Constantinos Bakogiannis

The MOGE(S) classification for cardiomyopathies: current status and future outlook

Cardiomyopathies are complex diseases of multifactorial pathogenesis and have a high morbidity and mortality. Over the past decades, several revisions of classifications and definitions of cardiomyopathies have been proposed, primarily focusing on the phenotypic characterization of cardiomyopathies. The MOGE(S) classification system published in 2013 encompasses the classification of rapidly growing knowledge on genetic mutations, acquired causes (i.e., intramyocardial inflammation, viral infections), and further conditions involved in the induction of cardiomyopathies (e.g., storage diseases, toxicity). It is based on five attributes, including morphofunctional characteristics (M), organ involvement (O), genetic or familial inheritance pattern (G), etiological annotation (E), and optional information about the heart failure functional status (S). This review summarizes the development, the cornerstones of the MOGE(S) classification, and the published data on the clinical relevance of the MOGE(S) classification. We furthermore discuss new issues which might be considered for future updates of the MOGE(S) classification of cardiomyopathies.

Platelet-derived chemokines in inflammation and atherosclerosis

Platelets are inflammatory anuclear cells with a well-established role in the development and manifestation of atherosclerosis. Activated platelets secrete a plethora of chemokines including CXCL4 or platelet factor 4 (PF4), CCL5, CXCL12 or stromal cell derived factor-1α (SDF-1α), CXCL16 and others, which initiate or promote local inflammatory processes at sites of vascular injury. These processes are mainly mediated by the recruitment of circulating haematopoietic stem cells, neutrophils, monocytes or lymphocytes on vascular wall. Under acute ischemic conditions platelet-derived chemokines may promote the mobilization of bone marrow-derived progenitor cells and their homing at lesion sites. This review focuses on the role of platelet-derived chemokines in inflammation and atherosclerosis. Further, we discuss the clinical value of plasma levels of chemokines in the prognosis of atherosclerotic heart disease.

GDF-15 predicts cardiovascular events in acute chest pain patients.

Background Treatment of patients presenting with possible acute myocardial infarction (AMI) is based on timely diagnosis and proper risk stratification aided by biomarkers. We aimed at evaluating the predictive value of GDF-15 in patients presenting with symptoms suggestive of AMI. Methods Consecutive patients presenting with suspected AMI were enrolled in three study centers. Cardiovascular events were assessed during a follow-up period of 6 months with a combined endpoint of death or MI. Results From the 1818 enrolled patients (m/f = 1208/610), 413 (22.7%) had an acute MI and 63 patients reached the combined endpoint. Patients with MI and patients with adverse outcome had higher GDF-15 levels compared with non-MI patients (967.1pg/mL vs. 692.2 pg/L, p<0.001) and with event-free patients (1660 pg/mL vs. 756.6 pg/L, p<0.001). GDF-15 levels were lower in patients with SYNTAX score ≤ 22 (797.3 pg/mL vs. 947.2 pg/L, p = 0.036). Increased GDF-15 levels on admission were associated with a hazard ratio of 2.1 for death or MI (95%CI: 1.67–2.65, p<0.001) in a model adjusted for age and sex and of 1.57 (1.13–2.19, p = 0.008) adjusted for the GRACE score variables. GDF-15 showed a relevant reclassification with regards to the GRACE score with an overall net reclassification index (NRI) of 12.5% and an integrated discrimination improvement (IDI) of 14.56% (p = 0.006). Conclusion GDF-15 is an independent predictor of future cardiovascular events in patients presenting with suspected MI. GDF-15 levels correlate with the severity of CAD and can identify and risk-stratify patients who need coronary revascularization.

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function

Background: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Methods: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m2), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m2), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

Serum Fas Ligand, Serum Myostatin and Urine TGF-β1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function

Background/Aims: The pathophysiology of renal disease progression in autosomal dominant polycystic disease (ADPKD) is largely unknown. Recent evidence suggests microvascular dysfunction leading to renal ischemia, as an additional pathway for renal function decline. This study examined the levels of serum Fas ligand (FasL), serum myostatin and urine transforming growth factor-beta 1 (TGF-β1) and their association with markers of endothelial dysfunction, in ADPKD patients with preserved or impaired renal function. Methods: Seventy-eight participants were enrolled in the study, divided in three groups: Group A consisted of 26 ADPKD patients with impaired renal function (eGFR 45-70 ml/min/1.73m2), Group B of 26 ADPKD patients with preserved renal function (eGFR > 70 ml/min/1.73m2), and Group C of 26 age- and sex- matched controls with no history of renal disease. Serum FasL, myostatin and urine levels of TGF-β1 were measured as biomarkers of vascular dysfunction, apoptosis and fibrosis with ELISA techniques. Results: Group A patients had significantly higher levels of FasL (13.12±1.69 ng/mL), myostatin (4.62±0.59 ng/mL) and urine logTGF-β1 (3.56±0.49 ng/24h) compared to Group B (9.6±1.28 ng/mL, 3.06±0.35, and 2.09±0.37, respectively, p< 0.001 for all comparisons) or controls (6.59±1.17 ng/mL, 2.18±0.45 ng/ml, and 1.58±0.21, respectively, p< 0.001 for all comparisons). Patients in Group B had also higher levels of all markers compared to controls (p< 0.001), despite having similar renal function. In ADKPD patients negative associations of eGFR with FasL (r=-0.799, p< 0.001), myostatin (r=-0.856, p< 0.001) and TGF-β1 (r=-0.476, p< 0.001) but positive correlations of these markers with asymmetric dimethylarginine (ADMA) (r=0.825; r=0.749; and r=0.599, respectively p< 0.001) were noted. Multivariate analysis demonstrated that FasL was independently associated with high urine TGF-β1 (OR 3.774, 95%CI 1.180-12.072, p=0.025). Conclusions: ADPKD patients with moderately preserved renal function have higher levels of FasL, myostatin and urine TGF-β1 than controls. These results indicate that an interplay between endothelial dysfunction and renal ischemia with mechanisms linked to apoptosis and fibrosis may be present even in early stages of ADPKD.

Left atrial deformation as a potent predictor for paroxysmal atrial fibrillation in patients with end-stage renal disease

It is widely known that various factors contribute to left atrial (LA) mechanical dysfunction in patients with end stage renal disease (ESRD). However, the connection between atrial dysfunction and arrhythmic events such as paroxysmal atrial fibrillation (PAF), in this group of patients, remains unclear. The purpose of our study was to evaluate prospectively the association between LA deformation indices and PAF in ESRD patients. 79 patients (41 men, mean age 57u2009±u200917) with ESRD and preserved left ventricular systolic function comprised the study population. All patients underwent a baseline comprehensive echocardiography study and were followed for a mean period of 16u2009±u20095 months. PAF episodes, first and the following events, were reported. LA longitudinal strain reflecting LA reservoir function and LA longitudinal strain rate reflecting LA pump function were specifically evaluated as LA deformation indices of interest, using 2D speckle tracking echocardiography. At the end of follow up period nine patients died. 15 of the rest 70 reported one or more episodes of PAF. LA indexed volumes were significantly higher in patients with PAF (32u2009±u200926 vs. 21.5u2009±u20099xa0ml/m2, pu2009=u20090.002), mean LA strain was significantly reduced (17u2009±u20097 vs. 27u2009±u20099%, pu2009<u20090.001) as well as mean LA stain rate (−u20091.19u2009±u20090.5 vs. −u20091.95u2009±u20090.5 1/s, pu2009<u20090.001). Multivariate analysis showed that LA strain rate when adjusted with age together with PAF history remained the single most significant echocardiographic parameter for PAF prediction. Impaired LA strain and LA strain rate are associated with PAF in ESRD patients. LA strain rate might be a better independent predictor of PAF, compared to standard echocardiographic indices. Further prospective studies are needed to validate its relevance in routine clinical practice.

Acute heart failure

Despite recent advances in the management of heart failure with reduced ejection fraction (HFrEF), the burden of acute heart failure (AHF) remains significant with axa0high morbidity and mortality that has not been improved by any treatment modality. Axa0meta-analysis summarized the study results on the effects of tolvaptan on AHF, which failed to demonstrate an improvement in short-term and long-term mortality, length of hospital stay and reduced frequency of worsening heart failure (WHF). Similar trial results were also reported in other AHF studies, such as the ASCEND-HF and the RELAX-AHF-2 trials. In view of these inconclusive studies it is evident that improving the prognosis of AHF patients remains an unmet medical need. Further efforts should focus on organ damage protection, individualized treatment, patient benefits and standardized management programs, including immediate identification and management of cardiogenic shock and establishment of HF networks for close monitoring of AHF patients.ZusammenfassungTrotz jüngster Fortschritte im Management der Herzinsuffizienz mit reduzierter Ejektionsfraktion (HFrEF) bleibt die Belastung des akuten Herzversagens („acute heart failure“, AHF) mit hoher Morbidität und Mortalität signifikant und konnte bisher durch kein Behandlungsverfahren verbessert werden. Eine Metaanalyse fasste die Studienergebnisse zu den Auswirkungen von Tolvaptan auf AHF zusammen, das keine Verbesserung in Kurzzeit- und Langzeitmortalität, Hospitalisationsdauer und reduzierter Häufigkeit einer Verschlimmerung der Herzinsuffizienz („worsening heart failure“, WHF) zeigen konnte. Ähnliche Ergebnisse wurden auch in anderen AHF-Studien berichtet, wie z.xa0B. der ACENT-HF- und der RELAX-AHF-2-Studie. In Anbetracht dieser nicht eindeutigen Studienlage stellt die Verbesserung der Prognose von AHF-Patienten offensichtlich einen unerfüllten medizinischen Bedarf dar. Zukünftige Bemühungen sollten auf den Schutz vor Organschäden, die individuelle Behandlung, den Nutzen für die Patienten sowie standardisierte Management-Programme fokussieren, einschließlich der sofortigen Identifizierung und des Managements eines kardiogenen Schocks sowie der Einrichtung von Herzinsuffizienz-Netzwerken für ein engmaschiges Monitoring von AHF-Patienten.

Acute heart failure@@@Akutes Herzversagen: An unmet medical need@@@Ein unerfüllter medizinischer Bedarf

Despite recent advances in the management of heart failure with reduced ejection fraction (HFrEF), the burden of acute heart failure (AHF) remains significant with axa0high morbidity and mortality that has not been improved by any treatment modality. Axa0meta-analysis summarized the study results on the effects of tolvaptan on AHF, which failed to demonstrate an improvement in short-term and long-term mortality, length of hospital stay and reduced frequency of worsening heart failure (WHF). Similar trial results were also reported in other AHF studies, such as the ASCEND-HF and the RELAX-AHF-2 trials. In view of these inconclusive studies it is evident that improving the prognosis of AHF patients remains an unmet medical need. Further efforts should focus on organ damage protection, individualized treatment, patient benefits and standardized management programs, including immediate identification and management of cardiogenic shock and establishment of HF networks for close monitoring of AHF patients.ZusammenfassungTrotz jüngster Fortschritte im Management der Herzinsuffizienz mit reduzierter Ejektionsfraktion (HFrEF) bleibt die Belastung des akuten Herzversagens („acute heart failure“, AHF) mit hoher Morbidität und Mortalität signifikant und konnte bisher durch kein Behandlungsverfahren verbessert werden. Eine Metaanalyse fasste die Studienergebnisse zu den Auswirkungen von Tolvaptan auf AHF zusammen, das keine Verbesserung in Kurzzeit- und Langzeitmortalität, Hospitalisationsdauer und reduzierter Häufigkeit einer Verschlimmerung der Herzinsuffizienz („worsening heart failure“, WHF) zeigen konnte. Ähnliche Ergebnisse wurden auch in anderen AHF-Studien berichtet, wie z.xa0B. der ACENT-HF- und der RELAX-AHF-2-Studie. In Anbetracht dieser nicht eindeutigen Studienlage stellt die Verbesserung der Prognose von AHF-Patienten offensichtlich einen unerfüllten medizinischen Bedarf dar. Zukünftige Bemühungen sollten auf den Schutz vor Organschäden, die individuelle Behandlung, den Nutzen für die Patienten sowie standardisierte Management-Programme fokussieren, einschließlich der sofortigen Identifizierung und des Managements eines kardiogenen Schocks sowie der Einrichtung von Herzinsuffizienz-Netzwerken für ein engmaschiges Monitoring von AHF-Patienten.