Abstract
Aims
Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM). We aim to study clinical parameters and long-term outcomes related to the TTNtv ...genotype and determine the related molecular changes at tissue level in TTNtv DCM patients.
Methods and results
A total of 303 consecutive and extensively phenotyped DCM patients (including cardiac imaging, Holter monitoring, and endomyocardial biopsy) underwent DNA sequencing of 47 cardiomyopathy-associated genes including TTN, yielding 38 TTNtv positive (13%) patients. At long-term follow-up (median of 45 months, up to 12 years), TTNtv DCM patients had increased ventricular arrhythmias compared to other DCM, but a similar survival. Arrhythmias are especially prominent in TTNtv patients with an additional environmental trigger (i.e. virus infection, cardiac inflammation, systemic disease, toxic exposure). Importantly, cardiac mass is reduced in TTNtv patients, despite similar cardiac function and dimensions at cardiac magnetic resonance. These enhanced life-threatening arrhythmias and decreased cardiac mass in TTNtv DCM patients go along with significant cardiac energetic and matrix alterations. All components of the mitochondrial electron transport chain are significantly upregulated in TTNtv hearts at RNA-sequencing. Also, interstitial fibrosis was augmented in TTNtv patients at histological and transcript level.
Conclusion
Truncating titin variants lead to pronounced cardiac alterations in mitochondrial function, with increased interstitial fibrosis and reduced hypertrophy. Those structural and metabolic alterations in TTNtv hearts go along with increased ventricular arrhythmias at long-term follow-up, with a similar survival and overall cardiac function.
Severe hypertension can induce thrombotic microangiopathy (TMA) in the renal vasculature, the occurrence of which has been linked to mechanical stress to the endothelium. Complement defects may be ...the culprit of disease in patients who present with severe renal disease and often progress to ESRD, despite BP control.
We studied a well defined cohort of 17 patients with hypertension-associated TMA to define the prevalence of complement defects by a specific
serum-based microvascular endothelial cell assay.
Compared with normal human serum and samples from patients with hypertensive arterionephrosclerosis, 14 of 16 (87.5%) serum samples collected at presentation from 16 patients with hypertension-associated TMA induced abnormal C5b9 formation on microvascular endothelial cells. We detected rare variants in complement genes in eight of 17 (47%) patients. ESRD occurred in 14 of 17 (82%) patients, and recurrent TMA after transplant occurred in seven of 11 (64%) donor kidneys. Eculizumab improved the renal function in three patients and prevented TMA recurrence in an allograft recipient.
These observations point to complement defects as the key causative factor of ESRD and recurrent TMA after transplant in patients presenting with severe hypertension. Complement defects can be identified by measurements of complement activation on microvascular endothelial cells, which should substantially influence treatment and prognosis.
The natural course of idiopathic membranous nephropathy (MN) varies, as it is known through favorable outcomes in most patients. However, one third of patients with idiopathic MN will slowly progress ...to end-stage renal disease (ESRD). To prevent disease progression, patients at high risk to develop ESRD are treated with immunosuppressive agents. Therefore, a correct selection of patients who need immunosuppressive treatment is important.
Here, we evaluated the prognostic value of anti-phospholipase A2 receptor 1 antibody (anti-PLA2R) levels regarding clinical outcome in a well-defined cohort of 73 PLA2R-related MN patients with long-term follow-up. At baseline, patients were subdivided into patients with either low or high antibody levels based on ELISA testing.
Spontaneous remission rates were highest among patients with low anti-PLA2R levels (79%; hazard ratio 2.72 (95% CI 1.22-6.08), p = 0.02) after a median follow-up of 2.9 (95% CI 0.8-5.0, p < 0.001) years, whereas high anti-PLA2R levels were associated with persistent proteinuria (p = 0.04) and/or the need for immunosuppressive therapy (p < 0.001). Renal survival rates were 97% at 5 years, 93% at 10 years, and 89% at 15 years; however, this was not different between the anti-PLA2R groups. ESRD occurred significantly faster in patients with severe proteinuria as compared to patients with either mild (p = 0.02) or moderate proteinuria (p = 0.05).
Low anti-PLA2R levels may predict spontaneous remissions in patients with PLA2R-related MN. Therefore, we suggest that quantification of anti-PLA2R is of value to monitor these patients.
Aims
Previous uncontrolled studies suggested a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)‐related dilated cardiomyopathy (DCM). This randomized, double‐blind, ...placebo‐controlled, single‐centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence.
Methods and results
Fifty patients (39 men; mean age 54 ± 11 years) with idiopathic chronic (>6 months) DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200 copies/µg DNA were blindly randomized to either IVIg (n = 26, 2 g/kg over 4 days) or placebo (n = 24). The primary outcome was change in LVEF at 6 months after randomization. Secondary outcomes were change in functional capacity assessed by 6‐min walk test (6MWT), quality of life Minnesota Living with Heart Failure Questionnaire (MLHFQ), left ventricular end‐diastolic volume (LVEDV), and EMB B19V load at 6 months after randomization. LVEF significantly improved in both IVIg and placebo groups (absolute mean increase 5 ± 9%, P = 0.011 and 6 ± 10%, P = 0.008, respectively), without a significant difference between groups (P = 0.609). Additionally, change in 6MWT median (interquartile range) IVIg 36 (13;82) vs. placebo 32 (5;80) m; P = 0.573, MLHFQ IVIg 0 (−7;5) vs. placebo −2 (−6;6), P = 0.904 and LVEDV (IVIg −16 ± 49 mL/m2 vs. placebo −29 ± 40 mL/m2; P = 0.334) did not significantly differ between groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups.
Conclusion
Intravenous immunoglobulin therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence.
Clinical Trial Registration: ClinicalTrials.gov ID NCT00892112.
No additional benefit of intravenous immunoglobulin (IVIg) therapy on cardiac systolic function in patients with idiopathic chronic dilated cardiomyopathy (DCM) and cardiac parvovirus B19 (B19V) persistence. EMB, endomyocardial biopsy; LVEF, left ventricular ejection fraction.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Macrophages are key players in the immunopathology of anti-neutrophil cytoplasmic antibody (ANCA) mediated-vasculitis (AAV) with glomerulonephritis (ANCA GN). Different macrophage phenotypes are ...expected to play distinct roles in ANCA GN. Macrophages expressing CD163 and CD206 are found in lesions associated with ANCA GN. Hence, we aimed to investigate the clinicopathological significance of CD206 and CD163 in ANCA GN in a multicenter retrospective cohort study.
Patients with ANCA-associated vasculitis, with clinical data, serum and urine samples were included from three cohorts. Serum soluble CD206 (ssCD206) and urinary soluble CD163 (usCD163) levels were measured. Human kidney tissue samples (n = 53) were stained for CD206 and CD163 using immunohistochemistry and immunofluorescence, and findings were correlated with clinical and pathological data.
In total, 210 patients were included (i.e., ANCA GN, n = 134; AAV without GN, n = 24; AAV in remission n = 52). Increased levels of both ssCD206 and usCD163 were seen in ANCA GN. High levels of ssCD206 declined after reaching remission, however, ssCD206 did not improve the accuracy of usCD163 to detect ANCA GN. Soluble markers correlated with histopathological findings. CD163+CD206- macrophages were found in the glomerulus and may play pivotal roles in glomerulonephritis, whereas CD206+CD163- and CD206+CD163+ macrophages were located tubulointerstitially and likely play a more prominent role in ANCA-associated tubulointerstitial inflammation. In ANCA GN patients increasing levels of ssCD206 increased the risk for end-stage renal disease and mortality.
Our results confirm and extend the notion that CD206+ and CD163+ macrophages are prominent components of the cellular infiltrate in ANCA GN. We found distinct macrophage phenotypes that may play distinct roles in the immunopathology of ANCA GN and elaborate on a potential mechanism underlying the findings of this study. usCD163 remains an excellent marker to detect active ANCA GN, whereas ssCD206 seems a more prominent marker for risk prediction.
•Distinct macrophage subsets can be found in biopsies of ANCA GN patients.•Distinct macrophage subsets correlate with histopathology and soluble markers.•Macrophage subsets can help assess treatment response & risk stratification in ANCA.•UsCD163 reflects ANCA GN activity.•SsCD206 can be useful for treatment response, prognosis for ESKD and death in ANCA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thrombotic microangiopathy (TMA) is a pattern of endothelial damage that can be found in association with diverse clinical conditions such as malignant hypertension. Although the pathophysiological ...mechanisms differ, accumulating evidence links complement dysregulation to various TMA syndromes and in particular the atypical hemolytic uremic syndrome. Here, we evaluated the role of complement in nine consecutive patients with biopsy-proven renal TMA attributed to severe hypertension. Profound hematologic symptoms of TMA were uncommon. In six out of nine patients, we found mutations C3 in three, CFI in one, CD46 in one, and/or CFH in two patients either with or without the risk CFH-H3 haplotype in four patients. Elevated levels of the soluble C5b-9 and renal deposits of C3c and C5b-9 along the vasculature and/or glomerular capillary wall, confirmed complement activation in vivo. In contrast to patients without genetic defects, patients with complement defects invariably progressed to end-stage renal disease, and disease recurrence after kidney transplantation seems common. Thus, a subset of patients with hypertension-associated TMA falls within the spectrum of complement-mediated TMA, the prognosis of which is poor. Hence, testing for genetic complement abnormalities is warranted in patients with severe hypertension and TMA on renal biopsy to adopt suitable treatment options and prophylactic measures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Collagen cross-linking is a fundamental process in dilated cardiomyopathy (DCM) and occurs when collagen deposition exceeds degradation, leading to impaired prognosis. This study ...investigated the associations of collagen-metabolism biomarkers with left ventricular function and prognosis in DCM. Methods: DCM patients who underwent endomyocardial biopsy, blood sampling, and cardiac MRI were included. The primary endpoint included death, heart failure hospitalization, or life-threatening arrhythmias, with a follow-up of 6 years (5–8). Results: In total, 209 DCM patients were included (aged 54 ± 13 years, 65% male). No associations were observed between collagen volume fraction, circulating carboxy-terminal propeptide of procollagen type-I (PICP), or collagen type I carboxy-terminal telopeptide CITP and matrix metalloproteinase MMP-1 ratio and cardiac function parameters. However, CITP:MMP-1 was significantly correlated with global longitudinal strain (GLS) in the total study sample (R = −0.40, p < 0.0001; lower CITP:MMP-1 ratio was associated with impaired GLS), with even stronger correlations in patients with LVEF > 40% (R = −0.70, p < 0.0001). Forty-seven (22%) patients reached the primary endpoint. Higher MMP-1 levels were associated with a worse outcome, even after adjustment for clinical and imaging predictors (1.026, 95% CI 1.002–1.051, p = 0.037), but CITP and CITP:MMP-1 were not. Combining MMP-1 and PICP improved the goodness-of-fit (LHR36.67, p = 0.004). Conclusion: The degree of myocardial cross-linking (CITP:MMP-1) is associated with myocardial longitudinal contraction, and MMP-1 is an independent predictor of outcome in DCM patients.
Aims
To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients.
Methods and results
We quantified fibrosis in 209 DCM patients at three levels: ...(i) non‐invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers amino‐terminal propeptide of procollagen type III (PIIINP) and carboxy‐terminal propeptide of procollagen type I (PICP), (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life‐threatening arrhythmias, after adjusting for known clinical predictors adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90–6.60; P < 0.001 and PICP 1.02, 95% CI 1.01–1.03; P = 0.001. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log‐rank P < 0.001). RNA‐sequencing and gene enrichment analysis of EMB showed an increased expression of pro‐fibrotic and pro‐inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE‐/PICP‐). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles.
Conclusion
The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro‐fibrotic and pro‐inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP.
Multilevel assessment of myocardial fibrosis demonstrates significant correlations between histology, non‐invasive imaging, and blood markers. A combined multi‐parametric approach with carboxy‐terminal propeptide of procollagen type I (PICP) and late gadolinium enhancement (LGE) allows the best risk stratification of idiopathic dilated cardiomyopathy (DCM) patients, accompanied with a profile of high expression of combined pro‐inflammatory and pro‐fibrotic genes, indicating a potential marker for disease activity.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Identification of p53-positive cells by immunohistochemistry in bone marrow from primary myelodysplastic syndrome patients correlates with the presence of TP53 mutations and poor prognosis. Mutations ...in the tumor suppressor gene TP53 are more frequent in therapy-related acute myeloid leukemia and myelodysplastic syndrome than in de novo disease, but the role of p53 immunohistochemistry in the therapy-related setting has not been specifically investigated. We studied p53 protein immunoreactivity in bone marrow biopsies of therapy-related myeloid neoplasms and correlated protein expression with TP53 mutation status, clinicopathologic features and outcome. We first studied 32 patients with therapy-related acute myeloid leukemia and 63 patients with therapy-related myelodysplastic syndrome/chronic myelomonocytic leukemia from one institution and then validated our results in a separate group of 32 patients with therapy-related acute myeloid leukemia and 56 patients with therapy-related myelodysplastic syndrome from a different institution. Strong p53 immunostaining in ≥1% of bone marrow cells was highly predictive of a TP53 gene mutation (P<0.0001) and was strongly associated with a high-risk karyotype (P<0.0001). The presence of ≥1% p53 strongly positive cells was associated with poorer overall and disease-specific survival, particularly in the subset of patients treated with stem-cell transplantation. In a multivariable Cox regression model, the presence of ≥1% p53 strongly expressing cells was an independent prognostic marker for overall survival in both cohorts, with hazard ratios of 3.434 (CI: 1.751-6.735, P<0.0001) and 3.156 (CI: 1.502-6.628, P=0.002). Our data indicate that p53 protein expression, evaluated in bone marrow biopsies by a widely available immunohistochemical method, prognostically stratifies patients with therapy-related myeloid neoplasms independent of other risk factors. p53 immunostaining thus represents an easily applicable method to assess risk in therapy-related acute myeloid leukemia/myelodysplastic syndrome patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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