Areas of intramyocardial late enhancement (LE) at delayed enhanced magnetic resonance imaging (DE... more Areas of intramyocardial late enhancement (LE) at delayed enhanced magnetic resonance imaging (DE-MRI) and reduction of myocardial phosphocreatine (PCr)/ATP-ratio at phosphorus magnetic resonance spectroscopy ((31)P-MRS) are both reported in hypertrophic cardiomyopathy (HCM) and indicate areas of increased interstitial myocardial space with fibrosis and impairment of myocardial energy metabolism, respectively. We sought to ascertain whether in HCM patients the abnormal features of left ventricular (LV) interstitial space revealed by DE-MRI correlated with impaired LV energy metabolism shown at (31)P-MRS. 19 patients with HCM proved by histological analysis of multiple endomyocardial biopsies and with normal coronary arteries, underwent cardiac MRI including DE-MRI and (31)P-MRS. DE-MRI for detection and quantification of late enhancement (LE) and (31)P-MRS to assess the myocardial PCr/ATP-ratio were performed by means of a 1.5-T magnet. 19 healthy subjects, matched for gender and age were studied by (31)P-MRS as control group. LE areas in the LV wall were found in 17 out of 19 patients with an extension ranging from 0.8% to 19.5% of the LV-mass (mean value 7.6% (SD 5.6%). The PCr/ATP-ratio was lower in HCM patients than in control subjects (2.18 (0.41) vs 2.41 (0.30); p<0.05). LE% and PCr/ATP-ratio were inversely related (R = -0.57; p<0.05) and LE% was the stronger predictor of PCr/ATP-ratio by multivariate analysis. This study demonstrated that the known alteration of the PCr/ATP-ratio observed in HCM patients is correlated with the presence of fibrotic areas in the myocardium of the left ventricle.
Background: Abnormal aldosterone signaling is a recognized source of cardiovascular damage. Its i... more Background: Abnormal aldosterone signaling is a recognized source of cardiovascular damage. Its influence on cardiomyocyte structure, function, and hormonal receptors when associated with heart failure is still unreported. Methods: Twenty-six consecutive patients with heart failure (LVEF < 40%) and normal coronaries and valves underwent left ventricular endomyocardial biopsy (EMB) for evaluation of myocardial substrate. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western blot analysis of myocardial aldosterone receptor and aquaporin-1 correlated with plasma aldosterone (AD) and renin activity (PRA). Eight patients with virus-negative inflammatory cardiomyopathy (ICM) had a control EMB after 6 months of immunosuppressive therapy and recovery of cardiac function with re-evaluation of cardiomyocyte structure and receptor expression. Results: EMB in addition to the diagnosis of myocarditis (15 cases), dilated cardiomyopathy CM (6), alco...
Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical rele... more Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical relevance are unclear. Basal troponin I level, exercise stress test, single-photon emission computed tomography imaging with (99m)Tc sestamibi, coronary angiography with thrombolysis in myocardial infarction (TIMI) frame count and left ventricular angiography and endomyocardial biopsy were obtained in 13 patients with FD with angina. Ratio of external to lumen diameter of intramural arteries (E/L ratio), myocyte diameter, and extent of fibrosis were morphometrically evaluated by using tissue sections. Controls for coronary angiography and histology were 25 patients with FD without angina and 20 mitral stenosis patients with normal left ventricular function. Troponin I level was elevated in 6 of the 13 patients. Exercise stress test showed evidence of myocardial ischemia, and single-photon emission computed tomography was positive for stress-induced perfusion defects in all patients with FD w...
The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observat... more The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long...
The patient’s father was admitted to our hospital for progressive dyspnea. He had vertebrobasilar... more The patient’s father was admitted to our hospital for progressive dyspnea. He had vertebrobasilar stroke 5 years before and a pacemaker implantation because of total atrioventricular block. A two-dimensional transthoracic echocardiogram (2D TTE) revealed severe concentric biventricular hypertrophy and thickened interatrial septum. Screening for Fabry disease demonstrated the presence of a low enzymatic activity and the N215S mutation of the alphagalactosidase A gene. A few days after admission the patient died because of heart failure. Our patient, screened for Fabry disease, resulted as a carrier of the same mutation.
Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the pa... more Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for clas...
BACKGROUND Fabry disease, an X-linked lysosomal storage disease, results from deficient α-galacto... more BACKGROUND Fabry disease, an X-linked lysosomal storage disease, results from deficient α-galactosidase A (α-GalA) activity and the systemic accumulation of α-galactosyl-terminated glycosphingolipids. Two major phenotypes, "Classic" and "Later-Onset", lead to renal failure, and/or cardiac disease, and early demise. To date, the evolution and progression of the cardiac pathology and resultant clinical manifestations in family members of phenotype have not been well characterized. METHODS AND RESULTS In a Classic family with nine affected members (GLA mutation c.983delG), cardiac imaging, angiography, and cardiac biopsies were performed in four males and two heterozygous females. Tissues were examined histologically, ultrastructurally, and myocardial necrosis and apoptosis were evaluated by in situ ligation with hairpin probes. Increasing cardiac pathology correlated with ECG and cardiac magnetic resonance findings. Young affected males with "pre-hypertrophy" had 18-20μm cardiomyocyte diameters, <30% vacuolar areas in myocytes, and normal levels of necrosis and apoptosis. Patients with "moderate hypertrophy" (maximal wall thickness (MWT) ≤16mm) had 30-35μm cardiomyocyte diameters, ~45% vacuolar areas, and moderate levels of necrosis and apoptosis. In contrast, the oldest male with severe hypertrophy (MWT=21mm) had 38-40μm cell diameters, >60% vacuolar areas, and marked necrosis and apoptosis. CONCLUSION Progressive gender-specific cardiac pathology and clinical manifestations were documented in affected Classic family members. Increasing cardiomyocyte diameter was correlated with disease severity, age, and gender. Fibrosis was presumably caused by cell death of enlarged, substrate-engorged cardiomyocytes. These results support early enzyme therapy in Classic males to prevent/minimize irreversible cardiac damage.
Global early gadolinium enhancement (EGE) is an accepted cardiac magnetic resonance (CMR) criteri... more Global early gadolinium enhancement (EGE) is an accepted cardiac magnetic resonance (CMR) criterion for diagnosis of myocarditis. However, recommended enhancement thresholds are based specifically on standard-relaxivity Gd-chelates. We evaluated the performance of a high relaxivity MR contrast agent for detection of myocardial hyperemia in patients referred for endomyocardial biopsy (EMB). We retrospectively enrolled 54 patients (mean age: 44.1 years [range=18-77years]; 72% men) with suspected myocarditis who underwent CMR and EMB within four weeks of clinical onset. CMR imaging protocol included T2-weighted short tau inversion-recovery sequence, EGE and late gadolinium enhanced (LGE) imaging. For EGE imaging, free-breathing ECG-gated turbo spin echo T1-weighted (TSE T1w) sequences were acquired before and within the first three minutes after gadobenate dimeglumine (0.1mmol/Kg) administration. The ratio (EGEr) between myocardial and musculoskeletal early enhancement was calculated. Myocardial edema, EGE and late gadolinium enhancement (LGE) were correlated with EMB results. Receiver operating characteristic (ROC) curve analysis of EGE values was applied on the overall population. EMB revealed myocarditis in 34/54 patients. Sensitivity, specificity and accuracy values of 0.61, 0.85 and 0.70, respectively, were obtained for a standard EGE threshold (EGEr&gt;4.0). ROC analysis revealed an area under the curve of 0.701 for EGEr (IC95%:0.556-0.846, p=0.014) and 0.706 for absolute enhancement (IC95%:0.563-0.849, p=0.012). Sensitivity, specificity and accuracy values were 0.67, 0.80 and 0.72, respectively, for myocardial edema and 0.76, 0.75 and 0.76, respectively, for LGE. High relaxivity contrast agents provide comparable results to standard-relaxivity chelates for EGE assessment in diagnosing myocarditis.
Areas of intramyocardial late enhancement (LE) at delayed enhanced magnetic resonance imaging (DE... more Areas of intramyocardial late enhancement (LE) at delayed enhanced magnetic resonance imaging (DE-MRI) and reduction of myocardial phosphocreatine (PCr)/ATP-ratio at phosphorus magnetic resonance spectroscopy ((31)P-MRS) are both reported in hypertrophic cardiomyopathy (HCM) and indicate areas of increased interstitial myocardial space with fibrosis and impairment of myocardial energy metabolism, respectively. We sought to ascertain whether in HCM patients the abnormal features of left ventricular (LV) interstitial space revealed by DE-MRI correlated with impaired LV energy metabolism shown at (31)P-MRS. 19 patients with HCM proved by histological analysis of multiple endomyocardial biopsies and with normal coronary arteries, underwent cardiac MRI including DE-MRI and (31)P-MRS. DE-MRI for detection and quantification of late enhancement (LE) and (31)P-MRS to assess the myocardial PCr/ATP-ratio were performed by means of a 1.5-T magnet. 19 healthy subjects, matched for gender and age were studied by (31)P-MRS as control group. LE areas in the LV wall were found in 17 out of 19 patients with an extension ranging from 0.8% to 19.5% of the LV-mass (mean value 7.6% (SD 5.6%). The PCr/ATP-ratio was lower in HCM patients than in control subjects (2.18 (0.41) vs 2.41 (0.30); p&amp;amp;amp;amp;amp;amp;lt;0.05). LE% and PCr/ATP-ratio were inversely related (R = -0.57; p&amp;amp;amp;amp;amp;amp;lt;0.05) and LE% was the stronger predictor of PCr/ATP-ratio by multivariate analysis. This study demonstrated that the known alteration of the PCr/ATP-ratio observed in HCM patients is correlated with the presence of fibrotic areas in the myocardium of the left ventricle.
Background: Abnormal aldosterone signaling is a recognized source of cardiovascular damage. Its i... more Background: Abnormal aldosterone signaling is a recognized source of cardiovascular damage. Its influence on cardiomyocyte structure, function, and hormonal receptors when associated with heart failure is still unreported. Methods: Twenty-six consecutive patients with heart failure (LVEF < 40%) and normal coronaries and valves underwent left ventricular endomyocardial biopsy (EMB) for evaluation of myocardial substrate. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western blot analysis of myocardial aldosterone receptor and aquaporin-1 correlated with plasma aldosterone (AD) and renin activity (PRA). Eight patients with virus-negative inflammatory cardiomyopathy (ICM) had a control EMB after 6 months of immunosuppressive therapy and recovery of cardiac function with re-evaluation of cardiomyocyte structure and receptor expression. Results: EMB in addition to the diagnosis of myocarditis (15 cases), dilated cardiomyopathy CM (6), alco...
Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical rele... more Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical relevance are unclear. Basal troponin I level, exercise stress test, single-photon emission computed tomography imaging with (99m)Tc sestamibi, coronary angiography with thrombolysis in myocardial infarction (TIMI) frame count and left ventricular angiography and endomyocardial biopsy were obtained in 13 patients with FD with angina. Ratio of external to lumen diameter of intramural arteries (E/L ratio), myocyte diameter, and extent of fibrosis were morphometrically evaluated by using tissue sections. Controls for coronary angiography and histology were 25 patients with FD without angina and 20 mitral stenosis patients with normal left ventricular function. Troponin I level was elevated in 6 of the 13 patients. Exercise stress test showed evidence of myocardial ischemia, and single-photon emission computed tomography was positive for stress-induced perfusion defects in all patients with FD w...
The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observat... more The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long...
The patient’s father was admitted to our hospital for progressive dyspnea. He had vertebrobasilar... more The patient’s father was admitted to our hospital for progressive dyspnea. He had vertebrobasilar stroke 5 years before and a pacemaker implantation because of total atrioventricular block. A two-dimensional transthoracic echocardiogram (2D TTE) revealed severe concentric biventricular hypertrophy and thickened interatrial septum. Screening for Fabry disease demonstrated the presence of a low enzymatic activity and the N215S mutation of the alphagalactosidase A gene. A few days after admission the patient died because of heart failure. Our patient, screened for Fabry disease, resulted as a carrier of the same mutation.
Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the pa... more Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for clas...
BACKGROUND Fabry disease, an X-linked lysosomal storage disease, results from deficient α-galacto... more BACKGROUND Fabry disease, an X-linked lysosomal storage disease, results from deficient α-galactosidase A (α-GalA) activity and the systemic accumulation of α-galactosyl-terminated glycosphingolipids. Two major phenotypes, "Classic" and "Later-Onset", lead to renal failure, and/or cardiac disease, and early demise. To date, the evolution and progression of the cardiac pathology and resultant clinical manifestations in family members of phenotype have not been well characterized. METHODS AND RESULTS In a Classic family with nine affected members (GLA mutation c.983delG), cardiac imaging, angiography, and cardiac biopsies were performed in four males and two heterozygous females. Tissues were examined histologically, ultrastructurally, and myocardial necrosis and apoptosis were evaluated by in situ ligation with hairpin probes. Increasing cardiac pathology correlated with ECG and cardiac magnetic resonance findings. Young affected males with "pre-hypertrophy" had 18-20μm cardiomyocyte diameters, <30% vacuolar areas in myocytes, and normal levels of necrosis and apoptosis. Patients with "moderate hypertrophy" (maximal wall thickness (MWT) ≤16mm) had 30-35μm cardiomyocyte diameters, ~45% vacuolar areas, and moderate levels of necrosis and apoptosis. In contrast, the oldest male with severe hypertrophy (MWT=21mm) had 38-40μm cell diameters, >60% vacuolar areas, and marked necrosis and apoptosis. CONCLUSION Progressive gender-specific cardiac pathology and clinical manifestations were documented in affected Classic family members. Increasing cardiomyocyte diameter was correlated with disease severity, age, and gender. Fibrosis was presumably caused by cell death of enlarged, substrate-engorged cardiomyocytes. These results support early enzyme therapy in Classic males to prevent/minimize irreversible cardiac damage.
Global early gadolinium enhancement (EGE) is an accepted cardiac magnetic resonance (CMR) criteri... more Global early gadolinium enhancement (EGE) is an accepted cardiac magnetic resonance (CMR) criterion for diagnosis of myocarditis. However, recommended enhancement thresholds are based specifically on standard-relaxivity Gd-chelates. We evaluated the performance of a high relaxivity MR contrast agent for detection of myocardial hyperemia in patients referred for endomyocardial biopsy (EMB). We retrospectively enrolled 54 patients (mean age: 44.1 years [range=18-77years]; 72% men) with suspected myocarditis who underwent CMR and EMB within four weeks of clinical onset. CMR imaging protocol included T2-weighted short tau inversion-recovery sequence, EGE and late gadolinium enhanced (LGE) imaging. For EGE imaging, free-breathing ECG-gated turbo spin echo T1-weighted (TSE T1w) sequences were acquired before and within the first three minutes after gadobenate dimeglumine (0.1mmol/Kg) administration. The ratio (EGEr) between myocardial and musculoskeletal early enhancement was calculated. Myocardial edema, EGE and late gadolinium enhancement (LGE) were correlated with EMB results. Receiver operating characteristic (ROC) curve analysis of EGE values was applied on the overall population. EMB revealed myocarditis in 34/54 patients. Sensitivity, specificity and accuracy values of 0.61, 0.85 and 0.70, respectively, were obtained for a standard EGE threshold (EGEr&gt;4.0). ROC analysis revealed an area under the curve of 0.701 for EGEr (IC95%:0.556-0.846, p=0.014) and 0.706 for absolute enhancement (IC95%:0.563-0.849, p=0.012). Sensitivity, specificity and accuracy values were 0.67, 0.80 and 0.72, respectively, for myocardial edema and 0.76, 0.75 and 0.76, respectively, for LGE. High relaxivity contrast agents provide comparable results to standard-relaxivity chelates for EGE assessment in diagnosing myocarditis.
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Papers by Andrea Frustaci