Uždegiminė diliatacinė kardiomiopatija: nauji diagnostikos ir gydymo būdai

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1 Uždegiminė diliatacinė kardiomiopatija: nauji diagnostikos ir gydymo būdai Inflammatory dilated cardiomyopathy: new perspective in diagnostics and treatment Dainius Daunoravičius 1, Virginija Grabauskienė 1, 2, Algimantas Jasulaitis 1 1 Vilnius University Faculty of Medicine, Department of Pathology, Forensic Medicine and Pharmacology 2 Vilnius University Faculty of Medicine, Clinic of Cardiovascular Diseases 1 Vilniaus universiteto Medicinos fakulteto Patologijos, teismo medicinos ir farmakologijos katedra 2 Vilniaus universiteto Medicinos fakulteto Širdies ir kraujagyslių ligų klinika SANTRAUKA Reikšminiai žodžiai: uždegiminė diliatacinė kardiomiopatija, širdies nepakankamumas, etiologija, gydymas. Neišeminės kilmės, uždegiminė diliatacinė kardiomiopatija (udkmp) yra viena svarbiausių širdies nepakankamumo ir širdies transplantacijų priežasčių. Širdies raumuo gali būti organas taikinys virusinei, bakterinei, pirmuonių ar parazitinei infekcijai, tačiau taip pat gali nukentėti ir netiesiogiai, dėl infekcinių organizmų ir kryžminio antikūnų poveikio. Kliniškai miokarditas ir uždegiminė kardiomiopatija gali pasireikšti daugybe simptomų nuo asimptominės eigos iki miokardo infarkto ar net sunkaus kardiogeninio šoko. Tokie pacientai gali spontaniškai pasveikti, tačiau dažniausiai jiems pamažu progresuoja širdies nepakankamumas ir tenka transplantuoti širdį. Pastarojo meto diliatacinės kardiomiopatijos etiologijos tyrimai parodė, kad pagrindinės šios ligos priežastys yra virusinė infekcija, genetiniai sutrikimai ir autoimuniniai mechanizmai. Nors buvo pasiekta didelė pažanga gydant širdies nepakankamumą kaip kardiomiopatijos pasekmę, vis dar nemažėja pacientų su gydymui atspariu širdies nepakankamumu, o jų būklė negerėja nepaisant viso prieinamo gydymo. Siekdami pademonstruoti šiuolaikines udkmp diagnostines ir etiopatogenetinio gydymo galimybes, pateikiame du klinikinius atvejus ir trumpą literatūros apžvalgą. ABSTRACT Key words: Myocarditis; Inflammatory cardiomyopathy; Heart Failure; Endomyocardial Biopsy, Virus genome; Aetiologydirected treatment. Non-ischemic, inflammatory dilated cardiomyopathy (icmp) is an important cause of heart failure and heart transplantation. The heart can be the primary target of a viral, bacterial, protozoic or parasitic infection or it could be involved in the collateral damage of infective organisms and cross-reactive antibodies. Clinical manifestation of myocarditis or inflammatory cardiomyopathy varies, with a broad spectrum of symptoms ranging from asymptomatic courses over presentations with signs of myocardial infarction to devastating illness with cardiogenic shock. The affected patients may recover or develop dilated cardiomyopathy with heart failure and the need for heart transplantation. The recent progress in study on etiology of dilative cardiomyopathy has shown that viral infection, genetic abnormalities and autoimmune mechanisms are major causes of this disease. Although significant progress has been achieved in the treatment of heart failure as a result of cardiomyopathy, it is a still matter of fact that there are many patients with refractory heart failure who do not respond despite every available treatment. Presently, feasible clinical pathways are available, which can lead to a correct diagnosis and specific treatment. Two cases are presented to illustrate the possibilities of the diagnosis of distinct icmp subentities and aetiology-directed treatment strategies. Dainius Daunoravičius Vilniaus universiteto Medicinos fakulteto Patologijos, teismo medicinos ir farmakologijos katedra Čiurlionio g. 21/27,Vilnius daunoravicius@gmail.com teorija ir praktika T. 18 (Nr. 3), p. 299

2 INTRODUCTION The management of patients with non-ischemic, inflammatory dilated cardiomyopathy (DCM) can be extremely challenging, in addition, it is an important cause of heart failure and heart transplantation. Cardiomyopathy used to be a chronic disease of unknown etiology, and its clinical outcome was extremely poor [1]. However the recent progress in study on etiology of DCM has shown that viral infection, genetic abnormalities and autoimmune mechanisms are major causes of this disease [2 4]. The history and clinical features are often nonspecific, and practical serological markers are not available during the acute phase of the disease. A causal involvement of myocardial inflammation and viral agents in the pathogenesis of DCM is supported by recent findings of myocardial viral genome persistence in up to 67 % of DCM patients [5 8]. The heart can be the primary target of a viral, bacterial, protozoic or parasitic infection or it could be involved in the collateral damage of infective organisms (by toxins, chemokines/cytokines) and cross-reactive antibodies. Moreover, it could be exposed to the native and acquired immune response through T-, B-cells, monocytes and macrophages. Infective agents show a remarkable organotropicity: viral infections, toxic and autoreactive processes primarily affect the myocardium and the pericardium [9]. The progression from acute injury to chronic dilated cardiomyopathy may be simplified into a three phases: phase 1 is dominated by viral infection itself (initial myocyte damage by virus or toxin), phase 2 by the onset of multiple autoimmune (innate and acquired) reactions, and phase 3 by the progression to cardiac dilatation with or without an infectious agent and cardiac inflammation [6, 9 11]. Inflammatory cardiomyopathy has been identified as an important causal factor responsible for the progression to dilated cardiomyopathy [12 17] and currently the most frequent reason for heart transplantation [18]. Clinical manifestation of myocarditis or inflammatory cardiomyopathy varies, with a broad spectrum of symptoms ranging from asymptomatic courses over presentations with signs of myocardial infarction to devastating illness with cardiogenic shock. The affected patients may recover or develop dilated cardiomyopathy with heart failure and the need for heart transplantation [18 21]. The application of molecular-biological, histological and immunohistochemical diagnostic techniques has furthered the definition of specific disease sub-groups responding to immunomodulating, immunosuppressive and antiviral therapy options have been identified based on the underlying pathophysiological mechanisms [9, 22 25]. In the light of these data two cases will be discussed, which illustrate the state-of-the-art approach to diagnosis and treatment of them. Case 1: J.B. 48 Years, Male The 48-year-old male patient hospitalized with general weakness, discomfort in the chest during physical activity, NYHA class III, LVEF 22 %, LVEDD 8.4 cm, PCWP 16 mmhg, PAP (mean) 25 mmhg, BNP 830 (ng/l). Coronary angiogram was normal. Endomyocardial biopsy revealed an infiltrate with more than 14 cells (10 CD3+ and 10 CD68+ cells) and moderate degree of interstitial fibrosis. PCR for cardiotropic viruses (adenovirus, herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpes virus 6, parvovirus (B19), enterovirus, hepatitis C virus and rubella virus) was negative. Comment regarding treatment: The positive effect of immunosuppressive treatment of virus-negative inflammatory DCM was confirmed on LV function in a pilot study TIMIC, with no case of death or cardiac transplantation during treatment and in the following 6 months [24]. The improvement was accompanied by the disappearance of inflammatory infiltrates and progression from the active towards a healed myocarditis. Bearing this in mind, this patient, besides the conventional HF treatment would probably benefit from additional immunosuppressive treatment with prednisolone and azathioprine. Compared with other treatment methods (immunoabsorbtion, plasmapheresis, immunomodulation), immunosuppressive treatment is relatively cheap and could be widely applied. Case 1:A.Z. 27 Years, Female The 27-year-old female patient hospitalized with general weakness, discomfort in the chest during physical activity, NYHA class III, LVEF 23 %, LVEDD 7.5 cm, PCWP 11 mmhg, PAP (mean) 13 mmhg, BNP 17.3 (ng/l). Coronary angiography showed normal coronary arteries. Endomyocardial biopsy revealed an infiltrate with more than 14 cells (8 CD3+ and 8 CD68+ cells) and mild degree of interstitial fibrosis. PCR for cardiotropic viruses was positive for parvovirus B19. Comment regarding treatment: In a recent study patients with virus myocarditis (inflammation-positive IHC, and virus positive PCR for adenovirus and parvovirus B19) were treated with intravenous Pentaglobin (enriched IgG, IgA and IgM preparation, Biotest) therapy [44]. The study had demonstrated a significant clinical improvement of patients NYHA class, exercise capacity and their LVEF independent from the respective virus. In 52 of the 73 patients (71 %) inflammation had resolved. The biopsy was repeated for 19 patients, in 17 of those (90 %) with a positive PCR for adenovirus before therapy no viral DNA was detected after treatment and inflammation had resolved completely. In parvovirus B19 myocarditis patients, inflammation had resolved in 31 of the 44 (70 %), whereas parvovirus B teorija ir praktika T. 18 (Nr. 3)

3 DNA was eradicated in only in 18 out of 44 (40 %). When both viruses and inflammation were eradicated the end-diastolic LV dimension decreased and EF increased significantly [9, 44]. The causative treatment of parvovirus B19 associated myocarditis remains complicated however, the intravenous immunoglobulin treatment with Pentaglobin may be beneficial for virus myocarditis sub-group patients. DISSCUSION Classification of inflammatory heart disease The gold standard for diagnosis of myocarditis and inflammatory DCM is endomyocardial biopsy (EMB). It is now recognized that the Dallas criteria are not sensitive for myocarditis because they do not consider the presence of viral genome in the heart [26]. The use of histological Dallas criteria in conjunction with new tools of immunohistochemistry and viral polymerase chain reaction (PCR) has provided a better identification of the aetiology of inflammatory DCM and renewed interest in the mechanisms of the inflammatory process in the heart [9, 14, 27]. These new insights of the disease are mandatory to allow the development of novel aetiology-directed treatment strategies. Although significant progress has been achieved in the treatment of heart failure as a result of cardiomyopathy, it is still a matter of fact that there are many patients with refractory heart failure who do not respond despite every available treatment. Recent studies have provided evidence of a positive clinical impact of immunosuppressive therapy in up to 90 % of patients with negative cardiac PCR for the main cardiotropic viruses [9, 24, 28]. However, currently there is no agreement on the specific treatment of this entity in addition to conventional anti-heart failure therapy. Myocarditis is defined as inflammation of the heart after immunohistochemical detection of focal or diffuse mononuclear infiltrates with >14 leukocytes per 1 mm2 (CD3+ T lymphocytes and/or CD68+ macrophages) independent of the clinical phenotype or the presence of heart failure or ventricular dilatation [8, 19, 29, 30]. If there is hemodynamic compromise together with cardiac dilatation (LVEDD [left ventricular end-diastolic diameter] > 55 mm and the ejection fraction is <50 %, histological myocarditis is categorized as inflammatory cardiomyopathy [29]. The classification of inflammatory heart disease, myocarditis and perimyocarditis is based on several consensus documents on the classification of cardiomyopathies [18, 30], the American Heart Association (AHA) guidelines on heart failure [31], the ESC guidelines on the management of pericardial and perimyocardial disease [32] and current knowledge on the diagnosis and treatment of cardiac inflammation from peer review publications [1, 2, 6, 9, 19, 20, 22, 23, 25, 26, 33 41]. VIRAL GENOME Viral infection of the heart is increasingly recognized as an important cause of both acute and chronic heart failure [6, 7, 10, 33, 38]. The etiology of inflammation can be defined by the molecular PCR analysis of the underlying infective agents. A decade ago the most prevalent viruses among the patients with inflammatory DCM were enteroviruses and adenoviruses. The recent day research revealed a new set of prevalent viruses: parvoviruses B19 followed by CMV (Cytomegalovirus), EBV (Epstein-Barr virus), HHV-6 (human herpesvirus type 6) and only then the classic enteroviruses and adenoviruses [4, 6, 20, 26, 38]. In a recent multicenter analysis of 624 patients in the United States with histologically proven myocarditis, the presence of various virus genomes was confirmed in 239 of biopsy samples (38%) [42].The presence of viral genome in endomyocardial biopsy samples has also been reported in a subset of patients with idiopathic DCM even in the absence of classic histological myocarditis [7, 42]. Although it is clear that viral genomes can be identified in a subset of patients with acute myocarditis and DCM, the impact of the presence of viral genomes on cardiac function and clinical outcome is still controversial. One clinical study showed the association between viral persistence in the heart and progressive cardiac dysfunction [7, 19]. In contrast, another clinical study reported that the presence of viral genomes per se could not be a predictor of cardiac death or heart transplantation in patients with clinically suspected myocarditis [19]. The latter clinical study further pointed out that the presence of inflammatory T cells and/ or macrophages with enhanced expression of HLA class II molecules in the heart can be a promising predictor of the clinical outcome even in the absence of viral genomes and Dallas criteria positive findings [19]. Recent biopsy series in patients with DCM have revealed that long term persistence of cardiotrophic viruses triggers heart failure at long term: >70 % of patients with idiopathic DCM carry a cardiotrophic virus in the heart [7, 41]. Direct cytopathic effects and immune dysregulation induced by the viral myocarditis trigger cardiac dysfunction. Cardiotrophic viruses are able to degrade cell-cell, cell-matrix, and intracellular elements. These proteases aim to facilitate the entry of the virus into cells, but result in myocyte slippage, injury, and cardiac dysfunction [43]. The presence of viral genomes on endomyocardial biopsy is associated with subsequent worsening of heart function, the need for cardiac transplantation, and death [7, 19] and it could be used to guide the treatment in acute and chronic inflammatory DCM [14]. teorija ir praktika T. 18 (Nr. 3) 301

4 Clinical pathway for diagnosis and treatment possibilities On the basis of results from biopsy sample analysis of immunohistochemistry (IHC) and PCR for virus detection it is possible to identify distinct subentities of myocarditis and inflammatory DCM (Figure 1) [9]: 1. Virus positive myocarditis (inflammation-positive IHC and virus-positive PCR). 2. Auto-reactive myocarditis (inflammation-positive IHC and virus-negative PCR). 3. Viral heart disease (inflammation-negative IHC and virus-positive PCR). 4. No myocarditis (inflammation-negative IHC and virus-negative PCR). Figure 1. Myocarditis diagnostics and possible ethiopatogenetic treatment (adopted by [9]) CAD: coronary artery disease, MRI: magnetic resonance imaging Present evidence suggests that auto-reactive myocarditis patients (identified by inflammation-positive IHC and virus-negative PCR) may benefit from immunosuppressive or immunomodulatory therapy [9, 23, 24, 27]. Results of the recent TIMIC trial confirmed the positive impact of immunosuppression on recovery of LV function in a high rate (88 %) of patients with no case of death or cardiac transplantation during treatment and in the following 6 months [24]. Remarkably a striking improvement occurred even in patients with extreme LV dilatation and dysfunction and it was accompanied at histological examination by the disappearance of inflammatory infiltrates with progression of the disease from an active towards a healed myocarditis. A retrospective study on patients with inflammatory cardiomyopathy receiving immunosuppression showed a high prevalence (90 %) of virus-negative myocardial PCR for cardiotropic viruses among responders and a high rate of virus-positive PCR (85 %) among non-responders [23]. Viral heart disease diagnosed patients (inflammationnegative IHC and virus-positive PCR) might be candidates for agent-specific antiviral treatment. Virus-positive myocarditis patients (identified by inflammation-positive IHC and virus-positive PCR) might also benefit from agent-specific antiviral treatment and, after virus clearance, immunosuppression or combined anti-viral and immunosuppressive therapy [7]. Interferon-beta therapy shows the myocardial clearance of adenoviruses and enteroviruses and a parallel improvement of left ventricular function. A recent study showed that intravenous Pentaglobin treatment 302 teorija ir praktika T. 18 (Nr. 3)

5 is highly effective in resolving myocardial inflammation independent of the underlying viral etiology. However, it eradicates adenoviral infection better than parvovirus B19 infection [9, 44]. The cases negative for both inflammation and cardiotropic viruses might be classified as no myocarditis and should receive basic heart failure and antiarrhythmic therapy. In theory, these cases could reflect viral myocarditis, owing to yet unknown pathogens, or, most likely, a cellmediated autoimmune form that might also benefit of immunosuppression [9]. CONCLUSION Diagnosis and treatment of myocarditis should follow the clinical pathways outlined in this contribution. On the basis of results from myocardial biopsy sample analysis of immunohistochemistry (IHC) and PCR for virus detection it is possible to identify distinct subentities of myocarditis and inflammatory DCM. 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