Exercise and myocardial injury in hypertrophic cardiomyopathy

Objective: Troponin and high signal intensity on T2-weighted (HighT2) cardiovascular magnetic resonance imaging (CMRi) are both markers of myocardial injury in hypertrophic cardiomyopathy (HCM). The interplay between exercise and disease development remains uncertain in HCM. We sought to assess the occurrence of postexercise troponin rises and its determinants. Methods: Multicentre project on patients with HCM and mutation carriers without hypertrophy (controls). Participants performed a symptom limited bicycle test with hs-cTnT assessment pre-exercise and 6 hours postexercise. Pre-exercise CMRi was performed in patients with HCM to assess measures of hypertrophy and myocardial injury. Depending on baseline troponin (13 ng/L), a rise was defined as a >50% or >20% increase, respectively. Results: Troponin rises occurred in 18% (23/127) of patients with HCM and 4% (2/53) in mutation carriers (p=0.01). Comparing patients with HCM with and without a postexercise troponin rise, maximum heart rates (157±19 vs 143±23, p=0.004) and maximal wall thickness (20 mm vs 17 mm, p=0.023) were higher in the former, as was the presence of late gadolinium enhancement (85% vs 57%, p=0.02). HighT2 was seen in 65% (13/20) and 19% (15/79), respectively (p<0.001). HighT2 was the only independent predictor of troponin rise (adjusted odds ratio 7.9; 95% CI 2.7 to 23.3; p<0.001). Conclusions: Postexercise troponin rises were seen in about 20% of patients with HCM, almost five times more frequent than in mutation carriers. HighT2 on CMRi may identify a group of particularly vulnerable patients, supporting the concept that HighT2 reflects an active disease state, prone to additional injury after a short episode of high oxygen demand

Clinical characteristics of women captured by extending the definition of severe postpartum haemorrhage with 'refractoriness to treatment': a cohort study

Background: The absence of a uniform and clinically relevant definition of severe postpartum haemorrhage hampers comparative studies and optimization of clinical management. The concept of persistent postpartum haemorrhage, based on refractoriness to initial first-line treatment, was proposed as an alternative to common definitions that are either based on estimations of blood loss or transfused units of packed red blood cells (RBC). We compared characteristics and outcomes of women with severe postpartum haemorrhage captured by these three types of definitions. Methods: In this large retrospective cohort study in 61 hospitals in the Netherlands we included 1391 consecutive women with postpartum haemorrhage who received either ≥4 units of RBC or a multicomponent transfusion. Clinical characteristics and outcomes of women with severe postpartum haemorrhage defined as persistent postpartum haemorrhage were compared to definitions based on estimated blood loss or transfused units of RBC within 24 h following birth. Adverse maternal outcome was a composite of maternal mortality, hysterectomy, arterial embolisation and intensive care unit admission. Results: One thousand two hundred sixty out of 1391 women (90.6%) with postpartum haemorrhage fulfilled the definition of persistent postpartum haemorrhage. The majority, 820/1260 (65.1%), fulfilled this definition within 1 h following birth, compared to 819/1391 (58.7%) applying the definition of ≥1 L blood loss and 37/845 (4.4%) applying the definition of ≥4 units of RBC. The definition persistent postpartum haemorrhage captured 430/471 adverse maternal outcomes (91.3%), compared to 471/471 (100%) for ≥1 L blood loss and 383/471 (81.3%) for ≥4 units of RBC. Persistent postpartum haemorrhage did not capture all adverse outcomes because of missing data on timing of initial, first-line treatment. Conclusion: The definition persistent postpartum haemo

Clinical significance of soluble interleukin-2 receptor measurement in patients with idiopathic retroperitoneal fibrosis

Background Idiopathic retroperitoneal fibrosis (iRPF) is a rare chronic fibro-inflammatory disorder of unknown etiology. Activated T-helper cells, which shed soluble interleukin-2 receptor (sIL-2R) into the circulation, may play a pathogenetic role. Hence, measuring sIL-2R may be of value in monitoring disease activity and treatment response in iRPF patients. Methods We performed a prospective inception cohort study of 82 patients with untreated (re)active iRPF stratified by elevated (> 623 U/mL) or normal sIL-2R level at baseline and compared disease characteristics among these groups. Baseline and changes in sIL-2R levels following treatment with tamoxifen (TMX) or prednisone (PDN) were analyzed and related to treatment response. Results Median sIL-2R level was 668 U/mL (IQR 502.8-827.5); 48 patients (59%) had elevated baseline sIL-2R levels. Patients with elevated sIL-2R presented with higher CRP (P = 0.049) and serum creatinine (sCr) levels (P < 0.001) and more often had hydroureteronephrosis (P = 0.01). There was an age and sex adjusted linear association between baseline sIL-2R and both CRP (P = 0.02) and sCr (P < 0.001). Baseline and serial levels of sIL-2R were predictive and concordant, respectively, with clinical response in patients treated with PDN. ROC curve analyses of sIL-2R on a continuous scale and PDN treatment success showed an AUC of 0.84. A serum sIL-2R cut-off value for PDN treatment success of <= 703 U/mL was found with a sensitivity of 100% and specificity of 72%. Conclusion Serial measurement of sIL-2R may be of value in monitoring disease activity and PDN treatment response in iRPF patients.Personalised Therapeutic

The heterogeneous nuclear ribonucleoproteins I and K interact with a subset of the ro ribonucleoprotein-associated Y RNAs in vitro and in vivo.

The hY RNAs are a group of four small cytoplasmic RNAs of unknown function that are stably associated with at least two proteins, Ro60 and La, to form Ro ribonucleoprotein complexes. Here we show that the heterogeneous nuclear ribonucleoproteins (hnRNP) I and K are able to associate with a subset of hY RNAs in vitro and demonstrate these interactions to occur also in vivo in a yeast three-hybrid system. Experiments performed in vitro and in vivo with deletion mutants of hY1 RNA revealed its pyrimidine-rich central loop to be involved in interactions with both hnRNP I and K and clearly showed their binding sites to be different from the Ro60 binding site. Both hY1 and hY3 RNAs coprecipitated with hnRNP I in immunoprecipitation experiments performed with HeLa S100 extracts and cell extracts from COS-1 cells transiently transfected with VSV-G-tagged hnRNP-I, respectively. Furthermore, both anti-Ro60 and anti-La antibodies coprecipitated hnRNP I, whereas coprecipitation of hnRNP K was not observed. Taken together, these data strongly suggest that hnRNP I is a stable component of a subpopulation of Ro RNPs, whereas hnRNP K may be transiently bound or interact only with (rare) Y RNAs that are devoid of Ro60 and La. Given that functions related to translation regulation have been assigned to both proteins and also to La, our findings may provide novel clues toward understanding the role of Y RNAs and their respective RNP complexes

The human La (SS-B) autoantigen interacts with DDX15/hPrp43, a putative DEAH-box RNA helicase

The human La (SS-B) autoantigen is an abundantly expressed putative RNA chaperone, functioning in various intracellular processes involving RNA. To further explore the molecular mechanisms by which La functions in these processes, we performed large-scale immunoprecipitations of La from HeLa S100 extracts using the anti-La monoclonal antibody SW5. La-associated proteins were subsequently identified by sequence analysis. This approach allowed the identification of DDX15 as a protein interacting with La. DDX15, the human ortholog of yeast Prp43, is a member of the superfamily of DEAH-box RNA helicases that appeared to interact with La both in vivo and in vitro. The region needed for the interaction with La partly overlaps the DEAH-box domain of DDX15. Immunofluorescence data indicated that endogenous DDX15 accumulates in U snRNP containing nuclear speckles in HEp-2 cells. Surprisingly DDX15 also accumulates in the nucleoli of HEp-2 cells. Moreover, DDX15 and La seem to colocalize in the nucleoli. Regions of DDX15 involved in nuclear, nuclear speckle, and nucleolar localization are located within the N- and C-terminal regions flanking the DEAH-box. RNA coprecipitation experiments indicated that DDX15 is associated with spliceosomal U small nuclear RNAs in HeLa cell extracts. The possible functional implications of the interaction between La and DDX15 are discussed

High T2-weighted signal intensity is associated with elevated troponin T in hypertrophic cardiomyopathy

OBJECTIVE: Areas of high signal intensity (HighT2) on T2-weighted cardiovascular magnetic resonance (CMR) imaging have been demonstrated in hypertrophic cardiomyopathy (HCM). It has been hypothesised that HighT2 may indicate active tissue injury in HCM. In this context, we studied HighT2 in relation to cardiac troponin. METHODS: Outpatient HCM patients without a history of coronary artery disease underwent CMR imaging at 1.5 T using T2-weighted, cine and late gadolinium enhancement (LGE) imaging to assess HighT2, left ventricular (LV) function, LV mass and the presence and extent of LGE. Highly sensitive cardiac troponin T (hs-cTnT) was assessed as a marker of injury, with hs-cTnT >/=14 and >3 ng/L defined as an elevated and detectable troponin. RESULTS: HighT2 was present in 28% of patients (28/101). An elevated hs-cTnT was present in 54% of patients with HighT2 (15/28) compared with 14% of patients without HighT2 (10/73) (p<0.001). Hs-cTnT was detectable in 96% of patients with HighT2 (27/28) compared with 66% of patients without HighT2 (48/73) (p=0.002). In case of an undetectable hs-cTnT, HighT2 was only seen in 4% (1/26). In addition, the extent of HighT2 was related with increasing hs-cTnT concentrations (Spearman's rho: 0.42, p<0.001). CONCLUSIONS: In this CMR study of patients with HCM, we observed HighT2 in a quarter of patients, and demonstrated that HighT2 was associated with an elevated hs-cTnT. This observation, combined with the very high negative predictive value of an undetectable hs-cTnT for HighT2, provides supportive evidence for the hypothesis that HighT2 is indicative of recently sustained myocyte injury

Relation of highly sensitive cardiac troponin T in hypertrophic cardiomyopathy to left ventricular mass and cardiovascular risk

Contains fulltext : 133874.pdf (publisher's version ) (Closed access)Elevated cardiac troponin can be seen in patients with left ventricular (LV) hypertrophy and in asymptomatic subjects with a high a priori risk of cardiovascular disease (CVD). In hypertrophic cardiomyopathy (HC) troponin can be detected as well, but little is known about the contribution of LV mass, on the one hand, and the long-term risk of CVD, on the other. In an observational single-center study of 62 patients with HC, without a history of CVD, we assessed the Framingham Heart 10-year risk score (FH10yrs), LV mass index (LVMI) using magnetic resonance imaging, and highly sensitive cardiac troponin T (hs-cTnT). Hs-cTnT (>3 ng/L) was detectable in 74% of patients (46 of 62). Hs-cTnT was elevated in 26% (16 of 62) of patients (ninety-ninth percentile reference limit of 14 ng/L or more). From 3 to 14 ng/L, patients were older, more often had hypertension, and the FH10yrs was higher. Hs-cTnT correlated positively with LVMI (p <0.001) and maximal wall thickness (p <0.001). In addition, LVMI and hypertension were independently associated with increasing hs-cTnT concentrations in linear regression. Using multivariate binary logistic regression, both LVMI and FH10yrs were independently associated with detectable hs-cTnT levels. In contrast, only LVMI was associated with elevated hs-cTnT levels. In conclusion, hs-cTnT was detectable in 3 quarters and elevated in a quarter of our patients with HC. Although detectable hs-cTnT is associated with both LV mass and CVD risk, elevated hs-cTnT relates to LV mass only. This indicates that hypertrophy more than the risk of CVD seems the most important drive for hs-cTnT to occur in these patients

Exercise and myocardial injury in hypertrophic cardiomyopathy

Objective: Troponin and high signal intensity on T2-weighted (HighT2) cardiovascular magnetic resonance imaging (CMRi) are both markers of myocardial injury in hypertrophic cardiomyopathy (HCM). The interplay between exercise and disease development remains uncertain in HCM. We sought to assess the occurrence of postexercise troponin rises and its determinants. Methods: Multicentre project on patients with HCM and mutation carriers without hypertrophy (controls). Participants performed a symptom limited bicycle test with hs-cTnT assessment pre-exercise and 6 hours postexercise. Pre-exercise CMRi was performed in patients with HCM to assess measures of hypertrophy and myocardial injury. Depending on baseline troponin (13 ng/L), a rise was defined as a >50% or >20% increase, respectively. Results: Troponin rises occurred in 18% (23/127) of patients with HCM and 4% (2/53) in mutation carriers (p=0.01). Comparing patients with HCM with and without a postexercise troponin rise, maximum heart rates (157±19 vs 143±23, p=0.004) and maximal wall thickness (20 mm vs 17 mm, p=0.023) were higher in the former, as was the presence of late gadolinium enhancement (85% vs 57%, p=0.02). HighT2 was seen in 65% (13/20) and 19% (15/79), respectively (p<0.001). HighT2 was the only independent predictor of troponin rise (adjusted odds ratio 7.9; 95% CI 2.7 to 23.3; p<0.001). Conclusions: Postexercise troponin rises were seen in about 20% of patients with HCM, almost five times more frequent than in mutation carriers. HighT2 on CMRi may identify a group of particularly vulnerable patients, supporting the concept that HighT2 reflects an active disease state, prone to additional injury after a short episode of high oxygen demand

Prediction of Extensive Myocardial Fibrosis in Nonhigh Risk Patients With Hypertrophic Cardiomyopathy

Contains fulltext : 196255.pdf (publisher's version ) (Open Access)In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGEext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGEext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGEext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGEext, that is, LGE >/=15% of the left ventricular mass. LGEext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGEext, in addition to the improved clinical model of diagnostic accuracy (p=0.04). A biomarker-only strategy allowed the exclusion of LGEext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff (Youden index; 8 ng/L-sensitivity 100%, specificity 54%). In conclusion, in this nonhigh risk HC cohort, the pretest likelihood of LGEext can be altered using clinical variables and the addition of hs-cTnT. The promising findings with the use of hs-cTnT only call for new initiatives to study its impact on efficacious CMR imaging in a larger HC population, either with or without additional use of clinical variables

High T2-weighted signal intensity for risk prediction of sudden cardiac death in hypertrophic cardiomyopathy

In search of improved risk stratification in hypertrophic cardiomyopathy (HCM), CMR imaging has been implicated as a potential tool for prediction of sudden cardiac death (SCD). In follow-up of the promising results with extensive late gadolinium enhancement (LGE), high signal-intensity on T2-weighted imaging (HighT2) has become subject of interest given its association with markers of adverse disease progression, such as LGE, elevated troponin and non-sustained ventricular tachycardia. In lack of follow-up cohorts, we initiated an exploratory study on the association between HighT2 and the internationally defined risk categories of SCD. In a cohort of 109 HCM patients from a multicenter study on CMR imaging and biomarkers, we estimated the 5-year SCD risk (HCM Risk-SCD model). Patients were categorized as low (< 4%), intermediate (≥ 4–<6%) or high (≥ 6%) risk. In addition, risk categorization according to the ACC/AHA guidelines was performed. HighT2 was present in 27% (29/109). Patients with HighT2 were more often at an intermediate-high risk of SCD according to the European (28 vs. 10%, p = .032) and American guidelines (41 vs. 18%, p = .010) compared to those without HighT2. The estimated 5-year SCD risk of our cohort was 1.9% (IQR 1.3–2.9%), and projected SCD rates were higher in patients with than without HighT2 (2.8 vs. 1.8%, p = .002). In conclusion, HCM patients with HighT2 were more likely to be intermediate-high risk, with projected SCD rates that were 1.5 fold higher than in patients without HighT2. These pilot findings call for corroborative studies with more intermediate-high risk HCM patients and clinical fo