Angelo Carbone

Validation of cardiovascular magnetic resonance assessment of pericardial adipose tissue volume

BackgroundPericardial adipose tissue (PAT) has been shown to be an independent predictor of coronary artery disease. To date its assessment has been restricted to the use of surrogate echocardiographic indices such as measurement of epicardial fat thickness over the right ventricular free wall, which have limitations. Cardiovascular magnetic resonance (CMR) offers the potential to non-invasively assess total PAT, however like other imaging modalities, CMR has not yet been validated for this purpose. Thus, we sought to describe a novel technique for assessing total PAT with validation in an ovine model.Methods11 merino sheep were studied. A standard clinical series of ventricular short axis CMR images (1.5T Siemens Sonata) were obtained during mechanical ventilation breath-holds. Beginning at the mitral annulus, consecutive end-diastolic ventricular images were used to determine the area and volume of epicardial, paracardial and pericardial adipose tissue. In addition adipose thickness was measured at the right ventricular free wall. Following euthanasia, the paracardial adipose tissue was removed from the ventricle and weighed to allow comparison with corresponding CMR measurements.ResultsThere was a strong correlation between CMR-derived paracardial adipose tissue volume and ex vivo paracardial mass (R2 = 0.89, p < 0.001). In contrast, CMR measurements of corresponding RV free wall paracardial adipose thickness did not correlate with ex vivo paracardial mass (R2 = 0.003, p = 0.878).ConclusionIn this ovine model, CMR-derived paracardial adipose tissue volume, but not the corresponding and conventional measure of paracardial adipose thickness over the RV free wall, accurately reflected paracardial adipose tissue mass. This study validates for the first time, the use of clinically utilised CMR sequences for the accurate and reproducible assessment of pericardial adiposity. Furthermore this non-invasive modality does not use ionising radiation and therefore is ideally suited for future studies of PAT and its role in cardiovascular risk prediction and disease in clinical practice.

Cardiovascular magnetic resonance-derived aortic distensibility: validation and observed regional differences in the elderly.

Objective Applanation tonometry evaluation of pulse wave velocity is widely accepted as the ‘gold standard’ method for noninvasively assessing arterial stiffness. Newer noninvasive tools such as cardiovascular magnetic resonance can also evaluate arterial stiffness, but have not been validated. The aim of this study was to validate cardiovascular magnetic resonance-derived aortic distensibility with pulse wave velocity and to investigate age-related changes in regional aortic distensibility. Methods Ten young (20–30 years) and ten old (60–70 years) patients underwent applanation tonometry assessment of pulse wave velocity. Cardiovascular magnetic resonance measurements of arterial stiffness were evaluated by aortic distensibility (10−3 mmHg−1) at three separate locations, the ascending aorta, proximal descending aorta and distal descending aorta. Results Pulse wave velocity correlated strongly with aortic distensibility measurements at each site: ascending aorta R2 = 0.57, proximal descending aorta R2 = 0.60 and distal descending aorta R2 = 0.72. As expected, the old cohort had significantly increased aortic stiffness compared with the young cohort (P < 0.01). Post-hoc comparison showed an increase in proximal stiffness in the old cohort compared with the young cohort (P = 0.018). Conclusion Cardiovascular magnetic resonance-derived aortic distensibility is an accurate measure of arterial stiffness and can evaluate regional stiffness through the aorta. Furthermore, our results suggest that aortic stiffening may preferentially occur in the proximal aortic segments in the elderly.

Reparative Effects of Allogeneic Mesenchymal Precursor Cells Delivered Transendocardially in Experimental Nonischemic Cardiomyopathy

OBJECTIVESnThis study set out to evaluate the safety and efficacy of allogeneic bone marrow mesenchymal precursor cells (MPC) delivered by multisegmental, transendocardial implantation in the setting of nonischemic cardiomyopathy (NICM).nnnBACKGROUNDnProspectively isolated MPC have shown capacity to mediate cardiovascular repair in myocardial ischemia. However, their efficacy in NICM remains undetermined.nnnMETHODSnMesenchymal precursor cells were prepared from ovine bone marrow by immunoselection using the tissue nonspecific alkaline phosphatase, or STRO-3, monoclonal antibody. Fifteen sheep with anthracycline-induced NICM were assigned to catheter-based, transendocardial injections of allogeneic MPC (n = 7) or placebo (n = 8), under electromechanical mapping guidance. Follow-up was for 8 weeks, with end points assessed by cardiac magnetic resonance, echocardiography, and histology.nnnRESULTSnIntramyocardial injections were distributed similarly throughout the left ventricle in both groups. Cell transplantation was associated with 1 death late in follow-up, compared with 3 early deaths among placebo animals. Left ventricular end-diastolic size increased in both cohorts, but MPC therapy attenuated end-systolic dilation and stabilized ejection fraction, with a nonsignificant increase (37.3 ± 2.8% before, 39.2 ± 1.4% after) compared with progressive deterioration after placebo (38.8 ± 4.4% before, 32.5 ± 4.9% after, p < 0.05). Histological outcomes of cell therapy included less fibrosis burden than in the placebo group and an increased density of karyokinetic cardiomyocytes and myocardial arterioles (p < 0.05 for each). These changes occurred in the presence of modest cellular engraftment after transplantation.nnnCONCLUSIONSnMultisegmental, transendocardial delivery of cell therapy can be achieved effectively in NICM using electromechanical navigation. The pleiotropic properties of immunoselected MPC confer benefit to nonischemic cardiac disease, extending their therapeutic potential beyond the setting of myocardial ischemia.

Coronary β2-adrenoreceptors mediate endothelium-dependent vasoreactivity in humans: novel insights from an in vivo intravascular ultrasound study

AIMSnThe interaction between coronary β(2)-adrenoreceptors and segmental plaque burden is complex and poorly understood in humans. We aimed to validate intracoronary (IC) salbutamol as a novel endothelium-dependent vasodilator utilizing intravascular ultrasound (IVUS), and thus assess relationships between coronary β(2)-adrenoreceptors, regional plaque burden and segmental endothelial function.nnnMETHODS AND RESULTSnIn 29 patients with near-normal coronary angiograms, IVUS-upon-Doppler Flowire imaging protocols were performed. Protocol 1: incremental IC salbutamol (0.15, 0.30, 0.60 μg/min) infusions (15 patients, 103 segments); protocol 2: salbutamol (0.30 μg/min) infusion before and after IC administration of N(G)-monomethyl-L-arginine (L-NMMA) (10 patients, 82 segments). Vehicle infusions (IC dextrose) were performed in 4 patients (21 segments). Macrovascular response [% change segmental lumen volume (ΔSLV)] and plaque burden [per cent atheroma volume (PAV)] were studied in 5-mm coronary segments. Microvascular response [per cent change in coronary blood flow (ΔCBF)] was calculated following each infusion. Intracoronary salbutamol demonstrated significant dose-response ΔSLV and ΔCBF from baseline, respectively (0.15 μg/min: 3.5 ± 1.3%, 28 ± 14%, P = 0.04, P = NS; 0.30 μg/min: 5.5 ± 1.4%, 54 ± 17%, P = 0.001, P < 0.0001; 0.60 μg/min: 4.8 ± 1.6%, 66 ± 15%, P = 0.02, P < 0.0001), with ΔSLV responses further exemplified in low vs. high plaque burden groups. Salbutamol vasomotor responses were suppressed by l-NMMA, supporting nitric oxide-dependent mechanisms. Vehicle infusions resulted in no significant ΔSLV or ΔCBF. Multivariate analysis including conventional cardiovascular risk factors, PAV, segmental remodelling and plaque eccentricity indices identified PAV as the only significant predictor of a ΔSLV to IC salbutamol (coefficient -0.18, 95% CI -0.32 to -0.044, P = 0.015). Conclusions Intracoronary salbutamol is a novel endothelium-dependent epicardial and microvascular coronary vasodilator. Intravascular ultrasound-derived regional plaque burden is a major determinant of segmental coronary endothelial function.

Atrial remodeling in an ovine model of anthracycline-induced nonischemic cardiomyopathy: remodeling of the same sort.

Atrial Remodeling in Doxorubicin Cardiomyopathy. Introduction: All preclinical studies of atrial remodeling in heart failure (HF) have been confined to a single model of rapid ventricular pacing. To evaluate whether the atrial changes were specific to the model or represented an end result of HF, this study aimed to characterize atrial remodeling in an ovine model of doxorubicin‐induced cardiomyopathy.

Percutaneous closure of atrial septal defects leads to normalisation of atrial and ventricular volumes.

BackgroundPercutaneous closure of atrial septal defects (ASDs) should potentially reduce right heart volumes by removing left-to-right shunting. Due to ventricular interdependence, this may be associated with impaired left ventricular filling and potentially function. Furthermore, atrial changes post-ASD closure have been poorly understood and may be important for understanding risk of atrial arrhythmia post-ASD closure. Cardiovascular magnetic resonance (CMR) is an accurate and reproducible imaging modality for the assessment of cardiac function and volumes. We assessed cardiac volumes pre- and post-percutaneous ASD closure using CMR.MethodsConsecutive patients (n = 23) underwent CMR pre- and 6 months post-ASD closure. Steady state free precession cine CMR was performed using contiguous slices in both short and long axis views through the ASD. Data was collected for assessment of left and right atrial, ventricular end diastolic volumes (EDV) and end systolic volumes (ESV). Data is presented as mean ± SD, volumes as mL, and paired t-testing performed between groups. Statistical significance was taken as p < 0.05.ResultsThere was a significant reduction in right ventricular volumes at 6 months post-ASD closure (RVEDV: 208.7 ± 76.7 vs. 140.6 ± 60.4 mL, p < 0.0001) and RVEF was significantly increased (RVEF 35.5 ± 15.5 vs. 42.0 ± 15.2%, p = 0.025). There was a significant increase in the left ventricular volumes (LVEDV 84.8 ± 32.3 vs. 106.3 ± 38.1 mL, p = 0.003 and LVESV 37.4 ± 20.9 vs. 46.8 ± 18.5 mL, p = 0.016). However, there was no significant difference in LVEF and LV mass post-ASD closure. There was a significant reduction in right atrial volumes at 6 months post-ASD closure (pre-closure 110.5 ± 55.7 vs. post-closure 90.7 ± 69.3 mL, p = 0.019). Although there was a trend to a decrease in left atrial volumes post-ASD closure, this was not statistically significant (84.5 ± 34.8 mL to 81.8 ± 44.2 mL, p = NS).ConclusionASD closure leads to normalisation of ventricular volumes and also a reduction in right atrial volume. Further follow-up is required to assess how this predicts outcomes such as risk of atrial arrhythmias after such procedures.

Measurement of bone defects adjacent to acetabular components of hip replacement

Computed tomography can assist in the detection of periprosthetic osteolysis, but it has not been used to measure the actual volume of bone defects adjacent to hip replacement components because of the scanning artifact caused by metal. The aim of the current study was to develop a spiral computed tomography technique that provides precise and reliable volumetric measurement of bone defects adjacent to uncemented metal-backed acetabular components. Computed tomography scans were taken of small and large defects of known volume created in the ilium in a bovine hemipelvis and a pelvis from a cadaver. Scans were analyzed by two independent observers. The computed tomography operating conditions were determined that enabled volumetric measurements and that were accurate to within 96% for small and large defects and precise to greater than 98% for small and large defects. This computed tomography technique has the capability to measure accurately and precisely the volume of bone defects in the ilium adjacent to metal-backed acetabular components. This technique has clear advantages over plain radiographs. It will allow investigation of the natural history of osteolytic lesions, enhance preoperative planning, and improve monitoring of the outcomes of treatments of osteolysis.

Impact of Timing and Dose of Mesenchymal Stromal Cell Therapy in a Preclinical Model of Acute Myocardial Infarction

BACKGROUNDnAlthough mesenchymal stem/stromal cells (MSC) have shown therapeutic promise after myocardial infarction (MI), the impact of cell dose and timing of intervention remains uncertain. We compared immediate and deferred administration of 2 doses of MSC in a rat model of MI.nnnMETHODS AND RESULTSnSprague-Dawley rats were used. Allogeneic prospectively isolated MSC (low dose 1 × 10(6) or high dose 2 × 10(6) cells) were delivered by transepicardial injection immediately afterxa0MI (early-low, early-high), or 1 week later (late-low, late-high). Control subjects received cryopreservant solution alone. Left ventricular dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance. All 4 MSC-treatment cohorts demonstrated higher EF than control animals 4 weeks after MI (P values <.01 to <.0001), with function most preserved in the early-high group (absolute reduction in EF from baseline: control 39.1 ± 1.7%, early-low 26.5 ± 3.2%, early-high 7.9 ± 2.6%, late-low 19.6 ± 3.5%, late-high 17.9 ± 4.0%). Cell treatment also attenuated left ventricular dilatation and fibrosis and augmented left ventricular mass, systolic wall thickening (SWT), and microvascular density. Although early intervention selectively increased SWT and vascular density in the infarct territory, delayed treatment caused greater benefit in remote (noninfarct) myocardium. All outcomes demonstrated dose dependence for early MSC treatment, but not for later cell administration.nnnCONCLUSIONSnThe nature and magnitude of benefit from MSC after acute MI is strongly influenced by timing of cell delivery, with dose dependence most evident for early intervention. These novel insights have potential implications for cell therapy after MI in human patients.

Assessment of myocardial fibrosis by endoventricular electromechanical mapping in experimental nonischemic cardiomyopathy

Cardiac fibrosis plays an important prognostic role in nonischemic cardiomyopathy (NICM), making it a potential therapeutic target. Although electromechanical mapping has been used to identify myocardial scar and facilitate intramyocardial intervention in the setting of ischemic heart disease, its application has not been described in NICM. We assessed the detection of myocardial fibrosis by endoventricular electromechanical mapping in an experimental model of NICM. The NOGA® XP system was used to perform left ventricular mapping in twelve sheep that had undergone intracoronary doxorubicin dosing to induce NICM and in six healthy control animals. Results for endocardial voltage and mechanical shortening were evaluated against myocardial fibrosis burden, as determined by delayed-enhancement cardiac magnetic resonance and quantitative histomorphometry. Doxorubicin treatment resulted in dilated cardiomyopathy with moderate-severe impairment of left ventricular ejection fraction. Late gadolinium uptake was present in 9/12 doxorubicin animals, while histological fibrosis was approximately doubled compared to controls and was distributed multisegmentally throughout the left ventricle. Cardiomyopathy was associated with widespread reductions in unipolar and bipolar voltage amplitude and endocardial shortening. Each parameter showed an inverse relationship with the burden of fibrosis. Moreover, unipolar voltage and linear local shortening ratio displayed moderate accuracy for identifying myocardial segments with delayed contrast enhancement or increased fibrosis content, with optimal discriminatory thresholds of 7.5xa0mV and 11.5%, respectively. In this model of NICM, electromechanical mapping shows potential for delineating segmental differences in fibrosis. Pending clinical evaluation, it may therefore have applicability for directing targeted intramyocardial interventions in nonischemic heart disease.

Atrial protective effects of n-3 polyunsaturated fatty acids: A long-term study in ovine chronic heart failure

BACKGROUNDnIt has been suggested that omega-3 polyunsaturated fatty acids (n-3 PUFAs) may prevent the development of atrial fibrillation (AF).nnnOBJECTIVEnThe purpose of this study was to evaluate the impact of these agents on development of the AF substrate in heart failure (HF).nnnMETHODSnIn this study, HF was induced by intracoronary doxorubicin infusions. Twenty-one sheep [7 with n-3 PUFAs treated HF (HF-PUFA), 7 with olive oil-treated HF controls (HF-CTL), 7 controls (CTL)] were studied. Open chest electrophysiologic study was performed with assessment of biatrial effective refractory period (ERP) and conduction. Cardiac function was monitored by magnetic resonance imaging. Atrial n-3 PUFAs levels were quantified using chromatography. Structural analysis was also performed.nnnRESULTSnAtrial n-3 PUFAs levels were twofold to threefold higher in the HF-PUFA group. n-3 PUFAs prevented the development of HF-related left atrial enlargement (P = .001) but not left ventricular/atrial dysfunction. Atrial ERP was significantly lower in the HF-PUFA group (P <.001), but ERP heterogeneity was unchanged. In addition, n-3 PUFAs suppressed atrial conduction abnormalities seen in HF of prolonged P-wave duration (P = .01) and slowed (P <.001) and heterogeneous (P <.05) conduction. The duration of induced AF episodes in HF-PUFA was shorter (P = .02), although AF inducibility was unaltered (P = NS). A 20% reduction of atrial interstitial fibrosis was seen in the HF-PUFA group (P <.05).nnnCONCLUSIONnIn this ovine HF study, chronic n-3 PUFAs use protected against adverse atrial remodeling by preventing atrial enlargement, fibrosis, and conduction abnormalities leading to shorter AF episodes despite lower ERP.