Extracellular cardiac matrix biomarkers in patients with reduced ejection fraction heart failure as predictors of response to cardiac resynchronisation therapy: a systematic review

Abstract

ObjectiveCardiac resynchronisation therapy (CRT) is an effective therapy for selected patients with heart failure (HF); however, a significant non-response rate exists. We examined current evidence on extracellular cardiac matrix (ECM) biomarkers in predicting response following CRT.MethodsComplete literature review of PubMed, Ovid SP MEDLINE, Cochrane Library and TRIP, reference lists, international cardiology conferences and ongoing studies between December 1999 and December 2015 conducted according to prospectively registered study selection and analysis criteria (PROSPERO:CRD42016025864) was performed. All observational and randomised control trials (RCT) were included if they tested prespecified ECM biomarkers’ ability to predict CRT response. Risk of bias assessment and data extraction determined pooling of included studies was not feasible due to heterogeneity of the selected studies.ResultsA total of 217 studies were screened; six (five prospective cohort and one RCT substudy) were included in analysis with 415 participants in total. Study sizes varied (n=55–260), cohort characteristics contrasted (male: 67.8%–83.6%, ischaemic aetiology: 40.2%–70.3%) and CRT response definitions differed (three clinical/functional, three echocardiographic). Consistent observation in all ECM biomarker behaviour before and after CRT implantation was not observed between studies. Lower type I and type III collagen synthesis biomarkers (N-terminal propeptides of type I and III procollagens) expression demonstrated replicated ability to predict reverse left ventricular remodelling.ConclusionCollagen synthesis biomarkers offer the most potential as ECM biomarkers for predicting CRT response. Heterogeneity between these studies was large and limited the ability to pool and compare results numerically. Use of different response definitions was one of the biggest challenges.

Characterisation of circulating biomarkers before and after cardiac resynchronisation therapy and their role in predicting CRT response: the COVERT-HF study

“… 3 Over the last decade, specific ECM biomarkers have been associated with poor HF outcomes 2 and to predict response to CRT. 4 Alteration in collagen synthesis and deposition, demonstrated by PINP/PICP for type I and PIIINP for type III, have been observed to predict response in several observational studies for functional and echocardiographic criteria. The exact behaviour and significance of collagen turnover have not been consistently replicated, 4 principally due to variation in response definitions.…”

“… 4 Alteration in collagen synthesis and deposition, demonstrated by PINP/PICP for type I and PIIINP for type III, have been observed to predict response in several observational studies for functional and echocardiographic criteria. The exact behaviour and significance of collagen turnover have not been consistently replicated, 4 principally due to variation in response definitions. No biomarkers in our study predicted response; CTx trended towards predicting response but did not reach significance.…”

“…As key regulators of ECM turnover, matrix metalloproteinases (MMP-2 and MMP-9) have been implicated as biomarkers of HF diagnosis and prognosis. 4 Growth Differentiation Factor-15 (GDF-15) is a member of the transforming growth factor-β cytokine superfamily involved in regulation of cell survival, proliferation and differentiation that is associated with poor HF outcomes and has been suggested as a predictor of CRT response. 5 …”

“…Markers of collagen turnover have previously been studied to establish their value as predictors of CRT response, but outcomes have thus far been inconsistent; 4 miRNAs are novel biomarkers with variation reported in HFrEF, 6 but limited information is available on their ability to predict CRT response. 7 9 Our aim was to characterise biomarkers of ECM remodelling and established dysregulated miRNAs before and after CRT to assess whether they predict CRT response and survival.…”

Multimarker approach for assessing efficiency of cardiac resynchronization therapy in patients with sinus rhythm

“…Установлена связь увеличения концентрации MMP-9, TIMP-1 [19,20] с тяжестью ХСН. Имеющаяся информация относительно их прогностической полезности при ХСН и СРТ, является спорной [21]. В одних исследованиях не было отмечено динамики уровня ММР-9, TIMP-1на фоне СРТ [22], в других было выявлено их значимое снижение [23].…”