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Analyses from administrative databases have suggested an increased cancer incidence among individuals who experienced a myocardial infarction, especially within the first 6 months. It remains unclear to what extent this represents an underlying biological link, or can be explained by detection of pre-symptomatic cancers and shared risk factors. Cancer incidence among 1809 consecutive patients surviving hospitalization for thrombotic ST-segment-elevation myocardial infarction (STEMI; mean age 62.6 years; 26% women; 115 incident cancers) was compared to the cancer incidence among 10,052 individuals of the general population (Rotterdam Study; mean age 63.1 years; 57% women; 677 incident cancers). Pathology-confirmed cancer diagnoses were obtained through identical linkage of both cohorts with the Netherlands Cancer Registry. Cox models were used to obtain hazards ratios (HRs) adjusted for factors associated with both atherosclerosis and cancer. Over 5-year follow-up, there was no significant difference in the incidence of cancer between STEMI patients and the general population (HR 0.96, 95% CI 0.78-1.19). In the first 3 months after STEMI, cancer incidence was markedly higher among STEMI patients compared to the general population (HR 2.45, 95% CI 1.13-5.30), which gradually dissolved during follow-up (P-for-trend 0.004). Among STEMI patients, higher C-reactive protein, higher platelet counts, and lower hemoglobin were associated with cancer incidence during the first year after STEMI (HRs 2.93 for C-reactive protein > 10 mg/dL, 2.10 for platelet count > 300*10 9 , and 3.92 for hemoglobin < 7.5 mmol/L). Although rare, thrombotic STEMI might be a paraneoplastic manifestation of yet to be diagnosed cancer, and is hallmarked by a pro-inflammatory status and anemia.Trial registration Registered into the Netherlands National Trial Register and WHO International Clinical Trials Registry Platform under shared catalogue number NTR6831., (© 2023. The Author(s).)

Background: Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk., Methods: TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling., Results: Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78-2.57) unadjusted, 1.96 (1.49-2.53) after adjustment for clinical confounders and 1.44 (1.05-1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78-3.33) and 1.52 (1.15-2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785)., Conclusions: Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice., Registration: URL: https://www.trialregister.nl/trial/1783; Unique Identifier: NTR1893. (The trial can be found temporarily at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893.).

Objectives: This study sought to assess the effectiveness, efficiency, and safety of a tiered, comprehensive cardiac computed tomography (CT) protocol in comparison with functional testing., Background: Although CT angiography accurately rules out coronary artery disease (CAD), incorporation of CT myocardial perfusion imaging as part of a tiered diagnostic approach could improve the clinical value and efficiency of cardiac CT in the diagnostic work-up of patients with angina pectoris., Methods: Between July 2013 and November 2015, 268 patients (mean age 58 years; 49% female) with stable angina (mean pre-test probability 54%) were prospectively randomized between cardiac CT and standard guideline-directed functional testing (95% exercise electrocardiography). The tiered cardiac CT protocol included a calcium scan, followed by CT angiography if calcium was detected. Patients with ≥50% stenosis on CT angiography underwent CT myocardial perfusion imaging., Results: By 6 months, the primary endpoint, the rate of invasive coronary angiograms without a European Society of Cardiology class I indication for revascularization, was lower in the CT group than in the functional testing group (2 of 130 [1.5%] vs. 10 of 138 [7.2%]; p = 0.035), whereas the proportion of invasive angiograms with a revascularization indication was higher (88% vs. 50%; p = 0.017). The median duration until the final diagnosis was 0 (0 of 0) days in the CT group and 0 (0 of 17) in the functional testing group (p < 0.001). Overall, 13% of patients randomized to CT required further testing, compared with 37% in the functional testing group (p < 0.001). The adverse event rate was similar (3% vs. 3%; p = 1.000), although the median cumulative radiation dose was higher for the CT group (3.1 mSv [interquartile range: 1.6 to 7.8] vs. 0 mSv [interquartile range: 0.0 to 7.1]; p < 0.001)., Conclusions: In patients with suspected stable CAD, a tiered cardiac CT protocol with dynamic perfusion imaging offers a fast and efficient alternative to functional testing. (Comprehensive Cardiac CT Versus Exercise Testing in Suspected Coronary Artery Disease 2 [CRESCENT2]; NCT02291484)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the emergency department. The CHA 2 DS 2 -VASc score helps to predict thromboembolic risk; however, the rate of other adverse cardiac events is more difficult to predict., Hypothesis: The biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) has prognostic value in patients presenting to the emergency department with AF., Methods: During a 1.5-year period, a prospective study was performed in consecutive patients presenting to the emergency department with AF on the presenting electrocardiogram. At baseline, NT-proBNP was measured. The primary endpoints were all-cause death and major adverse cardiac events (MACE: all-cause mortality, myocardial infarction, or revascularization)., Results: A total of 355 patients were included (mean age, 71 years; 55% male). The median duration of follow-up was 2 years. After adjustment for baseline variables, the logNT-proBNP was independently correlated with death (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.18-1.99) and MACE (HR: 1.27, 95% CI: 1.03-1.58). After adjustment for baseline variables, a high NT-proBNP value (>500 pmol/L) was independently correlated with death (HR: 2.26, 95% CI: 1.19-4.28), and for MACE a trend was seen (HR: 1.67, 95% CI: 0.96-2.91) compared with a low value (<250 pmol/L)., Conclusions: In patients presenting to the emergency department with AF, higher NT-proBNP values are independently associated with an increased mortality and MACE. Therefore, this biomarker may be a useful prognostic marker in the management and treatment of these patients., (© 2018 Wiley Periodicals, Inc.)

Aims: Previous studies have identified candidate circulating microRNAs (circmiRs) as biomarkers for heart failure (HF) using relatively insensitive arrays, validated in small cohorts. The present study used RNA sequencing to identify novel candidate circmiRs and compared these with previously identified circmiRs in a large, prospective cohort of patients with acute HF (AHF)., Methods and Results: RNA sequencing of plasma from instrumented pigs was used to identify circmiRs produced by myocardium. Production of known myomiRs and microRNA (miR)-1306-5p was identified. The prognostic values of this and 11 other circmiRs were tested in a prospective cohort of 496 AHF patients, from whom blood samples were collected at up to seven time-points during the study's 1-year follow-up. The primary endpoint was the composite of all-cause mortality and HF rehospitalization. In the prospective AHF cohort, 188 patients reached the primary endpoint, and higher values of repeatedly measured miR-1306-5p were positively associated with risk for reaching the primary endpoint at the same time-point [hazard ratio (HR) 4.69, 95% confidence interval (CI) 2.18-10.06], independent of clinical characteristics and NT-proBNP. Baseline miR-1306-5p did not improve model discrimination/reclassification significantly compared with NT-proBNP. For miR-320a, miR-378a-3p, miR-423-5p and miR-1254, associations with the primary endpoint were present after adjustment for age and sex (HR 1.38, 95% CI 1.12-1.70; HR 1.35, 95% CI 1.04-1.74; HR 1.45, 95% CI 1.10-1.92; HR 1.22, 95% CI 1.00-1.50, respectively). Rates of detection of myomiRs miR-208a-3p and miR-499a-5p were very low., Conclusions: Repeatedly measured miR-1306-5p was positively associated with adverse clinical outcome in AHF, even after multivariable adjustment including NT-proBNP. However, baseline miR-1306-5p did not add significant discriminatory value to NT-proBNP. Low-abundance, heart-enriched myomiRs are often undetectable, which mandates the development of more sensitive assays., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Khat is a stimulating agent used by many people in the Horn of Africa and the Arabian peninsula. Khat chewing is a known cardiovascular risk factor and is thought to cause vasoconstriction, systemic hypertension, and thrombogenicity. A 33-year-old Somalian man initially presented with loss of neurological function of the left arm, hazy vision, and headache. He smokes tobacco and chews two bundles of khat a week for more than 10 years. His ECG on admission showed a Q wave in V1 and V2 and 2 mm ST-elevations in V1, V2, and V3 and a terminal negative T wave in I, aVL, V2, V3, and V4, consistent with a recent, evolving anterior infarction. A noncontrast enhanced CT of the brain showed ischemia in the right middle cerebral artery vascular territory. An MRI showed recent ischemia in the vascular territory of the posterior division of the right middle cerebral artery. Coronary angiography showed a 70% stenosis with haziness of the proximal left anterior descending artery. Diagnostic tests and imaging are consistent with recent myocardial infarction in the LAD vascular territory because of coronary spasm and cerebral infarction in the middle cerebral artery vascular territory probably related to khat chewing.

We present a case of acute respiratory insufficiency with right-to-left atrial shunting under normal intracardiac pressures discovered several days after aortic surgery for aortic dissection. We discuss the possible mechanisms and management of right-to-left atrial shunting through an atrial septum defect with normal intracardiac pressures following cardiac surgery., (© 2011 Wiley Periodicals, Inc.)

A 77-year-old woman presented with dyspnoea and respiratory-related thoracic pain, which was accompanied by dizziness and fatigue but no syncopal attacks. Auscultation of the heart disclosed an opening snap with mid-diastolic murmur. Laboratory assessment revealed no abnormalities but an elevated D-dimer level (1.49 mg/l). Electrocardiography was normal. The chest radiograph showed an enlarged heart without other abnormalities. Computed tomography (CT) scan for a suspected diagnosis of pulmonary embolism was performed. The CT scan did not reveal pulmonary embolism, but a large cardiac tumour in the left atrium.

Purpose of Review: Atrial fibrillation is a significant public health issue considering its high prevalence in the general population, and is associated with an increased risk of cardiovascular mortality and morbidity and thrombo-embolic complications.Asymptomatic paroxysms of atrial fibrillation occur frequently in the first stages of the disease but patients present to the doctor at a relatively late stage when the associated complications have already taken place. It is crucial to identify such patients as early as possible in order to start preventive therapy. Clinical diagnostic tests to identify patients prone to atrial fibrillation complications have not yet been developed as the exact mechanism and substrate of subclinical atrial fibrillation are not known. Further research is necessary to understand the pathophysiology of subclinical atrial fibrillation and to identify potential risk markers that determine the development and prognosis of the disease., Recent Findings: Biomarkers have recently been identified which have been shown to be related to the incidence of atrial fibrillation and its prognosis. They reflect inflammation, neurohumoral activation and subclinical heart damage., Summary: New biomarkers may help to understand the mechanisms of subclinical atrial fibrillation and signal the likelihood of disease progression. Such biomarkers, though subject to further validation, may be of value in predicting the prognosis and guiding the treatment of patients with atrial fibrillation. They may enhance the ability of risk scores to guide anticoagulant treatment strategies.

Aims: In patients with atrial fibrillation, minor troponin I elevation is regularly detected; however, the prognostic significance of this finding is unknown. We therefore sought to examine the prognostic value of elevated troponin I in patients with atrial fibrillation., Methods and Results: A prospective study was conducted analysing all consecutive patients admitted with atrial fibrillation in a 2-year period. Patients with an ST-elevation myocardial infarction (MI) were excluded. Minor troponin elevation was defined as a troponin I level between 0.15 and 0.65 ng/mL, which is still below the 99th percentile of the upper reference limit. A positive troponin I was defined as ≥ 0.65 ng/mL. Study outcomes were all-cause mortality (death), death and myocardial infarction (death/MI), or all major adverse cardiac events (MACE: death, MI, or revascularization). A total of 407 patients were eligible for inclusion. The median duration of follow-up was 688 days. A minor elevation occurred in 81 (20%) patients and 77 (19%) had a positive troponin I. In a multivariate model, minor troponin I elevation and a positive troponin I were independently associated with death [hazard ratio (HR): 2.36, 95% confidence interval (CI): 1.17-4.73 for minor elevation and HR: 3.77, 95% CI: 1.42-10.02 for positive troponin I]. Also, there was an independent correlation between the combined endpoints of death/MI and MACE and both a minor elevation and a positive troponin I., Conclusion: Minor elevations in troponin I on hospital admission are associated with mortality and cardiac events in patients with atrial fibrillation and might be useful for risk stratification.

During the last decade transplantation of cells into the heart has emerged as a novel therapy for the prevention and treatment of heart failure. Although various cell types have been used, most experience has been obtained with the progenitor cells of skeletal muscle, also called myoblasts, and a wide array of bone marrow-derived cell types. The first preclinical studies demonstrated an improvement in global and regional heart function that was attributed mainly to a direct contractile effect of the transplanted cells. Furthermore, it was suggested that multiple cell types are able to form true cardiomyocytes and truly 'regenerate' the myocardium. More recent studies have questioned these early findings. Other mechanisms such as paracrine effects on the infarct and remote myocardium, a reduction in adverse remodelling and improvement of mechanical properties of the infarct tissue likely play a more important role. On the basis of encouraging preclinical studies, multiple early-phase clinical trials and several randomised controlled trials have been conducted that have demonstrated the feasibility, safety and potential efficacy of this novel therapy in humans. This review summarises the available evidence on cardiac cell transplantation and provides an outlook on future preclinical and clinical research that has to fill in the remaining gaps. (Neth Heart J 2008;16:88-95.).

Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at the onset of reperfusion following index ischemia limits myocardial infarct size. Whereas there is evidence that the algorithm of the POC stimulus is an important determinant of the protective efficacy, the importance of the duration of index ischemia on the outcome of the effects of POC has received little attention. Pentobarbital sodium-anesthetized Wistar rats were therefore subjected to index ischemia produced by coronary artery occlusions (CAO) of varying duration (15-120 min) followed by reperfusion, without or with postconditioning produced by three cycles of 30-s reperfusion and reocclusion (3POC30). 3POC30 limited infarct size produced by 45-min CAO (CAO45) from 45 +/- 3% to 31 +/- 5%, and CAO60 from 60 +/- 3% to 47 +/- 6% (both P < or = 0.05). In contrast, 3POC30 increased infarct size produced by CAO15 from 3 +/- 1% to 19 +/- 6% and CAO30 from 36 +/- 6 to 48 +/- 4% (both P < or = 0.05). This deleterious effect of 3POC30 was not stimulus sensitive because postconditioning with 3POC5 and 3POC15 after CAO30 also increased infarct size. The cardioprotection by 3POC30 after CAO60 was accompanied by an increased stimulation of Akt phosphorylation at 7 min of reperfusion and a 36% lower superoxide production, measured by dihydroethidium fluorescence, after 2 h of reperfusion. Consistent with these results, cardioprotection by 3POC30 was abolished by phosphatidylinositol-3-OH-kinase inhibition, as well as nitric oxide (NO) synthase inhibition. The deleterious effect of 3POC30 after CAO15 was accompanied by an increased superoxide production with no change in Akt phosphorylation and was not affected by NO synthase inhibition. In conclusion, the effect of cardiac POC depends critically on the duration of the index ischemia and can be either beneficial or detrimental. These paradoxical effects of POC may be related to the divergent effects on Akt phosphorylation and superoxide production.

Aims: Stem cell therapy after myocardial infarction (MI) has been studied in models of permanent coronary occlusion. We studied the effect of intracoronary administration of unselected bone marrow (BM) and mononuclear cells (MNC) in a porcine model of reperfused MI., Methods and Results: In 34 swine, the left circumflex coronary artery was balloon-occluded for 2 h followed by reperfusion. Ten swine without MI served as controls. All swine underwent magnetic resonance imaging (MRI) 1 week post-MI. The next day, 10 of the 30 surviving MI swine received BM, 10 other MI swine received MNC, and the remaining MI swine received medium intracoronary. Four weeks later, all swine underwent a follow-up MRI. One week after MI, end-diastolic volume (92+/-16 mL) and left ventricular (LV) weight (78+/-12 g) were greater, whereas ejection fraction (40+/-8%) was lower than in controls (69+/-11 mL, 62+/-13 g, and 53+/-6%). Injection of BM or MNC had no effect on the MI-induced changes in global or regional LV-function. However, there was a significant reduction in infarct size 4 weeks after MNC injection (-6+/-3%) compared with the medium (-3+/-5%)., Conclusion: Intracoronary injection of BM or MNC in swine does not improve regional or global LV-function 4 weeks after injection. However, a reduction in infarct-size was noted after MNC injection.

Aims: Magnetic resonance imaging (MRI) has been proposed as a tool to track iron oxide-labelled cells within myocardial infarction (MI). However, infarct reperfusion aggravates microvascular obstruction (MO) and causes haemorrhage. We hypothesized that haemorrhagic MI causes magnetic susceptibility-induced signal voids that may interfere with iron oxide-labelled cell detection., Methods and Results: Pigs (n = 23) underwent 2 h occlusion of the left circumflex artery. Cine, T2*-weighted, perfusion, and delayed enhancement MRI scans were performed at 1 and 5 weeks, followed by ex vivo high-resolution scanning. At 1 week, MO was observed in 17 out of 21 animals. Signal voids were observed on T2*-weighted scans in five out of eight animals, comprising 24 +/- 22% of the infarct area. A linear correlation was found between area of MO and signal voids (R2 = 0.87; P = 0.002). At 5 weeks, MO was observed in two out of 13 animals. Signal voids were identified in three out of seven animals. Ex vivo scanning showed signal voids on T2*-weighted scanning in all animals because of the presence of haemorrhage, as confirmed by histology. Signal voids interfered with the detection of iron oxide-labelled cells ex vivo (n = 21 injections)., Conclusion: Haemorrhage in reperfused MI produces MRI signal voids, which may hamper tracking of iron oxide-labelled cells.

Iron oxide-labelled, single, living human umbilical vein endothelial cells (HUVECs) were imaged over time in vitro using a clinical 3.0-T magnetic resonance (MR) microscopy system. Labelling efficiency, toxicity, cell viability, proliferation and differentiation were assessed using flow cytometry, magnetic cell sorting and a phenanthroline assay. MR images were compared with normal light and fluorescence microscopy. Efficient uptake of iron oxide into HUVECs was shown, although with higher label uptake dose-dependent cytotoxic effects were observed, affecting cell viability. For MR imaging, a T2* weighted three-dimensional protocol was used with in-plane resolution of 39 x 48 microm2 and 100-microm slices with a scan time of 13 min. MRI could detect living cells in standard culture dishes at single-cell resolution, although label loss was observed that corresponded with the intracellular iron measurements. MR microscopy using iron oxide labels is a promising tool for studying HUVEC migration and cell biology in vitro and in vivo, but possible toxic effects of label uptake and loss of label over time should be taken into account.

Mouse myocardial infarction (MI) models are frequently used research tools. The most commonly applied model is coronary artery ligation. However, coronary ligation often gives rise to apical aneurysmatic infarcts of variable size. Other infarct models include cryoinfarction, which produces reproducible infarcts of the anterior wall. Thus far, this model has not been extensively described in mice. Therefore, we developed a murine cryoinfarction model and compared it with coronary ligation. Studies were performed under isoflurane anesthesia with a follow-up of 4 and 8 wk. Cryoinfarction was induced using a 2- or 3-mm cryoprobe. Two-dimensional guided M-mode echocardiography was used to assess fractional shortening and left ventricular (LV) dimensions at baseline and end point. At end point, hemodynamics were assessed using a 1.4-Fr Millar catheter. Pressure-diameter relations were constructed by combining echocardiography and hemodynamic data. Histological and morphometric analyses of infarct and remote areas were performed. At 4 wk, 3-mm cryoinfarction resulted in decreased LV fractional shortening as well as decreased global LV contractility and relaxation, which was comparable with coronary ligation. No adverse remodeling was observed at this time point, in contrast with the ligation model. However, progressive LV remodeling occured between 4 and 8 wk after cryoinfarction with a further decline in hemodynamic parameters and LV pump function. Histologically, cryoinfarction resulted in highly reproducible, transmural, cone-shaped infarcts with reperfusion at the macrovascular level. These results indicate that the cryoinfarction model represents the anterior myocardial infarct with modest adverse remodeling and may thus be representative for infarcts encountered in clinical practice.

Background: Contraction of transplanted myoblasts and their effects on function and remodeling after myocardial infarction remain controversial., Aim: We used magnetic resonance imaging (MRI) to study wall thickening and left ventricular (LV) function and geometry after myoblast transplantation., Methods and Results: Three weeks after cryo-infarction rabbits were randomized to receive an injection of approximately 2 x 10(8) myoblasts (n=8) or medium (n=9) into the scar. Cine MRI and contrast enhanced (ce) MRI images were acquired before injection (baseline) and 4 weeks later (endpoint). Regional wall thickening was measured at the site of transmural hyperenhancement. In the control group, regional wall thickening decreased to -15.3+/-8.6% at baseline, which further decreased to -18.3+/-5.7% at endpoint. Further, end-diastolic volume increased from 3.96+/-0.27 to 5.00+/-0.46 ml and end-systolic volume from 2.23+/-0.19 to 2.96+/-0.30 ml (both P<0.05 vs. baseline), which was accompanied by increased LV wall volumes (P<0.05 vs. baseline). In contrast, myoblast transplantation increased regional wall thickening from -11.9+/-15.9% at baseline to 26.9+/-17.0% (P<0.05 vs. control), which resulted in significantly improved two-dimensional ejection fractions at the infarct level and prevented the increase in end-diastolic and end-systolic volumes and wall volume., Conclusion: Intracardiac myoblast transplantation after myocardial infarction improves regional wall thickening and prevents progressive left ventricular remodeling.

Background: Pre-clinical and clinical studies suggest that transplantation of bone marrow-derived stem cells can improve global cardiac function. However, no quantitative assessment of regional systolic contraction and correlation with phenotype has been made. Therefore, we used our model of cryoinfarcted rabbit myocardium for intracardiac transplantation of a mixed population of bone marrow-derived cells and assessed both regional function and myogenic conversion of the cells., Methods: Nineteen New Zealand white rabbits underwent cryoinjury of the left ventricle. Autologous bone marrow (BM) cells were expanded in vitro. After 2 weeks, either 1 x 10(8) mixed BM-derived progenitor cells (BM group, n = 11) or vehicle (control group, n = 8) were injected into the cryoinjured region. Regional systolic function was measured using micromanometry and sonomicrometry before and 4 weeks after cell injection; cell phenotype was evaluated histologically., Results: All animals in the BM group significantly improved both systolic shortening (0.11 +/- 0.7 vs -0.05 +/- 0.05 mm in the control group, p < 0.05) and regional stroke work when compared with control (9.6 +/- 2.4 vs -1.2 +/- 1.2 mm . mm Hg, p < 0.003). In addition, the BM group had improved global diastolic function, as measured by minimum dP/dt and end-diastolic pressure. On histologic assessment, BM cells differentiated toward a myogenic phenotype., Conclusions: Transplanting a mixed population of marrow-derived cells that can adopt a myogenic phenotype improves regional contractility and diastolic relaxation after myocardial infarction.

Myoblast transplantation is a promising means of restoring cardiac function in infarcted areas. For optimization of transplant protocols, tracking the location and fate of the injected cells is necessary. An attractive imaging modality for this is magnetic resonance imaging (MRI) as it is noninvasive and as iron-labeled myoblasts provide a signal attenuation in T2*-weighted protocols. The aim of this study was to develop an efficient iron-labeling protocol for myoblasts and to visualize single-labeled cells using a clinical 1.5-T scanner. Pig myoblasts were labeled with a superparamagnetic iron oxide (SPIO) agent using a liposome transfection agent. Labeling efficiency, toxicity, cell viability, and proliferative capacity were measured for 10 days. Magnetic resonance (MR) of myoblast cultures used a T2*-weighted three-dimensional protocol with a maximum in-plane resolution of 19.5 x 26.0 microm2 and 50 microm slices. Use of liposomes improved SPIO labeling efficiency. Labeling did not induce toxicity or affect cell viability or proliferation. The cell distribution as observed with light and fluorescence microscopy matched the signal voids observed in the MRI datasets. Liposomes promote fast, nontoxic and efficient SPIO labeling of myoblasts that can be tracked by MRI microscopy in clinical scanners using susceptibility-weighted protocols.

Purpose: Currently, cells are transplanted into injured myocardium either through thoracotomy for open surgical delivery or through catheterization for endoventricular or intracoronary delivery; both methods have limitations. Open surgical delivery limits the potential patient population, whereas catheter-based delivery limits the ability to visualize the injection site and confirm delivery of the cells to the appropriate region. In this study, we examine the feasibility of cell transplantation into myocardium using a minimally invasive thoracoscopic approach., Description: Seven swine underwent thoracoscopic cell transplantation. Using a prototype injection device, approximately 10 million myoblasts were injected into the anterior, lateral, posterior, and apical regions of myocardium. Animals were recovered up to 7 days, and after euthanasia, hearts were explanted for histology., Evaluation: All seven swine had successful delivery of myoblasts into the defined injection sites, as confirmed by analysis of an operative video, magnetic resonance imaging of iron-oxide-labeled cells, and histologic examination., Conclusions: Thoracoscopic cellular cardiomyoplasty is feasible and allows the surgeon the benefits of direct visualization of the cell injection while minimizing morbidity associated with open cell delivery.

Background: To date, no data exist on the linearity and, therefore, the usefulness of the preload recruitable stroke work (PRSW) and end-systolic pressure-volume (ESPVR) relationships during acute afterload changes in heart failure., Aims: Our aim was, therefore, to characterize both relationships in a model of ventricular pacing induced heart failure at baseline and during acute changes in afterload., Methods: Dynamic left ventricular volume and transmural pressure were measured in 10 conscious dogs using sonomicrometry and micromanometry under control conditions and during heart failure produced by 3 weeks of rapid right ventricular pacing. Afterload was varied from baseline with intravenous infusions of nitroprusside and phenylephrine. Left ventricular function was assessed using the PRSW and ESPVR relationships., Results: Cardiac output demonstrated a linear inverse relationship with afterload in both normal and failing hearts (r2>0.5, P<0.001) with failure producing a parallel, downward shift of the afterload (x) vs. cardiac output (y) relationship (P<0.01). Yet, afterload variation did not affect PRSW or ESPVR relationships in either normal or failing hearts (r2<0.12, P>0.05)., Conclusion: Thus, the PRSW and ESPVR relationships are insensitive to acute afterload changes in both failing and normal hearts, and the failing left ventricle is no more afterload-sensitive than the normal heart.

Background: Multiple cell types are being proposed for cardiac repair, but side-by-side comparisons are lacking. We tested the hypothesis that intracardiac transplantation of autologous bone marrow- or skeletal muscle-derived progenitor cells improve regional heart function to a similar degree., Methods and Results: Thirty-nine New Zealand White rabbits underwent cryoinjury of the left ventricle and simultaneous hind limb bone marrow aspiration or soleus muscle biopsy. Both muscle and bone marrow cells were expanded in vitro. After 2 weeks, 10(8) skeletal muscle (SM group) or bone marrow-derived progenitor cells (BM group) were injected into the cryoinjured region (SM: n=12; BM: n=8). Medium alone was injected into the remaining animals (Control: n=16). Regional systolic function was measured using micromanometry and sonomicrometry at baseline, before, and 4 weeks after cell injection. Cell treatment resulted in a similar degree of improvement in a derivative of stroke work in the SM and BM groups (P=0.0026 and P=0.0085 versus Control, respectively). No significant difference was seen between BM and SM groups (P=0.9). On histology, engrafted cells were found in all of the cell treated animals. Injected myoblasts formed myotubes or muscle cells throughout the scar that expressed slow and fast myosin heavy chain. A subset of bone marrow cells differentiated toward a myogenic phenotype, as indicated by expression of desmin and alpha-sarcomeric actin in the engrafted areas., Conclusions: Transplantation and myogenic differentiation of bone marrow-derived progenitor cells increased regional systolic heart function after myocardial injury to a similar degree as skeletal myoblasts.

Heart failure has become the most prevalent cardiovascular syndrome, and its incidence continues to increase. Most cases of heart failure develop as a result of myocardial infarction. Although current treatment modalities have brought us the opportunity to reduce mortality and morbidity after myocardial infarction, our progress has plateaued due to our inability to treat the underlying problem, death of cardiomyocytes. Recently, a new option has emerged. Transplantation of undifferentiated cells into the damaged heart is a promising new treatment modality. These cells may have the capability of adapting to the cardiac environment, regenerating the damaged muscle, restoring cardiac function and preventing transition to heart failure. During the last few years many cell types have been proposed for cardiac repair and promising pre-clinical studies have moved some of these into the clinic. The most widely studied cell type is the progenitor cell of adult muscle, or the myoblast. When transplanted into the heart myoblasts are able to engraft and to a large degree regenerate the infarcted area. Although the feasibility of myoblast transplantation has been proven in animal models of infarction, many questions remain unanswered. In this review we will try to present an overview of where intracardiac myoblast transplantation stands and where it is heading. We also provide our insight into the future potential for myoblast transplantation clinically.

Labeling stem cells with FDA-approved superparamagnetic iron oxide particles makes it possible to track cells in vivo with magnetic resonance imaging (MRI), but high intracellular levels of iron can cause free radical formation and cytotoxicity. We hypothesized that the use of cationic liposomes would increase labeling efficiency without toxic effects. Rabbit skeletal myoblasts were labeled with iron oxide by: 1) uptake of iron oxide incorporated into cationic transfection liposomes (group I) or 2) customary endocytosis (group II). In both groups, cell proliferation and differentiation were measured and toxicity was assayed using trypan blue and ratio fluorescence microscopy with BODIPY 581/591 C11. The effects of the intracellular iron oxide on magnetic resonance image intensities were assessed in vitro and in vivo. Both methods resulted in uptake of iron intracellularly, yielding contrast-inducing properties on MRI images. In group II, however, incubation with iron oxide at high concentrations required for endocytosis caused generation of free radicals, a decrease in proliferation, and cell death. Cytotoxic effects in the remaining cells were still visible 24 h after incubation. Conversely, in group I, sufficient intracellular uptake for detection in vivo by MRI could be achieved at 100-fold lower concentrations of iron oxide, which resulted in a high percentage of labeled cells, high retention of the label, and no cytotoxic effects even after stressing the cells with a hypoxia-reoxygenation insult. The use of cationic liposomes for iron oxide stem cell labeling increases labeling efficiency approximately 100-fold without toxic effects. This technique results in high-contrast-inducing properties on MRI images both in vitro and in vivo and could thus be a valuable tool for tracking stem cells noninvasively.

Background: Recent studies have postulated that mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel activation may modulate mitochondrial function with the resultant induction of a preconditioning phenotype in the heart. We hypothesized that the modulation of mitochondrial homeostasis might confer preconditioning-like cardioprotection., Methods: We used a model of regional ischemia in Langendorff-perfused isolated rat hearts. Short-term administration of 2,4-dinitrophenol (DNP), an uncoupler of oxidative phosphorylation and cyclosporin A (CSA), an inhibitor of mitochondrial respiration, was used in an attempt to elicit preconditioning-like cardioprotection. The anti-ischemic drug trimetazidine, known to attenuate CSA-induced disruption in mitochondrial function, and the mitoK(ATP) channel blocker 5-hydroxydecanoic acid (5-HD) were used to inhibit the effects of DNP and CSA. Finally, we studied the effect of trimetazidine on adenosine-induced and ischemic preconditioning. Risk zone and infarct size were measured and expressed as a percentage of the risk zone (I/R ratio)., Results: DNP, CSA and adenosine pretreatment reduced infarct size (I/R ratio: DNP 9.0+/-2.4%, CSA 12.5+/-1.4%, adenosine 11.9+/-3.6%, all P<0.001 vs. control, 30.2+/-1.3%) similarly to ischemic preconditioning (9.5+/-0.6%, P<0.001 vs. control). Trimetazidine limited the effect of ischemic preconditioning (22.2+/-2.0%, P<0.001 vs. ischemic preconditioning) and completely reversed the DNP, CSA, and the adenosine-mediated reduction in infarct size. 5-HD abolished the effect of ischemic preconditioning and CSA., Conclusion: DNP and CSA trigger preconditioning-like cardioprotection in the isolated rat heart. Trimetazidine, a known mitochondrial 'protector', attenuated both drug-induced and ischemic preconditioning. These data support the hypothesis that modulation of mitochondrial homeostasis may be a common downstream cellular event linking different triggers of preconditioning.