Clinical recommendations of cardiac magnetic resonance, Part II: inflammatory and congenital heart disease, cardiomyopathies and cardiac tumors: a position paper of the working group 'Applicazioni della Risonanza Magnetica' of the Italian Society of Cardiology.

The current document was developed by the working group on the 'application of cardiac magnetic resonance' of the Italian Society of Cardiology to provide a perspective on the current state of technical advances and clinical cardiac magnetic resonance applications and to inform cardiologists how to implement their clinical and diagnostic pathway with the introduction of this technique in the clinical practice. Appropriateness criteria were defined using a score system: score 1-3 = inappropriate (test is not generally acceptable and is not a reasonable approach for the indication), score 4-6 = uncertain (test may be generally acceptable and may be a reasonable approach for the indication but more research and/or patient information is needed to classify the indication definitively) and score 7-9 = appropriate (test is generally acceptable and is a reasonable approach for the indication).

Left atrial function in cardiac amyloidosis.

AIMS: Left atrium can be involved by amyloid deposition in familial amyloid polyneuropathy (FAP). The aim of our study is to assess left atrium function in atrial amyloidosis. METHODS: Twenty-eight FAP patients (53 ±â€Š12 years) and a control group of 22 asymptomatic individuals (49 ±â€Š11 years) underwent strain echocardiography and cardiac magnetic resonance (CMR). CMR by late gadolinium enhancement (LGE) was used to assess the left atrium amyloid deposition, whereas strain echocardiography was used to quantify the left atrium deformation. The following atrial longitudinal strain (ALS) parameters were assessed: peak at the end of ventricular systole (peak-ALS), peak at early diastole (early-ALS), negative peak in late diastole, precontraction (prec)-ALS (difference between peak-ALS and early-ALS), and late ALS (sum of negative peak and prec-ALS). RESULTS: CMR showed atrial LGE in 14 FAP patients (LGE-atrial group), whereas 14 FAP patients showed no LGE (no-LGE-atrial group). Peak-ALS was significantly lower in the LGE-atrial group (22.8 ±â€Š13%) compared with the no-LGE-atrial group (59.6 ±â€Š33.1%; P = 0.001) and controls (47.4 ±â€Š16.4%; P = 0.001). Early-ALS was lower in the LGE-atrial group (10.2 ±â€Š6.2%) compared with the controls (26.3 ±â€Š11.9%; P = 0.02) and the no-LGE-atrial group (30.2 ±â€Š22.4%; P = 0.01). Prec-ALS was lower (P = 0.001) in the LGE-atrial group (12.6 ±â€Š7.8%) compared with the no-LGE-atrial group (26.2 ±â€Š15%). Conversely, late-ALS was higher (P = 0.04) in the no-LGE-atrial group (22.8 ±â€Š12.3%) compared with the controls (13.9 ±â€Š9%); no significant differences were found in the negative peak among groups. CONCLUSIONS: Patients with atrial amyloidosis have an adverse left atrium remodeling associated with left atrium dysfunction. Left atrium assessment may provide useful information in the clinical and prognostic stratification of amyloidotic patients.

Regional evidence of modulation of cardiac adiponectin level in dilated cardiomyopathy: pilot study in a porcine animal model.

BACKGROUND: The role of systemic and myocardial adiponectin (ADN) in dilated cardiomyopathy is still debated. We tested the regulation of both systemic and myocardial ADN and the relationship with AMP-activated protein kinase (AMPK) activity in a swine model of non-ischemic dilated cardiomyopathy. METHODS AND RESULTS: Cardiac tissue was collected from seven instrumented adult male minipigs by pacing the left ventricular (LV) free wall (180 beats/min, 3 weeks), both from pacing (PS) and opposite sites (OS), and from five controls. Circulating ADN levels were inversely related to global and regional cardiac function. Myocardial ADN in PS was down-regulated compared to control (p < 0.05), yet ADN receptor 1 was significantly up-regulated (p < 0.05). No modifications of AMPK were observed in either region of the failing heart. Similarly, myocardial mRNA levels of PPARγ, PPARα, TNFα, iNOS were unchanged compared to controls. CONCLUSIONS: Paradoxically, circulating ADN did not show any cardioprotective effect, confirming its role as negative prognostic biomarker of heart failure. Myocardial ADN was reduced in PS compared to control in an AMPK-independent fashion, suggesting the occurrence of novel mechanisms by which reduced cardiac ADN levels may regionally mediate the decline of cardiac function.

Pacing-induced regional differences in adenosine receptors mRNA expression in a swine model of dilated cardiomyopathy.

The adenosinergic system is essential in the mediation of intrinsic protection and myocardial resistance to insult; it may be considered a cardioprotective molecule and adenosine receptors (ARs) represent potential therapeutic targets in the setting of heart failure (HF). The aim of the study was to test whether differences exist between mRNA expression of ARs in the anterior left ventricle (LV) wall (pacing site: PS) compared to the infero septal wall (opposite region: OS) in an experimental model of dilated cardiomyopathy. Cardiac tissue was collected from LV PS and OS of adult male minipigs with pacing-induced HF (n = 10) and from a control group (C, n = 4). ARs and TNF-α mRNA expression was measured by Real Time-PCR and the results were normalized with the three most stably expressed genes (GAPDH, HPRT1, TBP). Immunohistochemistry analysis was also performed. After 3 weeks of pacing higher levels of expression for each analyzed AR were observed in PS except for A(1)R (A(1)R: C = 0.6±0.2, PS = 0.1±0.04, OS = 0.04±0.01, p<0.0001 C vs. PS and OS respectively; A(2A)R: C = 1.04±0.59, PS = 2.62±0.79, OS = 2.99±0.79; A(2B)R: C = 1.2±0.1, PS = 5.59±2.3, OS = 1.59±0.46; A(3)R: C = 0.76±0.18, PS = 8.40±3.38, OS = 4.40±0.83). Significant contractile impairment and myocardial hypoperfusion were observed at PS after three weeks of pacing as compared to OS. TNF-α mRNA expression resulted similar in PS (6.3±2.4) and in OS (5.9±2.7) although higher than in control group (3.4±1.5). ARs expression was mainly detected in cardiomyocytes. This study provided new information on ARs local changes in the setting of LV dysfunction and on the role of these receptors in relation to pacing-induced abnormalities of myocardial perfusion and contraction. These results suggest a possible therapeutic role of adenosine in patients with HF and dyssynchronous LV contraction.

Endocardial and epicardial deformations in cardiac amyloidosis and hypertrophic cardiomyopathy.

BACKGROUND: The aim of the present study was to analyze epicardial (EPI) and endocardial (ENDO) strain (S) in patients with transthyretin-related cardiac amyloidosis (TTR-CA) and hypertrophic cardiomyopathy (HCM) using echocardiography (TTE) with 2-dimensional feature tracking imaging (FTI). METHODS AND RESULTS: Thirty-three subjects (11 with HCM, 11 with TTR-CA, and 11 healthy subjects as controls) with a New York Heart Association functional class ≤ II underwent conventional TTE and FTI. TTE was used for the evaluation of left ventricle (LV) wall thickness, mass, systolic and diastolic function. FTI was used for the evaluation of EPI and ENDO longitudinal, and circumferential, and radial S. LV wall thickness and mass were higher in both TTR-CA and HCM in comparison with controls (P < 0.001), but ejection fraction (EF) was similar among patients with TTR-CA, HCM and controls (63 ± 6%, 64 ± 6%, 61 ± 5%, respectively). ENDO and EPI longitudinal and circumferential S and radial S were significantly lower in HCM and TTR-CA when compared with controls (P < 0.01). No differences in EPI and ENDO longitudinal S, ENDO circumferential S and radial S were found between TTR-CA and HCM groups, while EPI circumferential S was significantly lower in the TTRCA group (6 ± 3.3%) than in the HCM group (8.1 ± 4.3%; P < 0.0001). CONCLUSIONS: Longitudinal, circumferential and radial LV deformations are impaired in patients with TTR-CA and HCM with a preserved EF. Impairment of EPI circumferential strain is greater in TTR-CA than in HCM.

Ferritin as a reporter gene for in vivo tracking of stem cells by 1.5-T cardiac MRI in a rat model of myocardial infarction.

The methods currently utilized to track stem cells by cardiac MRI are affected by important limitations, and new solutions are needed. We tested human ferritin heavy chain (hFTH) as a reporter gene for in vivo tracking of stem cells by cardiac MRI. Swine cardiac stem/progenitor cells were transduced with a lentiviral vector to overexpress hFTH and cultured to obtain cardiospheres (Cs). Myocardial infarction was induced in rats, and, after 45 min, the animals were subjected to intramyocardial injection of ∼200 hFTH-Cs or nontransduced Cs or saline solution in the border zone. By employing clinical standard 1.5-Tesla MRI scanner and a multiecho T2* gradient echo sequence, we localized iron-accumulating tissue only in hearts treated with hFTH-Cs. This signal was detectable at 1 wk after infarction, and its size did not change significantly after 4 wk (6.33 ± 3.05 vs. 4.41 ± 4.38 mm(2)). Cs transduction did not affect their cardioreparative potential, as indicated by the significantly better preserved left ventricular global and regional function and the 36% reduction in infarct size in both groups that received Cs compared with control infarcts. Prussian blue staining confirmed the presence of differentiated, iron-accumulating cells containing mitochondria of porcine origin. Cs-derived cells displayed CD31, α-smooth muscle, and α-sarcomeric actin antigens, indicating that the differentiation into endothelial, smooth muscle and cardiac muscle lineage was not affected by ferritin overexpression. In conclusion, hFTH can be used as a MRI reporter gene to track dividing/differentiating stem cells in the beating heart, while simultaneously monitoring cardiac morpho-functional changes.

Placental stem cells pre-treated with a hyaluronan mixed ester of butyric and retinoic acid to cure infarcted pig hearts: a multimodal study.

AIMS: Pre-treating placenta-derived human mesenchymal stem cells (FMhMSCs) with a hyaluronan mixed ester of butyric and retinoic acid (HBR) potentiates their reparative capacity in rodent hearts. Our aim was to test FMhMSCs in a large-animal model by employing a novel combination of in vivo and ex vivo analyses. METHODS AND RESULTS: Matched regional quantifications of myocardial function and viability were performed by magnetic resonance imaging (MRI) and positron emission tomography (PET) 4 weeks after myocardial infarction combined with intramyocardial injection of FMhMSCs (n = 7), or HBR-pre-treated FMhMSCs (HBR-FMhMSCs, n = 6), or saline solution (PBS, n = 7). Sham-operated pigs (n = 4) were used as control animals. Despite no differences in the ejection fraction and haemodynamics, regional MRI revealed, in pigs treated with HBR-FMhMSCs compared with the other infarcted groups, a 40% smaller infarct scar size and a significant improvement of the end-systolic wall thickening and circumferential shortening of the infarct border zone. Consistently, PET showed that myocardial perfusion and glucose uptake were, respectively, 35 and 23% higher in the border zone of pigs treated with HBR-FMhMSCs compared with the other infarcted groups. Histology supported in vivo imaging; the delivery of HBR-FMhMSCs significantly enhanced capillary density and decreased fibrous tissue by approximately 68%. Moreover, proteomic analysis of the border zone in the HBR-FMhMSCs group and the FMhMSCs group indicated, respectively, 45 and 30% phenotypic homology with healthy tissue, while this homology was only 26% in the border zone of the PBS group. CONCLUSION: Our results support a more pronounced reparative potential of HBR-pre-treated FMhMSCs in a clinically relevant animal model of infarction and highlight the necessity of using combined diagnostic imaging to avoid underestimations of stem cell therapeutic effects in the heart.

Intramural myocardial hemorrhagic rupture in a patient with metastatic cancer and myocardial infarction.

A 77-year-old man with anterior ST-elevated myocardial infarction and lateral myocardial rupture underwent successful percutaneous revascularization. Cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) unveiled a disseminated metastatic cancer, likely responsible not only for a prothrombotic paraneoplastic syndrome but also for ventricular metastasis and myocardial rupture. The patient unfortunately died because of noncardiovascular complications of cancer.

Hyaluronan mixed esters of butyric and retinoic acid affording myocardial survival and repair without stem cell transplantation.

Possible cardiac repair by adult stem cell transplantation is currently hampered by poor cell viability and delivery efficiency, uncertain differentiating fate in vivo, the needs of ex vivo cell expansion, and consequent delay in transplantation after the onset of heart attack. By the aid of magnetic resonance imaging, positron emission tomography, and immunohistochemistry, we show that injection of a hyaluronan mixed ester of butyric and retinoic acid (HBR) into infarcted rat hearts afforded substantial cardiovascular repair and recovery of myocardial performance. HBR restored cardiac [(18)F]fluorodeoxyglucose uptake and increased capillary density and led to the recruitment of endogenous Stro-1-positive stem cells. A terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay demonstrated that HBR-treated hearts exhibited a decrease in the number of apoptotic cardiomyocytes. In isolated rat cardiomyocytes and Stro-1 stem cells, HBR enhanced the transcription of vascular endothelial growth factor, hepatocyte growth factor, kdr, akt, and pim-1. HBR also increased the secretion of vascular endothelial growth factor and hepatocyte growth factor, suggesting that the mixed ester may have recruited both myocardial and Stro-1 cells also. An increase in capillarogenesis was induced in vitro with medium obtained from HBR-exposed cells. In the infarcted myocardium, HBR injection increased histone H4 acetylation significantly. Acetyl-H4 immunoreactivity increased in rat cardiomyocytes and Stro-1 cells exposed to HBR, compared with untreated cells. In conclusion, efficient cardiac regenerative therapy can be afforded by HBR without the need of stem cell transplantation or vector-mediated gene delivery.

The obesity paradox and myocardial infarct size.

OBJECTIVE: Obese subjects have a risk of death from cardiovascular disease higher than those with normal body weight. Obese patients, however, have a better outcome when undergoing coronary revascularisation, and when suffering from heart failure or chronic kidney disease. The term 'obesity paradox' underlines the divergence between increased risk and better outcome in sick obese patients. We tested the hypothesis that the obesity paradox could also occur in myocardial infarction. METHODS: A group of 89 patients (mean age 62 +/- 11 years) with previous myocardial infarction (Q-wave in 72 patients) underwent contrast-enhanced MRI. RESULTS: Areas of delayed contrast enhancement (which reflects myocardial necrosis) were present in 15 +/- 9% of left ventricular myocardium. Infarct size was not influenced by patient age, gender, history of arterial hypertension, hypercholesterolaemia, hypertriglyceridaemia nor tobacco smoking. Infarct size, however, was larger in insulin-dependent diabetic patients (P = 0.06) and in those with a family history of premature coronary artery disease (P = 0.06). Surprisingly, infarct size was smaller in obese patients (11 +/- 4% of left ventricular myocardium) than in those with normal body weight (16 +/- 9% of left ventricular myocardium, P = 0.03). Insulin-dependent diabetes mellitus, obesity and family history of coronary artery disease were the only independent predictors of infarct size at multiple linear regression analysis. CONCLUSIONS: Owing to its limitations (small sample size and exclusion of extremely obese patients), this study generates a working hypothesis, which should be tested in larger prospective studies, that the obesity paradox could also occur in myocardial infarction.