Giovanni Donato Aquaro

Myocardial fibrosis in isolated left ventricular non-compaction and its relation to disease severity.

The aim of the present study was to evaluate the prevalence and extent of myocardial fibrosis in patients with isolated left ventricular non‐compaction (LVNC) and to determine its relation to clinical status and LV systolic function.

Progression of Myocardial Fibrosis Assessed With Cardiac Magnetic Resonance in Hypertrophic Cardiomyopathy

OBJECTIVES This study sought to assess the rate of progression of fibrosis by 2 consecutive cardiac magnetic resonance (CMR) examinations and its relation with clinical variables. BACKGROUND In hypertrophic cardiomyopathy (HCM) myocardial fibrosis, detected by late gadolinium enhancement (LGE), is associated to a progressive ventricular dysfunction and worse prognosis. METHODS A total of 55 HCM patients (37 males; mean age 43 ± 18 years) underwent 2 CMR examinations (CMR-1 and CMR-2) separated by an interval of 719 ± 410 days. Extent of LGE was measured, and the rate of progression of LGE (LGE-rate) was calculated as the ratio between the increment of LGE (in grams) and the time (months) between the CMR examinations. RESULTS At CMR-1, LGE was detected in 45 subjects, with an extent of 13.3 ± 15.2 g. At CMR-2, 53 (96.4%) patients had LGE, with an extent of 24.6 ± 27.5 g. In 44 patients, LGE extent increased significantly (≥1 g). Patients with apical HCM had higher increments of LGE (p = 0.004) and LGE-rate (p < 0.001) than those with other patterns of hypertrophy. The extent of LGE at CMR-1 and the apical pattern of hypertrophy were independent predictors of the increment of LGE. Patients with worsened New York Heart Association functional class presented higher increase of LGE (p = 0.031) and LGE-rate (p < 0.05) than those with preserved functional status. CONCLUSIONS Myocardial fibrosis in HCM is a progressive and fast phenomenon. LGE increment, related to a worse clinical status, is more extensive in apical hypertrophy than in other patterns.

Myocardial Salvage by CMR Correlates With LV Remodeling and Early ST-Segment Resolution in Acute Myocardial Infarction

OBJECTIVES The purpose of this study was to assess the association of myocardial salvage by cardiac magnetic resonance (CMR) with left ventricular (LV) remodeling and early ST-segment resolution in patients with acute myocardial infarction (MI). BACKGROUND Experimental studies revealed that MI size is strongly influenced by the extent of the area at risk (AAR), limiting its accuracy as a marker of reperfusion treatment efficacy in acute MI studies. Hence, an index correcting MI size for AAR extent is warranted. T2-weighted CMR and delayed-enhancement CMR, respectively, enable the determination of AAR and MI size, and the myocardial salvage index (MSI) is calculated by correcting MI size for AAR extent. Nevertheless, the clinical value of CMR-derived MSI has not been evaluated yet. METHODS In a prospective cohort of 137 consecutive patients with acutely reperfused ST-segment elevation MI, CMR was performed at 1 week and 4 months. T2-weighted CMR was used to quantify AAR, whereas MI size was detected by delayed-enhancement imaging. MSI was defined as AAR extent minus MI size divided by AAR extent. Adverse LV remodeling was defined as an increase in LV end-systolic volume of >or=15%. The degree of ST-segment resolution 1 h after reperfusion was also calculated. RESULTS AAR extent was consistently larger than MI size (32+/-15% of LV vs. 18+/-13% of LV, p<0.0001), yielding an MSI of 0.46+/-0.24. MI size was closely related to AAR extent (r=0.81, p<0.0001). After correction for the main baseline characteristics by multivariate analyses, MSI was a major and independent determinant of adverse LV remodeling (odds ratio: 0.64; 95% confidence interval: 0.49 to 0.84, p=0.001) and was independently associated with early ST-segment resolution (B coefficient=0.61, p<0.0001). CONCLUSIONS In patients with reperfused ST-segment elevation MI, CMR-derived MSI is independently associated with adverse LV remodeling and early ST-segment resolution, opening new perspectives on its use in studies testing novel reperfusion strategies.

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.

Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardiovascular magnetic study

Background— In idiopathic dilated cardiomyopathy, there are scarce data on the influence of late gadolinium enhancement (LGE) assessed by cardiovascular magnetic resonance on left ventricular (LV) remodeling. Methods and Results— Fifty-eight consecutive patients with idiopathic dilated cardiomyopathy underwent baseline clinical, biohumoral, and instrumental workup. Medical therapy was optimized after study enrollment. Cardiovascular magnetic resonance was used to assess ventricular volumes, function, and LGE extent at baseline and 24-month follow-up. LV reverse remodeling (RR) was defined as an increase in LV ejection fraction ≥10 U, combined with a decrease in LV end-diastolic volume ≥10% at follow-up. &Dgr;LGE extent was the difference in LGE extent between follow-up and baseline. LV-RR was observed in 22 patients (38%). Multivariate regression analysis showed that the absence of LGE at baseline cardiovascular magnetic resonance was a strong predictor of LV-RR (odds ratio, 10.857 [95% confidence interval, 1.844–63.911]; P=0.008) after correction for age, heart rate, New York Heart Association class, LV volumes, and LV and right ventricular ejection fractions. All patients with baseline LGE (n=26; 45%) demonstrated LGE at follow-up, and no patient without baseline LGE developed LGE at follow-up. In LGE-positive patients, there was an increase in LGE extent over time (P=0.034), which was inversely related to LV ejection fraction variation (Spearman &rgr;, −0.440; P=0.041). Five patients showed an increase in LGE extent >75th percentile of &Dgr;LGE extent, and among these none experienced LV-RR and 4 had a decrease in LV ejection fraction ≥10 U at follow-up. Conclusions— In patients with idiopathic dilated cardiomyopathy, the absence of LGE at baseline is a strong independent predictor of LV-RR at 2-year follow-up, irrespective of the initial clinical status and the severity of ventricular dilatation and dysfunction. The increase in LGE extent during follow-up was associated with progressive LV dysfunction.

Cardiac Magnetic Resonance Predicts Outcome in Patients With Premature Ventricular Complexes of Left Bundle Branch Block Morphology

OBJECTIVES We investigated whether the presence of right ventricular (RV) abnormalities detected by cardiovascular magnetic resonance (CMR) predict adverse outcome in patients presenting with frequent premature ventricular complexes (PVCs) of left bundle branch block (LBBB) morphology. BACKGROUND CMR is a component of the diagnostic workup for the differential diagnosis between arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and idiopathic RV tachycardia. RV abnormalities evaluated by CMR could have prognostic importance. METHODS Four hundred forty consecutive patients with >1,000 PVCs of LBBB morphology (minor diagnostic criterion of ARVC/D) and no other pre-existing criteria were prospectively enrolled. RV wall motion (WM), signal abnormalities, dilation, and reduced ejection fraction evaluated by CMR were considered imaging criteria of ARVC/D. Follow-up was performed evaluating an index composite end point of 3 cardiac events: cardiac death, resuscitated cardiac arrest, and appropriate implantable cardiac-defibrillator shock. RESULTS Subjects with multiple RV abnormalities (RVA-2 group) had worse outcome than the no-RVA group (hazard ratio [HR]: 48.6; 95% confidence interval [CI]: 6.1 to 384.8; p < 0.001). Of the 61 patients in the RVA-2 group, only 6 had a definite diagnosis of ARVC/D applying the Task Force Criteria. Also, subjects with a single imaging criterion (RVA-1 group) had worse outcome than the no-RVA group (HR: 18.2; 95% CI: 2.0 to 162.6; p = 0.01). Patients with only WM abnormalities had higher prevalence of cardiac events than no-RVA (HR: 27.2; 95% CI: 3.0 to 244.0; p = 0.03). CONCLUSIONS In subjects with frequent PVC of LBBB morphology, CMR allows risk stratification. RV abnormalities were associated with worse outcome.

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 [18F]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.

Q-wave prediction of myocardial infarct location, size and transmural extent at magnetic resonance imaging.

ObjectiveWe investigated how pathologic Q waves or equivalents predict location, size and transmural extent of myocardial infarction (MI). MethodsMI characteristics, detected by contrast-enhanced magnetic resonance imaging, were compared with 12-lead electrocardiogram in 79 patients with previous first MI. ResultsQ waves involved only the anterior leads (V1–V4) in 13 patients: in all patients MI involved the anterior and anteroseptal walls and apex; 81% of scar tissue was within these regions. Q waves involved only the inferior leads (II, III, aVF) in 13 patients: in 12 of these patients MI involved the inferior and inferoseptal walls; however, only 59% of scar occupied these regions. Q waves involved only lateral leads (V5, V6, I, aVL) in 11 patients: in nine of these patients MI involved the lateral wall but only 27% of scar tissue was within this wall. Q waves involved two electrocardiogram locations in 42 patients. In the 79 patients as a whole, the number of anterior Q waves was related to anterior MI size (r=0.70); however, the number of inferior and lateral Q waves was only weakly related to MI size in corresponding territories (r=0.35 and 0.33). A tall and broad R wave in V1–V2 was a more powerful predictor of lateral MI size than Q waves. Finally, the number of Q waves accurately reflected the transmural extent of the infarction (r=0.70) only in anterior infarctions. ConclusionQ waves reliably predict MI location, size and transmural extent only in patients with anterior infarction. A tall and broad R wave in V1–V2 reflects a lateral MI.

A Prospective Randomized Trial of Thrombectomy Versus No Thrombectomy in Patients With ST-Segment Elevation Myocardial Infarction and Thrombus-Rich Lesions: MUSTELA (MUltidevice Thrombectomy in Acute ST-Segment ELevation Acute Myocardial Infarction) Trial

OBJECTIVES The aim of this study was to evaluate whether thrombectomy during primary percutaneous coronary intervention (pPCI) in patients with high thrombus burden improves myocardial reperfusion and reduces infarct size. BACKGROUND Thrombectomy aims at reducing distal thrombotic embolization during pPCI, improving myocardial reperfusion and clinical outcome. METHODS We randomized 208 patients with high thrombus burden in a 1:1 ratio to either pPCI with thrombectomy (Group T) or standard pPCI (Group S). Thrombectomy was performed with either rheolytic or manual aspiration catheters. Three-month magnetic resonance imaging was performed to assess infarct size and transmurality and microvascular obstruction (MVO). The primary endpoints were ST-segment elevation resolution (STR) >70% at 60 min and 3-month infarct size. RESULTS The baseline profile was similar between groups, except for a higher rate of initial Thrombolysis In Myocardial Infarction flow grade 3 in Group S (p = 0.002). Group T showed a significantly higher rate of STR (57.4% vs. 37.3%; p = 0.004) and of final myocardial blush 3 (68.3% vs. 52.9%; p = 0.03). Group T and Group S did not differ with regard to infarct size (20.4 ± 10.5% vs. 19.3 ± 10.6%; p = 0.54) and transmurality (11.9 ± 12.0% vs. 11.6 ± 12.7%; p = 0.92), but Group T showed significantly less MVO (11.4% vs. 26.7%; p = 0.02) and a higher prevalence of inhomogeneous scar (p < 0.0001). One-year freedom from major adverse cardiac events was similar between groups. CONCLUSIONS Thrombectomy as an adjunct to pPCI in patients with high thrombus load yielded better post-procedural STR and reduced MVO at 3 months but was not associated with a reduction in infarct size and transmurality. Thromboaspiration in Patients With High Thrombotic Burden Undergoing Primary Percutaneous (Coronary Intervention; NCT01472718).

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.