A case report of transthyretin amyloidosis following cardiac transplantation: thick ventricles that look alike.

Background: Transthyretin (ATTR) amyloidosis is more prevalent than initially thought. As much as 13% of patients hospitalized with heart failure with preserved ejection fraction may have ATTR-cardiomyopathy (CM). Conversely, heart transplant patients may manifest left ventricular hypertrophy or diastolic dysfunction, especially late after transplantation. Case summary: We present a case of a 82-year-old male heart transplant patient, 31 years following orthotopic heart transplantation. While he was satisfied with his exercise capacity as an octogenarian, several years before, he required pacemaker implantation due to third-degree atrioventricular block, had bilateral carpal tunnel syndrome treated with carpal tunnel release surgery, and experienced idiopathic sudden deafness. Based on increasing left ventricular wall thickness during routine follow-up, a diagnosis of ATTR amyloidosis was suspected. Ultimately, the diagnosis was confirmed non-invasively with a specific scintigraphic exam, while an additional physicochemical stain on an endomyocardial biopsy taken several years before provided pathological proof. We initiated tafamidis, yet stopped this treatment after 1 month because of gastrointestinal intolerance. Ultimately, our patient died 2 years later due to heart failure. Discussion: Our case shows the long delay between the onset of ATTR deposition, the presence of clinical signs, and the final diagnosis. Echocardiographic findings suggestive for ATTR-CM include left ventricular hypertrophy and diastolic dysfunction, which are both common in heart transplant patients. Yet, ATTR-CM should be considered in the differential diagnosis, especially late after transplantation, in this closely monitored population.

Mortality and Major Adverse Cardiac Events in Patients With Breast Cancer Receiving Radiotherapy: The First Decade.

Background Treatment for breast cancer (BC) frequently involves radiotherapy. Guidelines recommend screening for cardiac adverse events starting 10 years after radiotherapy. The rationale for this interval is unclear. Methods and Results We aimed to study cardiovascular event rates in the first decade following curative radiotherapy for BC. We compared mortality and cardiovascular event rates with an age- and risk factor-matched control population. We included 1095 patients with BC (mean age 56±12 years). Two hundred and eighteen (19.9%) women died. Cancer and cardiovascular mortality caused 107 (49.1%) and 22 (10.1%) deaths, respectively. A total of 904 cases were matched to female FLEMENGHO (Flemish Study on Environment, Genes and Health Outcomes) participants. Coronary artery disease incidence was similar (risk ratio [RR], 0.75 [95% CI, 0.48-1.18]), yet heart failure (RR, 1.97 [95% CI, 1.19-3.25]) and atrial fibrillation/flutter (RR, 1.82 [95% CI, 1.07-3.08]) occurred more often in patients with BC. Age (hazard ratio [HR], 1.033 [95% CI, 1.006-1.061], P=0.016), tumor grade (HR, 1.739 [95% CI, 1.166-2.591], P=0.007), and neoadjuvant treatment setting (HR, 2.782 [95% CI, 1.304-5.936], P=0.008) were risk factors for mortality. Risk factors for major adverse cardiac events were age (HR, 1.053 [95% CI, 1.013-1.093]; P=0.008), mean heart dose (HR, 1.093 [95% CI, 1.025-1.167]; P=0.007), history of cardiovascular disease (HR, 2.386 [95% CI, 1.096-6.197]; P=0.029) and Mayo Clinic Cardiotoxicity Risk Score (HR, 2.664 [95% CI, 1.625-4.367]; P<0.001). Conclusions Ten-year mortality following curative treatment for unilateral BC was mainly cancer related, but heart failure and atrial fibrillation/flutter were already common in the first decade following irradiation. Mean heart dose, pre-existing cardiovascular diseases, and Mayo Clinic Cardiotoxicity Risk Score were risk factors for cardiac adverse events. These results suggest a need for early dedicated cardio-oncological follow-up after radiotherapy.

Combination prophylaxis in CMV high risk heart transplant recipients: A single center experience.

INTRODUCTION: Cytomegalovirus (CMV) is the most clinically relevant infectious agent following heart transplantation (HTX). Data on the beneficial effects of prophylactic use of CMV immunoglobulins (CMVIG) are scarce. METHODS: In this single-center, retrospective study, we reported patient outcomes following cardiac transplantation using prophylactic CMV treatment, including CMVIG. Distinct clinically relevant outcomes were compared across different CMV risk groups (CMV D-/R-, CMV D-/R+, CMV D+/R+, and CMV D+/R- or CMV high risk group). RESULTS: We included 272 heart transplant procedures, performed between 1/1/2009 and 1/11/2020. Sixty-one (22%) procedures belonged to the CMV high risk group, while 96 (35%), 50 (18%), and 65 (24%) were CMV D-/R-, CMV D-/R+, and CMV D+/R+, respectively. Baseline donor and recipient characteristics (sex, age, body mass index, cause of death, indication for HTX), ischemia times and baseline immunosuppressive regimens were similar across the different CMV risk groups, yet fewer patients were bridged with a mechanical circulatory support in the CMV D+/R- group. CMV disease following cardiac transplantation was more common in the CMV D+/R- risk group (n = 40 or 66.7%; p < .001), yet mortality and re-transplantation rates, cardiac allograft vasculopathy (CAV) severity, rejection episodes, and development of donor-specific antibodies (DSA), post-transplant lymphoproliferative diseases (PTLD), and EBV infections were similar across all four CMV risk groups. CONCLUSION: High risk CMV D+/R- patients had a similar survival compared to low and intermediate CMV risk groups using a prophylactic strategy combining CMVIG and viral DNA polymerase inhibitors. This may be related to a number of factors unrelated to prophylaxis strategy as two out of three CMV D+/R- recipients developed CMV primary infection after prophylaxis was discontinued.

Predictability of cardiotoxicity: Experience of a Belgian cardio-oncology clinic.

BACKGROUND: New oncological treatments improved survival but also increased awareness of cardiovascular side-effects during and after cancer therapy. METHODS: We report the experience of the cardio-oncology clinic at a large Belgian tertiary care center and investigated the predictability of cardiotoxicity based on referring department, cardiovascular risk factors, cancer treatment and existing risk scores of the American Society of Clinical Oncologists (ASCO) and Mayo Clinic. Cardiotoxicity was defined as a 10% reduction in Left Ventricular Ejection Fraction (LVEF) compared to the baseline transthoracic echocardiography (TTE) in asymptomatic patients or 5% in symptomatic patients. RESULTS: Of the 324 patients included, 14.5% died during follow-up. Most deaths were oncological, yet 19% of deaths were attributable to cardiovascular diseases. Models based on cardiovascular risk factors alone and cardiovascular risk factors combined with cardiotoxic medication poorly predicted cardiotoxicity. Existing risk scores from ASCO and Mayo Clinic also poorly predicted cardiotoxicity. A weighed model based on the Mayo Clinic cardiotoxicity risk score was the best risk assessment tool with still a limited predictive value with an Area Under the Receiver Operating Characteristic curve of 0.654 (CI 95%: 0.601-0.715). CONCLUSION: Cardiovascular morbidity and mortality are common in cancer patients and survivors and stress the unmet need of adequate risk prediction tools for systematic screening and rigorous cardiovascular follow-up. In our outpatient cohort, cardiotoxicity risk could not be adequately predicted by cancer type, using classic cardiovascular risk factors, nor by the combination of cardiovascular risk factors and the proposed cancer treatment. Furthermore, we showed that existing cardiotoxicity risk scores are suboptimal and should thus be interpreted with caution.

Improved cardiac and venous pressures during hospital stay in patients with acute heart failure: an echocardiography and biomarkers study.

AIMS: Changes in echocardiographic parameters and biomarkers of cardiac and venous pressures or estimated plasma volume during hospitalization associated with decongestive treatments in acute heart failure (AHF) patients with either preserved left ventricular ejection fraction (LVEF) (HFPEF) or reduced LVEF (HFREF) are poorly assessed. METHODS AND RESULTS: From the metabolic road to diastolic heart failure: diastolic heart failure (MEDIA-DHF) study, 111 patients were included in this substudy: 77 AHF (43 HFPEF and 34 HFREF) and 34 non-cardiac dyspnea patients. Echocardiographic measurements and blood samples were obtained within 4 h of presentation at the emergency department and before hospital discharge. In AHF patients, echocardiographic indices of cardiac and venous pressures, including inferior vena cava diameter [from 22 (16-24) mm to 13 (11-18) mm, P = 0.009], its respiratory variability [from 32 (8-44) % to 43 (29-70) %, P = 0.04], medial E/e' [from 21.1 (15.8-29.6) to 16.6 (11.7-24.3), P = 0.004], and E wave deceleration time [from 129 (105-156) ms to 166 (128-203) ms, P = 0.003], improved during hospitalization, similarly in HFPEF and HFREF patients. By contrast, no changes were seen in non-cardiac dyspnea patients. In AHF patients, all plasma biomarkers of cardiac and venous pressures, namely B-type natriuretic peptide [from 935 (514-2037) pg/mL to 308 (183-609) pg/mL, P < 0.001], mid-regional pro-atrial natriuretic peptide [from 449 (274-653) pmol/L to 366 (242-549) pmol/L, P < 0.001], and soluble CD-146 levels [from 528 (406-654) ng/mL to 450 (374-529) ng/mL, P = 0.003], significantly decreased during hospitalization, similarly in HFPEF and HFREF patients. Echocardiographic parameters of cardiac chamber dimensions [left ventricular end-diastolic volume: from 120 (76-140) mL to 118 (95-176) mL, P = 0.23] and cardiac index [from 2.1 (1.6-2.6) mL/min/m2 to 1.9 (1.4-2.4) mL/min/m2 , P = 0.55] were unchanged in AHF patients, except tricuspid annular plane systolic excursion (TAPSE) that improved during hospitalization [from 16 (15-19) mm to 19 (17-21) mm, P = 0.04]. Estimated plasma volume increased in both AHF [from 4.8 (4.2-5.6) to 5.1 (4.4-5.8), P = 0.03] and non-cardiac dyspnea patients (P = 0.01). Serum creatinine [from 1.18 (0.90-1.53) to 1.19 (0.86-1.70) mg/dL, P = 0.89] and creatinine-based estimated glomerular filtration rate [from 59 (40-75) mL/min/1.73m2 to 56 (38-73) mL/min/1.73m2 , P = 0.09] were similar, while plasma cystatin C [from 1.50 (1.20-2.27) mg/L to 1.78 (1.33-2.59) mg/L, P < 0.001] and neutrophil gelatinase associated lipocalin (NGAL) [from 127 (95-260) ng/mL to 167 (104-263) ng/mL, P = 0.004] increased during hospitalization in AHF. CONCLUSIONS: Echocardiographic parameters and plasma biomarkers of cardiac and venous pressures improved during AHF hospitalization in both acute HFPEF and HFREF patients, while cardiac chamber dimensions, cardiac output, and estimated plasma volume showed minimal changes.

Long-term outcome of cardiac allograft vasculopathy: Importance of the International Society for Heart and Lung Transplantation angiographic grading scale.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major complication limiting long-term survival after heart transplantation (HTx). However, long-term outcome data of HTx recipients with detailed information on angiographic severity are scarce. METHODS: The study included 501 HTx recipients with angiographic follow-up up to 20 years post-transplant. All coronary angiograms were classified according to the International Society for Heart and Lung Transplantation (ISHLT) grading scale. RESULTS: CAV prevalence increased over time after transplantation, reaching 10% at 1 year, 44% at 10 years, and 59% at 20 years. Older donor age (hazard ratio [HR] 1.38 per 10 years, 1.20-1.59, p < 0.001), male donor sex (HR 1.86, 1.31-2.64, p < 0.001), stroke as donor cause of death (HR 1.47, 1.04-2.09, p = 0.03), recipient pre-transplant hemodynamic instability (HR 1.79, 1.15-2.77, p = 0.01), post-transplant smoking (HR 1.59, 1.06-2.39, p = 0.03), and first-year treated rejection episodes (HR 1.49, 1.01-2.20, p = 0.046) were independent risk factors for CAV. Baseline anti-metabolite drug use (HR 0.57, 0.34-0.95, p = 0.03) and more recent transplant date (HR 0.78 per 10 years, 0.62-0.99, p = 0.04) were protective factors. Compared with patients without CAV, the HR for death or retransplantation was 1.22 (0.85-1.76, p = 0.28) for CAV 1, 1.86 (1.08-3.22, p = 0.03) for CAV 2, and 5.71 (3.64-8.94, p < 0.001) for CAV 3. CONCLUSIONS: CAV is highly prevalent in HTx recipients and is explained by immunologic and non-immunologic factors. Higher ISHLT CAV grades are independently associated with worse graft survival.

Urinary peptidomic biomarkers of renal function in heart transplant recipients.

BACKGROUND: Chronic kidney disease (CKD) is common in patients after heart transplantation (HTx). We assessed whether in HTx recipients the proteomic urinary classifier CKD273 or sequenced urinary peptides revealing the parental proteins correlated with the estimated glomerular filtration rate (eGFR). METHODS: In 368 HTx patients, we measured the urinary peptidome and analysed CKD273 and 48 urinary peptides with a detectable signal in >95% of participants. After 9.1 months (median), eGFR and the urinary biomarkers were reassessed. RESULTS: In multivariable Bonferroni-corrected analyses of the baseline data, a 1-SD increase in CKD273 was associated with a 11.4 [95% confidence interval (CI) 7.25-15.5] mL/min/1.73 m2 lower eGFR and an odds ratio of 2.63 (1.56-4.46) for having eGFR <60 mL/min/1.73 m2. While relating eGFR category at follow-up to baseline urinary biomarkers, CKD273 had higher (P = 0.007) area under the curve (0.75; 95% CI 0.70-0.80) than 24-h proteinuria (0.64; 95% CI 0.58-0.69), but additional adjustment for baseline eGFR removed significance of both biomarkers. In partial least squares analysis, the strongest correlates of the multivariable-adjusted baseline eGFR were fragments of collagen I (positive) and the mucin-1 subunit α (inverse). Associations between the changes in eGFR and the urinary markers were inverse for CKD273 and mucin-1 and positive for urinary collagen I. CONCLUSIONS: With the exception of baseline eGFR, CKD273 was more closer associated with imminent renal dysfunction than 24-h proteinuria. Fragments of collagen I and mucin-1-respectively, positively and inversely associated with eGFR and change in eGFR-are single-peptide markers associated with renal dysfunction.

Urinary proteomic signatures associated with ß-blockade and heart rate in heart transplant recipients.

OBJECTIVES: Heart transplant (HTx) recipients have a high heart rate (HR), because of graft denervation and are frequently started on ß-blockade (BB). We assessed whether BB and HR post HTx are associated with a specific urinary proteomic signature. METHODS: In 336 HTx patients (mean age, 56.8 years; 22.3% women), we analyzed cross-sectional data obtained 7.3 years (median) after HTx. We recorded medication use, measured HR during right heart catheterization, and applied capillary electrophoresis coupled with mass spectrometry to determine the multidimensional urinary classifiers HF1 and HF2 (known to be associated with left ventricular dysfunction), ACSP75 (acute coronary syndrome) and CKD273 (renal dysfunction) and 48 sequenced urinary peptides revealing the parental proteins. RESULTS: In adjusted analyses, HF1, HF2 and CKD273 (p ≤ 0.024) were higher in BB users than non-users with a similar trend for ACSP75 (p = 0.06). Patients started on BB within 1 year after HTx and non-users had similar HF1 and HF2 levels (p ≥ 0.098), whereas starting BB later was associated with higher HF1 and HF2 compared with non-users (p ≤ 0.014). There were no differences in the urinary biomarkers (p ≥ 0.27) according to HR. BB use was associated with higher urinary levels of collagen II and III fragments and non-use with higher levels of collagen I fragments. CONCLUSIONS: BB use, but not HR, is associated with a urinary proteomic signature that is usually associated with worse outcome, because unhealthier conditions probably lead to initiation of BB. Starting BB early after HTx surgery might be beneficial.

Biomarkers to Assess Right Heart Pressures in Recipients of a Heart Transplant: A Proof-of-Concept Study.

BACKGROUND: This proof-of-concept study investigated the feasibility of using biomarkers to monitor right heart pressures (RHP) in heart transplanted (HTx) patients. METHODS: In 298 patients, we measured 7.6 years post-HTx mean pressures in the right atrium (mRAP) and pulmonary artery (mPAP) and capillaries (mPCWP) along with plasma high-sensitivity troponin T (hsTnT), a marker of cardiomyocyte injury, and the multidimensional urinary classifiers HF1 and HF2, mainly consisting of dysregulated collagen fragments. RESULTS: In multivariable models, mRAP and mPAP increased with hsTnT (per 1-SD, +0.91 and +1.26 mm Hg; P < 0.0001) and with HF2 (+0.42 and +0.62 mm Hg; P ≤ 0.035), but not with HF1. mPCWP increased with hsTnT (+1.16 mm Hg; P < 0.0001), but not with HF1 or HF2. The adjusted odds ratios for having elevated RHP (mRAP, mPAP or mPCWP ≥10, ≥24, ≥17 mm Hg, respectively) were 1.99 for hsTnT and 1.56 for HF2 (P ≤ 0.005). In detecting elevated RHPs, areas under the curve were similar for hsTnT and HF2 (0.63 vs 0.65; P = 0.66). Adding hsTnT continuous or per threshold or HF2 continuous to a basic model including all covariables did not increase diagnostic accuracy (P ≥ 0.11), whereas adding HF2 per optimized threshold increased both the integrated discrimination (+1.92%; P = 0.023) and net reclassification (+30.3%; P = 0.010) improvement. CONCLUSIONS: Correlating RHPs with noninvasive biomarkers in HTx patients is feasible. However, further refinement and validation of such biomarkers is required before their clinical application can be considered.

How to obtain and maintain favorable results after heart transplantation: keys to success?

We compared survival in our heart recipients with survival rates reported by the International Society of Heart and Lung Transplantation (ISHLT) Registry. As recipient and donor characteristics are changing over time, we studied four different eras. In order to differentiate between short- and long-term survival, we analyzed both overall survival and survival at one year. Obviously, this exercise is only relevant when baseline donor and recipient characteristics are comparable, as these differences may affect the outcome in opposite directions. To overcome this potential bias as much as possible, we calculated the Index for Mortality Prediction After Cardiac Transplantation (IMPACT)-scores and the Donor Risk Index (DRI). Looking to our results, we found that our DRIs in the different eras are almost equal to those obtained from the United Network for Organ Sharing database in the very same eras. Our IMPACT-scores, on the other hand, seem higher than those reported by ISHLT. Survival after transplantation and conditional on 1-year survival was higher than the outcome reported by the ISHLT Registry. As our operation technique and post-transplant immunosuppressive schedule did not differ from most centers, we speculated on potential factors that might contribute to our positive results. Patient selection and a relatively short waiting time are important contributors to the overall survival benefit. Our centralized follow-up may also have played an important role. Finally, the indefinite compulsory health insurance coverage in our country and easy access to different screening programs might also have influenced our outcome in a positive way. We are well aware that with challenges like donor organ shortage, more and more patients on mechanical circulatory support (MCS) will affect outcomes in the future.

Acutely decompensated heart failure with preserved and reduced ejection fraction present with comparable haemodynamic congestion.

AIMS: Congestion is a central feature of acute heart failure (HF) and its assessment is important for clinical decisions (e.g. tailoring decongestive treatments). It remains uncertain whether patients with acute HF with preserved ejection fraction (HFpEF) are comparably congested as in acute HF with reduced EF (HFrEF). This study assessed congestion, right ventricular (RV) and renal dysfunction in acute HFpEF, HFrEF and non-cardiac dyspnoea. METHODS AND RESULTS: We compared echocardiographic and circulating biomarkers of congestion in 146 patients from the MEDIA-DHF study: 101 with acute HF (38 HFpEF, 41 HFrEF, 22 HF with mid-range ejection fraction) and 45 with non-cardiac dyspnoea. Compared with non-cardiac dyspnoea, patients with acute HF had larger left and right atria, higher E/e', pulmonary artery systolic pressure and inferior vena cava (IVC) diameter at rest, and lower IVC variability (all P < 0.05). Mid-regional pro-atrial natriuretic peptide (MR-proANP) and soluble CD146 (sCD146), but not B-type natriuretic peptide (BNP), correlated with echocardiographic markers of venous congestion. Despite a lower BNP level, patients with HFpEF had similar evidence of venous congestion (enlarged IVC, left and right atria), RV dysfunction (tricuspid annular plane systolic excursion), elevated MR-proANP and sCD146, and renal impairment (estimated glomerular filtration rate; all P > 0.05) compared with HFrEF. CONCLUSION: In acute conditions, HFpEF and HFrEF presented in a comparable state of venous congestion, with similarly altered RV and kidney function, despite higher BNP in HFrEF.

High body mass index is a predictor of left ventricular reverse remodelling in heart failure with reduced ejection fraction.

AIMS: Structural and functional left ventricular alterations can occur in heart failure (HF), referred to as left ventricular reverse remodelling (LVRR). This study aimed to define novel predictors of LVRR besides well-known effects of medical and device therapy. METHODS AND RESULTS: From echographic database, we included 295 patients with both left ventricular ejection fraction (LVEF) ≤45% and indexed left ventricular end-diastolic diameter ≥33 mm/m2 and who had at least two echocardiographic exams with a delay between 3 and 12 months. LVRR was defined as the combination of (i) normalization of LVEF (LVEF ≥50%) or increase in LVEF ≥10% and (ii) a decrease in indexed left ventricular end-diastolic diameter ≥10%. Clinical follow-up was also obtained. LVRR occurred in 53 (18%) patients. Patients in the LVRR group were more likely to present with de novo HF (75% vs. 42%), had lower LVEF and left ventricular end-diastolic volumes at index examination, yet a higher body mass index (BMI) than non-LVRR patients. Obesity was observed in 25% of LVRR patients vs. 14% in others. In multivariate analyses, BMI (per each 1 kg/m2 increase) emerged as a predictor of LVRR: odds ratio 1.10 (95% confidence interval 1.02-1.19) after adjustment to other predictors of LVRR. During a mean follow-up of 37 months, 32% of patients had a major adverse cardiac event; de novo HF, age, and LVEF were associated with major adverse cardiac event. CONCLUSIONS: We identified significant relationship between high BMI and LVRR. This intriguing novel finding deserves further study.

Towards Holistic Heart Failure Management-How to Tackle the Iron Deficiency Epidemic?

PURPOSE OF REVIEW: Heart failure (HF) is a common, costly, disabling, and deadly clinical syndrome and often associated with one or several co-morbidities complicating its treatment or worsening its symptoms. During the last decade, iron deficiency (ID) got recognized as a frequent, debilitating yet easily treatable co-morbidity in HF. In this review, we focus on new evidence that emerged during the last 5 years and discuss the epidemiology, the causes, and the clinical consequences of ID in HF. RECENT FINDINGS: Apart from replenishing iron stores, intravenous iron improves patients' symptoms, perceived quality of life (QoL), exercise capacity, and hospitalization rates. These beneficial effects cannot be attributed to oral iron, as increased hepcidin levels, typical in inflammatory states such as HF, preclude resorption of iron from the gut. Intravenous iron is the only valid treatment option for ID in HF. However, there are several burning research questions and gaps in evidence remaining in this research field.

Natriuretic peptides in addition to Zwolle score to enhance safe and early discharge after acute myocardial infarction: A prospective observational cohort study.

BACKGROUND: The Zwolle score is recommended to identify low-risk patients eligible for early hospital discharge after ST-elevation myocardial infarction (STEMI), but since only one third of STEMI has low Zwolle score, hospital discharge is frequently delayed. B-type natriuretic peptide (BNP) also provides prognostic information after STEMI. The aim of the study was to test the hypothesis that patients with high Zwolle score associated with low BNP share similar outcomes than those with low Zwolle score. METHODS AND RESULTS: The study population consisted of 1032 consecutive STEMI patients in whom BNP was measured 24h after chest pain onset. The area under the curve of Zwolle score and plasma BNP for 30-day mortality were 0.82 and 0.87, p=0.39. A BNP threshold of 200pg/ml had sensitivity of 100% and specificity of 34% for predicting 30-day mortality. Patients with high Zwolle score and BNP≤200pg/ml (n=183) had similar mortality and hospital stay to those with low Zwolle score (0% vs. 0.5% and 5 vs. 5days, both p=1.0). By contrast, patients with high Zwolle score and BNP>200pg/ml had the highest mortality (6.7%) and the longest hospital stay (6days), both p<0.01. CONCLUSION: STEMI patients with high Zwolle score but low BNP share similar outcomes with those with low Zwolle score and should be eligible for early discharge. Hence, using the rule of "low-Zwolle or low-BNP" might increase the number of STEMI patients that might be eligible for early discharge.

Osteoglycin prevents cardiac dilatation and dysfunction after myocardial infarction through infarct collagen strengthening.

RATIONALE: To maintain cardiac mechanical and structural integrity after an ischemic insult, profound alterations occur within the extracellular matrix. Osteoglycin is a small leucine-rich proteoglycan previously described as a marker of cardiac hypertrophy. OBJECTIVE: To establish whether osteoglycin may play a role in cardiac integrity and function after myocardial infarction (MI). METHODS AND RESULTS: Osteoglycin expression is associated with collagen deposition and scar formation in mouse and human MI. Absence of osteoglycin in mice resulted in significantly increased rupture-related mortality with tissue disruption, intramyocardial bleeding, and increased cardiac dysfunction, despite equal infarct sizes. Surviving osteoglycin null mice had greater infarct expansion in comparison with wild-type mice because of impaired collagen fibrillogenesis and maturation in the infarcts as revealed by electron microscopy and collagen polarization. Absence of osteoglycin did not affect cardiomyocyte hypertrophy in the remodeling remote myocardium. In cultured fibroblasts, osteoglycin knockdown or supplementation did not alter transforming growth factor-ß signaling. Adenoviral overexpression of osteoglycin in wild-type mice significantly improved collagen quality, thereby blunting cardiac dilatation and dysfunction after MI. In osteoglycin null mice, adenoviral overexpression of osteoglycin was unable to prevent rupture-related mortality because of insufficiently restoring osteoglycin protein levels in the heart. Finally, circulating osteoglycin levels in patients with heart failure were significantly increased in the patients with a previous history of MI compared with those with nonischemic heart failure and correlated with survival, left ventricular volumes, and other markers of fibrosis. CONCLUSIONS: Increased osteoglycin expression in the infarct scar promotes proper collagen maturation and protects against cardiac disruption and adverse remodeling after MI. In human heart failure, osteoglycin is a promising biomarker for ischemic heart failure.

MicroRNAs as biomarkers for ischemic heart disease.

MicroRNAs (miRs) are short, noncoding RNAs that function as posttranscriptional inhibitors of mRNA translation to protein. They are essential for normal development and homeostasis. Dysregulated expression patterns both cause and result from disease states. Generally studied as intracellular mediators, miRs can be isolated from body fluids and exhibit remarkable stability to degradation. These features, in combination with their tissue specificity, make miRs attractive candidates as blood-derived biomarkers for coronary artery disease (CAD), the most frequent cause of death worldwide. The use of miRs as biomarkers in both symptomatic and asymptomatic CAD and the influence of conventional cardiovascular risk factors and CAD treatment on their circulating levels are the topics of this review. To conclude, it highlights the remaining hurdles to tackle before this promising application of miRs can enter into routine clinical practice.