Use of serial changes in biomarkers vs. baseline levels to predict left ventricular remodelling after STEMI

Aims: Cellular communication network factor 1 (CCN1) is an independent predictor of MACE after ACS and elevated levels correlated with infarct size after STEMI. We compared the prognostic accuracy of baseline levels of CCN1, NT-proBNP, hsTnT, and ST2 and changes in levels over time to predict the development of structural and functional alterations typical of LV remodelling. Methods: Serial 3-T cMRI scans were performed to determine LVEF, LVEDV, LVESV, infarct size, and relative infarct size, which were correlated with serial measurements of the four biomarkers. The prognostic significance of these biomarkers was assessed by multiple logistic regression analysis by examining their performance in predicting dichotomized cardiac MRI values 12 months after STEMI based on their median. For each biomarker three models were created using baseline (BL), the Δ value (BL to 6 months), and the two values together as predictors. All models were adjusted for age and renal function. Receiver operator curves were plotted with area under the curve (AUC) to discriminate the prognostic accuracy of individual biomarkers for MRI-based structural or functional changes. Results: A total of 44 predominantly male patients (88.6%) from the ETiCS (Etiology, Titre-Course, and Survival) study were identified at a mean age of 55.5 ± 11.5 (SD) years treated by successful percutaneous coronary intervention (97.7%) at a rate of 95.5% stent implantation within a median pain-to-balloon time of 260 min (IQR 124–591). Biomarkers hsTnT and ST2 were identified as strong predictors (AUC > 0.7) of LVEDV and LVEF. BL measurement to predict LVEF [hsTnT: AUC 0.870 (95% CI: 0.756–0.983), ST2: AUC 0.763 (95% CI: 0.615–0.911)] and the Δ value BL-6M [hsTnT: AUC 0.870 (95% CI: 0.756–0.983), ST2: AUC 0.809 (95% CI: 0.679–0.939)] showed a high prognostic value without a significant difference for the comparison of the BL model vs. the Δ-value model (BL-6M) for hsTnT (P = 1) and ST2 (P = 0.304). The combined model that included baseline and Δ value as predictors was not able to improve the ability to predict LVEF [hsTnT: AUC 0.891 (0.791–0.992), P = 0.444; ST2: AUC 0.778 (0.638–0.918), P = 0.799]. Baseline levels of CCN1 were closely associated with LVEDV at 12 months [AUC 0.708 (95% CI: 0.551–0.865)] and infarct size [AUC 0.703 (95% CI: 0.534–0.872)]. Conclusions: Baseline biomarker levels of hsTnT and ST2 were the strongest predictors of LVEF and LVEDV at 12 months after STEMI. The association of CCN1 with LVEDV and infarct size warrants further study into the underlying pathophysiology of this novel biomarker

Cyclopeptide COR-1 to treat beta1-adrenergic receptor antibody-induced heart failure.

RATIONALE:Despite advances in pharmacotherapy, heart failure still incurs significant morbidity and mortality. Stimulating antibodies directed against the secondextracellular loop of the human ß1-adrenergic receptor (anti-ß1EC2) cause myocyte damage and heart failure in rats. This receptor domain is 100% homologous between rats and humans. OBJECTIVE:ß1EC2-mimicking cyclopeptides (25-meric) markedly improved the development and/or course of anti-ß1EC2-mediated cardiomyopathy. Further developments should be investigated. METHODS AND RESULTS:The shortened 18-meric cyclic peptide COR-1, in which one of the two disulphide bonds was removed to enable reproducible GMP production, can also be used to treat cardiomyopathic rats. Echocardiography, catheterization and histopathology of the rat hearts revealed that monthly intravenous administrations of COR-1 almost fully reversed the cardiomyopathic phenotype within 6 months at doses of 1 to 4 mg/kg body weight. Administration of COR-1 resulted in markedly reduced anti-ß1EC2-expressing memory B lymphocytes in the spleen despite continued antigenic boosts, but did not significantly decrease overall peripheral anti-ß1EC2 titers. COR-1 did not induce any anti-ß1EC2 or other immune response in naïve rats (corresponding to findings in healthy human volunteers). It did not cause any toxic side effects in GLP studies in dogs, rats or mice, and the "no observed adverse effect level" (NOAEL) exceeded the therapeutic doses by 100-fold. CONCLUSION:The second generation immunomodulating epitope-mimicking cyclopeptide COR-1 (also termed JNJ-5442840) offers promise to treat immune-mediated cardiac diseases

Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by Anti−β1−AdrenoceptorAnti-β_1-Adrenoceptor Antibodies in a Human-Analogous Rat Model

Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the $β_1$ adrenergic receptor $(β_1EC2)$. In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195–225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking $β_1EC2$ ($β_1EC2-CP$, 1.0 mg/kg every 4 weeks) or administration of the $β_1-blocker$ bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received $β_1EC2-CP/bisoprolol$ co-treatment. We found that $β_1EC2-CP$ prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, $β_1EC2-CP$ mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free $anti-β_1EC2-antibodies$ and by targeting $β_1EC2$-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful $anti-β_1EC2-antibodies$ and also selectively depletes memory B-cells involved in the production of such antibodies. Treatment with immuno-modulating cyclopeptides alone or as an add-on to $β_1$-blockade represents a promising new therapeutic option in immune-mediated heart failure

Coagulation factor XIII activity predicts left ventricular remodelling after acute myocardial infarction

Aims Acute myocardial infarction (MI) is the major cause of chronic heart failure. The activity of blood coagulation factor XIII (FXIIIa) plays an important role in rodents as a healing factor after MI, whereas its role in healing and remodelling processes in humans remains unclear. We prospectively evaluated the relevance of FXIIIa after acute MI as a potential early prognostic marker for adequate healing. Methods and results This monocentric prospective cohort study investigated cardiac remodelling in patients with ST-elevation MI and followed them up for 1 year. Serum FXIIIa was serially assessed during the first 9 days after MI and after 2, 6, and 12 months. Cardiac magnetic resonance imaging was performed within 4 days after MI (Scan 1), after 7 to 9 days (Scan 2), and after 12 months (Scan 3). The FXIII valine-to-leucine (V34L) single-nucleotide polymorphism rs5985 was genotyped. One hundred forty-six patients were investigated (mean age 58 ± 11 years, 13% women). Median FXIIIa was 118 % (quartiles, 102–132%) and dropped to a trough on the second day after MI: 109%(98–109%; P < 0.001). FXIIIa recovered slowly over time, reaching the baseline level after 2 to 6 months and surpassed baseline levels only after 12 months: 124 % (110–142%). The development of FXIIIa after MI was independent of the genotype. FXIIIa on Day 2 was strongly and inversely associated with the relative size of MI in Scan 1 (Spearman’s ρ = –0.31; P = 0.01) and Scan 3 (ρ = –0.39; P < 0.01) and positively associated with left ventricular ejection fraction: ρ = 0.32 (P < 0.01) and ρ = 0.24 (P = 0.04), respectively. Conclusions FXIII activity after MI is highly dynamic, exhibiting a significant decline in the early healing period, with reconstitution 6 months later. Depressed FXIIIa early after MI predicted a greater size of MI and lower left ventricular ejection fraction after 1 year. The clinical relevance of these findings awaits to be tested in a randomized trial

Sustained Increase in Serum Glial Fibrillary Acidic Protein after First ST-Elevation Myocardial Infarction

Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0&ndash;4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (&rho; = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway

Direct evidence for a β(1)-adrenergic receptor–directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy

Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults and thus is a challenge for public health. About 30% of DCM cases are genetic in origin; however, the large majority of cases are sporadic, and a viral or immune pathogenesis is suspected. Following the established postulates for pathogenesis of autoimmune diseases, here we provide direct evidence that an autoimmune attack directed against the cardiac β(1)-adrenergic receptor may play a causal role in DCM. First, we immunized inbred rats against the second extracellular β(1)-receptor loop (β(1)-EC(II); 100% sequence identity between human and rat) every month. All these rats developed first, receptor-stimulating anti–β(1)-EC(II) Ab’s and then, after 9 months, progressive severe left ventricular dilatation and dysfunction. Second, we transferred sera from anti–β(1)-EC(II)–positive and Ab-negative animals every month to healthy rats of the same strain. Strikingly, all anti–β(1)-EC(II)–transferred rats also developed a similar cardiomyopathic phenotype within a similar time frame, underlining the pathogenic potential of these receptor Ab’s. As a consequence, β(1)-adrenergic receptor–targeted autoimmune DCM should now be categorized with other known receptor Ab-mediated autoimmune diseases, such as Graves disease or myasthenia gravis. Although carried out in an experimental animal model, our findings should further encourage the development of therapeutic strategies that combat harmful anti–β(1)-EC(II) in receptor Ab–positive DCM patients

Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy

Myocarditis can develop into inflammatory cardiomyopathy through chronic stimulation of myosin heavy chain 6-specific T helper (T$_{H}$)1 and T$_{H}$17 cells. However, mechanisms governing the cardiotoxicity programming of heart-specific T cells have remained elusive. Using a mouse model of spontaneous autoimmune myocarditis, we show that progression of myocarditis to lethal heart disease depends on cardiac myosin-specific T$_{H}$17 cells imprinted in the intestine by a commensal Bacteroides species peptide mimic. Both the successful prevention of lethal disease in mice by antibiotic therapy and the significantly elevated Bacteroides-specific CD4$^{+}$ T cell and B cell responses observed in human myocarditis patients suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible individuals. The ability to restrain cardiotoxic T cells through manipulation of the microbiome thereby transforms inflammatory cardiomyopathy into a targetable disease

Immunology of cyclic β1EC2-peptides: fate of β1EC2-specific T- and B-cells.

<p><b>(A)</b> Titer-course of anti-β₁EC2-abs in β₁EC2-CP-treated rats during the first 6 months of the prevention-study <i>before</i> and 24h <i>after</i> cyclopeptide-injection. Time-points of antigen-boosts are indicated by (red) lines, time-points of CP-injections by (green) arrows. For better readability error-bars are not shown in the graph. <b>(B)</b> Pre-experiments (antigenic recall-assays) performed with CD4⁺ T-cells prepared from spleens of GST/β₁EC2 fusion-protein (FP)-immunised untreated (n = 3, black) vs. 0.9%NaCl-injected control rats (n = 3, white). (<b>C</b> and <b>D</b>) Reactivities of CD4⁺ T-cells prepared from <b>(C)</b><i>preventively</i> or <b>(D)</b><i>therapeutically</i> β₁EC2-CP- (green) or bisoprolol-treated animals (blue) compared to cells prepared from immunised untreated (black) or corresponding 0.9%NaCl-injected control rats (white). Columns ± error bars represent mean T-cell reactivities ±SEM normalized to medium (abbreviations: EC2-CP, cyclopeptide mimicking β₁EC2; GST, glutathion-S-transferase; PPD, purified protein derivative; FP, GST/β₁EC2 fusion-protein). (<b>E</b> and <b>F</b>) ELISPOT-assays to detect long-lived plasma cells (PC) in bone marrow (BM) and spleens of untreated (black, n = 4) vs. β₁EC2-CP-treated immunised rats (green, n = 4, month 16). Columns in <b>(E)</b> depict the fraction of anti-β₁EC2-secreting PC 14 days after antigen-boost (in ‰ of IgG-producing cells), in <b>(F)</b> the total amount of IgG-producing cells per 10⁴cells. Error bars represent mean ±SEM in the indicated groups. (<b>G</b> to <b>J</b>) ELISPOT-assays carried out with bone marrow cells (BM) and splenocytes prepared from immunised untreated (black) vs. β₁EC2-CP-treated rats (green) from the prevention- (G and H, n = 2 vs. 3 rats) and the therapy-study (I and J, n = 3 vs. 3 rats). Columns in <b>(G)</b> and <b>(I)</b> depict the fraction of anti-β₁EC2-secreting cells 3 days after antigen-boost (vs. IgG-producing cells); columns in <b>(H)</b> and <b>(J)</b> show the total amount of IgG-producing cells per 10⁴cells. <b>(K</b> and <b>L)</b> Direct flow cytometric detection of β₁EC2-specific B-cells. The numbers in the dot plots indicate percentages per quadrant. <b>(M)</b> Concentration of anti-β₁EC2-IgG in the sera of recipient rats after adoptive transfer of B-cells from donors treated as indicated followed by suboptimal immunisation with FP in adjuvans. Error bars represent mean ±SEM in the indicated groups (Student’s t-test, *p<0.05).</p