The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be ...used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 .
Abstract Myocarditis, i.e. inflammation of the myocardium, is one of the leading causes of sudden cardiac death (SCD) and dilated cardiomyopathy (DCM) in young adults, and is an important cause of ...symptoms such as chest pain, dyspnea and palpitations. The pathophysiological process of disease progression leading to DCM involves an ongoing inflammation as a result of a viral-induced auto-immune response or a persisting viral infection. It is therefore crucial to detect the disease early in its course and prevent persisting inflammation that may lead to DCM and end-stage heart failure. Because of the highly variable clinical presentation, ranging from mild symptoms to severe heart failure, and the limited available diagnostic tools, the evaluation of patients with suspected myocarditis represents an important clinical dilemma in cardiology. New approaches for the diagnosis of myocarditis are needed in order to improve recognition, to help unravel its pathophysiology, and to develop new therapeutic strategies to treat the disease. In this review, we give a comprehensive overview of the current diagnostic strategies for patients with suspected myocarditis, and demonstrate several new techniques that may help to improve the diagnostic work-up.
Background Late gadolinium enhancement and left ventricular (LV) ejection fraction on cardiovascular magnetic resonance (CMR) are prognostic markers, but their predictive value for incident heart ...failure or life‐threatening arrhythmias in acute myocarditis patients is limited. CMR‐derived feature tracking provides a more sensitive analysis of myocardial function and may improve risk stratification in myocarditis. In this study, the prognostic value of LV, right ventricular, and left atrial strain in acute myocarditis patients is evaluated. Methods and Results In this multicenter retrospective study, patients with CMR‐proven acute myocarditis were included. The primary end point was occurrence of major adverse cardiovascular events: all‐cause mortality, heart transplantation, heart failure hospitalizations, and life threatening arrhythmias. LV global longitudinal strain, global circumferential strain and global radial strain, right ventricular‐global longitudinal strain and left atrial strain were measured. Unadjusted and adjusted cox proportional hazard regression analysis were performed. In total, 162 CMR‐proven myocarditis patients were included (41 ± 17 years, 75% men). Mean LV ejection fraction was 51 ± 12%, and 144 (89%) patients had presence of late gadolinium enhancement. Major adverse cardiovascular events occurred in 29 (18%) patients during a follow‐up of 5.5 (2.2–8.3) years. All LV strain parameters were independent predictors of outcome beyond clinical features, LV ejection fraction and late gadolinium enhancement (LV‐global longitudinal strain: hazard ratio HR 1.07, P =0.02; LV‐global circumferential strain: HR 1.15, P =0.02; LV‐global radial strain: HR 0.98, P =0.03), but right ventricular or left atrial strain did not predict outcome. Conclusions CMR‐derived LV strain analysis provides independent prognostic value on top of clinical parameters, LV ejection fraction and late gadolinium enhancement in acute myocarditis patients, while left atrial and right ventricular strain seem to be of less importance.
Background Remodeling biomarkers carry high potential for predicting adverse events in chronic heart failure ( CHF ) patients. However, temporal patterns during the course of CHF , and especially the ...trajectory before an adverse event, are unknown. We studied the prognostic value of temporal patterns of 14 cardiac remodeling biomarker candidates in stable patients with CHF from the Bio‐SHiFT (Serial Biomarker Measurements and New Echocardiographic Techniques in Chronic Heart Failure Patients Result in Tailored Prediction of Prognosis) study. Methods and Results In 263 CHF patients, we performed trimonthly blood sampling during a median follow‐up of 2.2 years. For the analysis, we selected all baseline samples, the 2 samples closest to the primary end point ( PE ), or the last sample available for end point–free patients. Thus, in 567 samples, we measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2, 3, and 9, tissue inhibitor metalloproteinase‐4, perlecan, aminopeptidase‐N, caspase‐3, cathepsin‐D, cathepsin‐Z, and cystatin‐B. The PE was a composite of cardiovascular mortality, heart transplantation, left ventricular assist device implantation, and HF hospitalization. Associations between repeatedly measured biomarker candidates and the PE were investigated by joint modeling. Median age was 68 (interquartile range: 59–76) years with 72% men; 70 patients reached the PE . Repeatedly measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2 and 9, tissue inhibitor metalloproteinase‐4, perlecan, cathepsin‐D, and cystatin‐B levels were significantly associated with the PE , and increased as the PE approached. The slopes of biomarker trajectories were also predictors of clinical outcome, independent of their absolute level. Associations persisted after adjustment for clinical characteristics and pharmacological treatment. Suppression of tumorigenicity‐2 was the strongest predictor (hazard ratio: 7.55 per SD difference, 95% CI : 5.53–10.30), followed by growth differentiation factor‐15 (4.06, 2.98–5.54) and matrix metalloproteinase‐2 (3.59, 2.55–5.05). Conclusions Temporal patterns of remodeling biomarker candidates predict adverse clinical outcomes in CHF . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01851538.
Background Hypertrophic cardiomyopathy is caused by pathogenic sarcomere gene variants. Individuals with a thin-filament variant present with milder hypertrophy than carriers of thick-filament ...variants, although prognosis is poorer. Herein, we defined if decreased energetic status of the heart is an early pathomechanism in
(troponin T gene) variant carriers. Methods and Results Fourteen individuals with
variants (genotype positive), without left ventricular hypertrophy (G+/LVH-; n=6) and with LVH (G+/LVH+; n=8) and 14 healthy controls were included. All participants underwent cardiac magnetic resonance and
C-acetate positron emission tomography imaging to assess LV myocardial oxygen consumption, contractile parameters and myocardial external efficiency. Cardiac efficiency was significantly reduced compared with controls in G+/LVH- and G+/LVH+. Lower myocardial external efficiency in G+/LVH- is explained by higher global and regional oxygen consumption compared with controls without changes in contractile parameters. Reduced myocardial external efficiency in G+/LVH+ is explained by the increase in LV mass and higher oxygen consumption. Septal oxygen consumption was significantly lower in G+/LVH+ compared with G+/LVH-. Although LV ejection fraction was higher in G+/LVH+, both systolic and diastolic strain parameters were lower compared with controls, which was most evident in the hypertrophied septal wall. Conclusions Using cardiac magnetic resonance and
C-acetate positron emission tomography imaging, we show that G+/LVH- have an initial increase in oxygen consumption preceding contractile dysfunction and cardiac hypertrophy, followed by a decline in oxygen consumption in G+/LVH+. This suggests that high oxygen consumption and reduced myocardial external efficiency characterize the early gene variant-mediated disease mechanisms that may be used for early diagnosis and development of preventive treatments.
We recently showed more severe diastolic dysfunction at the time of myectomy in female compared to male patients with obstructive hypertrophic cardiomyopathy. Early recognition of aberrant cardiac ...contracility using cardiovascular magnetic resonance (CMR) imaging may identify women at risk of cardiac dysfunction. To define myocardial function at an early disease stage, we studied regional cardiac function using CMR imaging with tissue tagging in asymptomatic female gene variant carriers. CMR imaging with tissue tagging was done in 13
MYBPC3
, 11
MYH7
and 6
TNNT2
gene carriers and 16 age-matched controls. Regional peak circumferential strain was derived from tissue tagging images of the basal and midventricular segments of the septum and lateral wall. Left ventricular wall thickness and global function were comparable between
MYBPC3
,
MYH7
,
TNNT2
carriers and controls.
MYH7
gene variant carriers showed a different strain pattern as compared to the other groups, with higher septal peak circumferential strain at the basal segments compared to the lateral wall, whereas
MYBPC3
,
TNNT2
carriers and controls showed higher strain at the lateral wall compared to the septum. Only subtle gene-specific changes in strain pattern occur in the myocardium preceding development of cardiac hypertrophy. Overall, our study shows that there are no major contractile deficits in asymptomatic females carrying a pathogenic gene variant, which would justify the use of CMR imaging for earlier diagnosis.
Background
It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes.
Hypothesis
...Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants.
Methods
During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N‐acetyl‐β‐d‐glucosaminidase (NAG), and kidney‐injury‐molecule (KIM)‐1. The degree of tubular injury was ranked according to NAG and KIM‐1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF‐hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation.
Results
Higher baseline NT‐proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR 95%CI, 95% confidence interval per doubling NT‐proBNP: 1.26 1.07‐1.49; per 10 mL/min/1.73 m2 eGFR decrease 1.16 1.03‐1.31). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 1.08‐1.62; spironolactone per 25 mg decrease: 1.76 1.07‐2.89; per 10 mL/min/1.73 m2 eGFR increase: 1.40 1.20‐1.63). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR 95%CI: WRF 1.9 1.1‐3.4, tubular 8.4 2.6‐27.9; when combined risk was highest 15.0 2.0‐111.0).
Conclusion
Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive.
This review and meta-analysis reviews the prognostic value of cardiac magnetic resonance (CMR) in nonischemic dilated cardiomyopathy (DCM).
Late gadolinium-enhanced (LGE) CMR is a noninvasive method ...to determine the underlying cause of DCM and previous studies reported the prognostic value of the presence of LGE to identify patients at risk of major adverse cardiovascular events.
PubMed was searched for studies describing the prognostic implication of LGE in patients with DCM for the specified endpoints cardiovascular mortality, major ventricular arrhythmic events including appropriate implantable cardioverter-defibrillator therapy, rehospitalization for heart failure, and left ventricular reverse remodeling.
Data from 34 studies were included, with a total of 4,554 patients. Contrast enhancement was present in 44.8% of DCM patients. Patients with LGE had increased cardiovascular mortality (odds ratio OR: 3.40; 95% confidence interval CI: 2.04 to 5.67), ventricular arrhythmic events (OR: 4.52; 95% CI: 3.41 to 5.99), and rehospitalization for heart failure (OR: 2.66; 95% CI: 1.67 to 4.24) compared with those without LGE. Moreover, the absence of LGE predicted left ventricular reverse remodeling (OR: 0.15; 95% CI: 0.06 to 0.36).
The presence of LGE on CMR substantially worsens prognosis for adverse cardiovascular events in DCM patients, and the absence indicates left ventricular reverse remodeling.
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Structural Abnormalities of the Inferoseptal Left Ventricular Wall Detected by Cardiac Magnetic Resonance Imaging in Carriers of Hypertrophic Cardiomyopathy Mutations
Tjeerd Germans, Arthur A. M. ...Wilde, Pieter A. Dijkmans, Wenxia Chai, Otto Kamp, Yigal M. Pinto, Albert C. van Rossum
So far, no macroscopical structural abnormalities of the left ventricle (LV) have been described in carriers of hypertrophic cardiomyopathy (HCM)-associated mutations before hypertrophy has developed. We used cardiovascular magnetic resonance imaging to evaluate whether structural abnormalities could be observed in HCM mutation carriers who had no hypertrophy on echocardiography. Additionally, electrocardiograms (ECGs) were performed. In 13 of 16 HCM mutation carriers, crypts were detected in the inferoseptal wall, even when the ECG and echocardiogram were normal. Thus, structural abnormalities of the LV are present in HCM mutation carriers who have not yet developed hypertrophy.
The purpose of this study was to evaluate whether structural left ventricular (LV) abnormalities can be observed in hypertrophic cardiomyopathy (HCM) mutation carriers who have not yet developed echocardiographic signs of hypertrophy by using cardiac magnetic resonance imaging (CMR).
Hypertrophic cardiomyopathy is caused by mutations of genes encoding for sarcomeric proteins. Myocyte disarray and interstitial fibrosis precede the development of regional hypertrophy in HCM mutation carriers (carriers). No macroscopic LV structural abnormalities have been observed in carriers without LV hypertrophy.
A CMR, echocardiogram, and electrocardiogram (ECG) were performed in 16 carriers. Delayed contrast enhancement imaging was used with CMR to detect fibrosis. In 16 age- and gender-matched control subjects, CMR and ECG were performed and an echocardiogram was made when structural abnormalities were detected with CMR. All carriers had an LV wall thickness <13 mm in the year before the study, measured by echocardiography.
In 13 carriers (81%), crypts were discerned with CMR in the basal and mid inferoseptal LV wall, not detected by routine echocardiography and not observed in healthy volunteers. In 4 of the crypt-positive carriers, both the echocardiogram and ECG were normal. Two HCM carriers revealed regional hypertrophy of the inferoseptum not detected by echocardiography, and in both carriers, focal fibrosis was present.
In carriers who have not yet developed frank hypertrophy, crypts can be detected with CMR in the inferoseptal LV wall, even when echocardiography and ECG are normal. The crypts might represent one of the early pathological alterations of myocardium in carriers that ultimately progress into manifest HCM.
Studies focusing on sex differences in circulating proteins in patients with heart failure with reduced ejection fraction (HFrEF) are scarce. Insight into sex-specific cardiovascular protein profiles ...and their associations with the risk of adverse outcomes may contribute to a better understanding of the pathophysiological processes involved in HFrEF. Moreover, it could provide a basis for the use of circulating protein measurements for prognostication in women and men, wherein the most relevant protein measurements are applied in each of the sexes.
In 382 patients with HFrEF, we performed tri-monthly blood sampling (median follow-up: 25 13-31 months). We selected all baseline samples and two samples closest to the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or censoring. We then applied an aptamer-based multiplex proteomic assay identifying 1105 proteins previously associated with cardiovascular disease. We used linear regression models and gene-enrichment analysis to study sex-based differences in baseline levels. We used time-dependent Cox models to study differences in the prognostic value of serially measured proteins. All models were adjusted for the MAGGIC HF mortality risk score and p-values for multiple testing.
In 104 women and 278 men (mean age 62 and 64 years, respectively) cumulative PEP incidence at 30 months was 25% and 35%, respectively. At baseline, 55 (5%) out of the 1105 proteins were significantly different between women and men. The female protein profile was most strongly associated with extracellular matrix organization, while the male profile was dominated by regulation of cell death. The association of endothelin-1 (P
< 0.001) and somatostatin (P
= 0.040) with the PEP was modified by sex, independent of clinical characteristics. Endothelin-1 was more strongly associated with the PEP in men (HR 2.62 95%CI, 1.98, 3.46, p < 0.001) compared to women (1.14 1.01, 1.29, p = 0.036). Somatostatin was positively associated with the PEP in men (1.23 1.10, 1.38, p < 0.001), but inversely associated in women (0.33 0.12, 0.93, p = 0.036).
Baseline cardiovascular protein levels differ between women and men. However, the predictive value of repeatedly measured circulating proteins does not seem to differ except for endothelin-1 and somatostatin.
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