortality by around 34% and a reduction in hospitaliza-tions from 28-36% for HF during the year. More than 90% of Brojni vazoaktivni lijekovi su istraæivani kod pacijenta s dija- patients in these studies with beta-blocker were treated with betiËkom kardiomiopatijom i u animalnim modelima. Najviπe studija ima s lijekovima koji blokiraju renin-angiotenzin-aldo-steronski sustav. Kao moguÊi mehanizam razvoja kardiomi- A number of vasoactive drugs were investigated in patients patije smatrala se i produkcija angiotenzina II u miokardu.
with diabetic cardiomyopathy and in animal models. Most Studije vezane uz aliskiren (inhibitor renina), benazeprilat i studies have been designed on drugs that block the renin- valsartan dokazale su njihovu protektivnu ulogu na razvoj angiotensin-aldosterone system. The production of angio- kardiomiopatije na æivotinjskim modelima49 i bolesnicima50.
tensin II in the myocardium was considered to be a potentialmechanism of developing cardiomyopathy. Studies related Lijekovi koji se trebaju izbjegavati i kod sistoliËko i dijasto- to aliskiren (renin inhibitor), benazepril and valsartan have liËkog zatajivanja srca su: blokatori kalcijevih kanala zbog proved their protective role in the development of cardiomy- njihovog negativnog inotropnog uËinka osim amlodipina i opathy in animal models49 and patients50.
felodipina, nesteroidni antireumatici i COX 2 inhibitori zbog Drugs to be avoided in case of systolic and diastolic HF are: retencije soli i vode i pogorπavanja funkcije bubrega te je po- calcium channel blockers due to their negative inotropic ef- trebno izbjegavati kombinaciju ACE inhibitora i ARB te lije- fect other than amlodipine and felodipine, non-steroidal anti- rheumatic drugs and COX 2 inhibitors for salt and water Od lijekova iz skupine tiazolidindiona, kod nas na træiπtu je retention and impairment of renal function, the combination prisutan pioglitazon, koji kao najznaËajniju nuspojavu ima of ACE inhibitor and ARB, and thiazolidinediones should be porast tjelesne mase zbog zadræavanja tekuÊine u tijelu re- tencijom resorpcije natrija u bubrezima. Kontraindiciran je Out of the drugs from the group of thiazolidinediones, piogli- kod pacijenta u NYHA III. i IV. funkcijskim razredom, a moæe tazone is present in our market, with a significant side-effect doÊi u obzir kod paæljivo odabranih bolesnika s NYHA I. i II.
such as a weight gain as a result of fluid retention in the bo- stupnju uz paæljivo praÊenje zbog moguÊe retencije teku- dy caused by renal sodium retention and reabsorption. It is Êine51. U animalnim modelima ima protupalno djelovanje i contraindicated in patients with NYHA functional class III moæe usporiti razvoj fibroze i time prevenirati dijabetiËku and IV, and can be considered in carefully selected patients with NYHA class I and II with careful monitoring for potential Metformin je najpropisivani oralni hipoglikemik u svijetu.
fluid retention51. In animal models it has anti-inflammatory PoveÊava perifernu osjetljivost na inzulin, poboljπava kon- effect and may slow down the development of fibrosis and trolu glikemije i u animalnim modelima moæe prevenirati raz- thus prevent diabetic cardiomyopathy52.
voj dijabetiËke kardiomiopatije, za πto joπ nema dokaza u Metformin is the most prescribed oral hyperglycemic agent in the world. It increases peripheral insulin sensitivity, impro- Abnormalnosti u lipidom profilu puno viπe πtete bolesnicima ves glycemic control and it can prevent the development of s dijabetesom nego u nedijabetiËkoj populaciji zbog njihove diabetic cardiomyopathy in animal models, for which there is sklonosti ubrzanoj aterosklerozi. Terapija statinima znaËa- still no evidence in persons with advanced cardiomyopa- jno smanjuje mortalitet dijabetiËkih bolesnika od kardiova- skularnih dogaaja. Terapija atrovastatinom, neovisno o vi- Abnormalities in lipid profile do much more harm to the pa- sini LDL kolestrola, smanjuje intramiokardijalnu upalu, fibro- tients with diabetes than to the non-diabetic population, due zu i poboljπava funkciju lijeve klijetke na animalnim modeli- to their tendency for accelerated atherosclerosis. Statin the- ma54. Na isti naËin je dokazana i sposobnost fluvastatina koji rapy significantly reduces mortality of diabetic patients from smanjuje intersticijsku fibrozu miokarda i njegovu disfunkci- cardiovascular events. Atorvastatin therapy, regardless of ju. Iako nema kliniËke studije koja bi dokazala uËinkovitost the amount of LDL cholesterol, reduces intramyocardial in- statina u prevenciji dijabetiËke kardiomiopatije, poæeljni efekti flammation, fibrosis and improves left ventricular function in lijeËenja dislipidemije imaju vaænu ulogu u primarnoj preven- animal models54. In the same way, the potency of fluvastatin that reduces interstitial myocardial fibrosis and its dysfunc- Cardiologia CROATICA
Uloga antioksidansa se intenzivno ispituje na æivotnjskim tion has been proved. Although there are no clinical studies modelima. Istraæuje se moguÊi uËinak riboflavina, luteolina i that would prove the efficacy of statins in the prevention of resferatrola na prevenciju dijabetiËke kardiomipatije. Za sa- diabetic cardiomyopathy, the desirable effects of treatment da je dokazan povoljan antioksidatvni uËinak trimetazidina of dyslipidemia play an important role in the primary preven- zbog njegovog djelovanja na dobivanje energije u miokardu iz oksidacije glukoze, a ne slobodnih masnih kiselina. Lijek The role of antioxidants is intensively being tested on animal ima obeÊajavuÊi uËinak kod ishemijske i dilatativne kardio- models. A potential effect of riboflavin, luteolin and resvera- miopatije i Ëini se, usporava razvoj dijabetiËke kardiomiopa- trol in the prevention of diabetic cardiomyopathy is being in- vestigated. A beneficial antioxidat effect of triemthazidine for eÊerna bolest je relativna kontraindikacija za transplantaci- its effect on production of energy in the myocardium from ju srca, iako se pokazalo da paælivo odabrani dijabetiËari ne- glucose oxidation, not from free fatty acid has been proven maju statistiËki znaËajno loπije preæivljenje godinu dana na- so far. The drug has a promising effect on ischemic and dila- kon transplantacije i nakon pet godina56. U tijeku su studije s ted cardiomyopathy and seems to be slowing down the de- matiËnim stanicama u cilju regeneracije beta stanica pan- kreasa i miokarda kako bi se poboljπao metabolizam gluko- Diabetes mellitus is a relative contraindication for heart trans- plantation, although it was shown that carefully selected dia-betic patients have significantly worse survival one year af- Prevencija dijabetiËke kardiomiopatije
ter the transplantation and after five years’ period56. The stu-dies with stem cells aimed at regenerating pancreatic beta Stroga kontrole glikemije smatrana je kao najvaæni Ëimbenik cells and myocardial cells in order to improve glucose meta- prevencije razvoja kardiomiopatije, no velike studije (UKP- bolism and recover the myocardial function are underway.30 DS 33. ACCOD, ADVANCE, VADT) nisu to i potvrdile57.
Stroga kontrola glikemije prevenira razvoj prvenstveno mi-kroangiopatije, nije joπ jasna njena uloga na prevenciju ma- Prevention of diabetic cardiomyopathy
kroangiopatije. Kako u patogenezi dijabetiËke kardiomiopati- Strict glycemic control is considered to be the most impor- je imaju znaËajnu ulogu upravo poremeÊaju na razini mikro- tant factor in preventing the development of cardiomyopa- cirkulacije, za oËekivati je da Êe bolja regulacije glikemije re- thy, but larger studies (UKPDS 33, ACCOD, ADVANCE, zultirati povoljnim uËinkom na njenu prevenciju. Preventivnimehanizmi ovise o stupnju razvoja kardiomiopatije. U naj- VADT) have not verified it57. Strict glycemic control primarily ranijoj fazi promjena stila æivota i pravilna prehrana siromaπ- prevents the development of microangiopathy, its role in the na masnoÊama i ugljikohidratima uz svakodvnu fiziËku aktiv- prevention of macroangiopathy is not clear yet. Since in the nost dokazano usporavaju razvoj kardiomiopatije. To podra- pathogenesis, diabetic cardiomyopathies have an important zumijeva i optimalizaciju tjelesne teæine i svakodnevnu fiziË- role in the disorder at the level of microcirculation, it is ex- ku aktivnost. FiziËka aktivnost je povezana sa znaËajnim pected that a better glycemic control will result in a benefi- smanjenjem svih uzroka smrtnosti i koronarne bolesti kod cial effect on its prevention. Preventive mechanisms depend dijabetiËkih bolesnika, a smanjuje i incidenciju dijabetiËke on the degree of development of cardiomyopathy. In the kardiomiopatije dokazano na animalnim modelima i u studi- earliest stage of lifestyle changes, even a proper diet low in fat and carbohydrates with a daily physical activity is provedto delay the development of cardiomyopathy. This includes Kod srednje teπke kardiomiopatije uz pravilnu prehranu i fi- the optimization of body weight and a daily physical activity.
ziËku aktivnost, terapija metforminom za tip 2, odnosno in- Physical activity is associated with a significant reduction in zulinom za tip 1 bolesti i pioglitazoni poboljπavaju dijastoliË- all-cause mortality and coronary heart disease in diabetic ku funkciju. U ovoj fazi za regulaciju arterijskog tlaka, opti- patients and it also reduces the incidence of diabetic car- diomyopathy demonstrated on animal models and studies U kasnom stupnju dijabetiËke kardiomiopatije sve mjere pre- vencije koje su navedene kod srednje teπkog stupnja su i In the moderate cardiomyopathy with proper nutrition and ovdje nuæne, ali uz angiografiju u cilju otkrivanja makroan- physical activity, the metformin therapy for type 2 or insulin for type 1 disease and pioglitazone improve the diastolicfunction. At this stage, the beta blockers are the optimal ZakljuËak
choice for the blood pressure control. In the late stage of diabetic cardiomyopathy, all the preven- DijabetiËka kardimiopatija je Ëesto neprepoznata komplika- tive measures mentioned for moderate degree of severity cija πeÊerne bolesti, a posljedica je morfoloπkih i struktural-nih promjena u miokardu koje nastaju zbog brojnih meta- are required here, but along with angiography aimed at de- boliËkih rekacija koje prate dugotrajnu, nereguliranu hiper- glikemiju. Zbog remodelacije miokarda u poËetnoj fazi bole-sti vidi se hipertofija miokarda uz razvoj dijastoliËke, potom i Conclusion
sistoliËke disfunkcije, πto znaËajno poveÊava srËano zataji-vanje i smrtnost dijabetiËkih bolesnika. Ehokardiografija je Diabetic cardimyopathy is often an unrecognized complica- najËeπÊe koriπtena metoda za procjenu funkcije miokarda, tion of diabetes, and is a consequence of morphological and nuæna je i u asimptomatskih dijabetiËkih bolesnika, a pose- structural changes in the myocardium that occur as a result bice u onih koji se æale na zaduhu i intoleranciju napora. Is- of a number of metabolic reactions accompanying long- traæivanja idu u smjeru otkrivanja novih specifiËnih biomark- term, not controlled hyperglycemia. Due to myocardial re- era, za sada najviπe obeÊava MiRNA, koji mogu otkriti bo- modeling in the initial stage, we can see the myocardial hy- lest veÊ u samom zaËetku promjena i pomoÊu kojih se moæe pertrophy with a development of diastolic and then systolic stupnjevati teæina dijabetiËke kardiomiopatije i provoditi ci- dysfunction, which significantly increases HF and mortality Cardiologia CROATICA
ljana terapija. U radu su prikazani postupci koji mogu uspori- of diabetic patients. Echocardiography is the most common- ti razvoj kardiomiopatije, ali potrebne su nove spoznaje i o ly used method for assessing myocardial function. It is ne- cessary in asymptomatic diabetic patients, especially in tho-se who complain of dyspnoea and intolerance of stress. Thegoal of the trials is to discover new specific biomarkers,where MiRNA is the most promising one, which can detectthe disease as soon as the changes start to occur and which Received: 17th Nov 2013; Updated: 3rd Dec 2013 are used for scoring the severity of diabetic cardiomyopathy *Address for correspondence: KliniËka bolnica “Sveti Duh”, Sveti Duh 64, HR-10000 and conducting the target therapy. This paper presents the procedures that can slow down the development of car- diomyopathy, but we also need some new insights about the Literature
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