Evidence of Carotid Atherosclerosis Vulnerability Regression in Real Life From Magnetic Resonance Imaging: Results of the MAGNETIC Prospective Study.

Background Atherosclerosis vulnerability regression has been evidenced mostly in randomized clinical trials with intensive lipid-lowering therapy. We aimed to demonstrate vulnerability regression in real life, with a comprehensive quantitative method, in patients with asymptomatic mild to moderate carotid atherosclerosis on a secondary prevention program. Methods and Results We conducted a single-center prospective observational study (MAGNETIC [Magnetic Resonance Imaging as a Gold Standard for Noninvasive Evaluation of Atherosclerotic Involvement of Carotid Arteries]): 260 patients enrolled at a cardiac rehabilitation center were followed for 3 years with serial magnetic resonance imaging. Per section cutoffs (95th/5th percentiles) were derived from a sample of 20 consecutive magnetic resonance imaging scans: (1) lipid-rich necrotic core: 26% of vessel wall area; (2) intraplaque hemorrhage: 12% of vessel wall area; and (3) fibrous cap: (a) minimum thickness: 0.06 mm, (b) mean thickness: 0.4 mm, (c) projection length: 11 mm. Patients with baseline magnetic resonance imaging of adequate quality (n=247) were classified as high (n=63, 26%), intermediate (n=65, 26%), or low risk (n=119, 48%), if vulnerability criteria were fulfilled in ≥2 contiguous sections, in 1 or multiple noncontiguous sections, or in any section, respectively. Among high-risk patients, a conversion to any lower-risk status was found in 11 (17%; P=0.614) at 6 months, in 16 (25%; P=0.197) at 1 year, and in 19 (30%; P=0.009) at 3 years. Among patients showing any degree of carotid plaque vulnerability, 21 (16%; P=0.014) were diagnosed at low risk at 3 years. Conclusions This study demonstrates with a quantitative approach that vulnerability regression is common in real life. A secondary prevention program can promote vulnerability regression in asymptomatic patients in the mid to long term.

Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors.

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).

Evolving determinants of carotid atherosclerosis vulnerability in asymptomatic patients from the MAGNETIC observational study.

MRI can assess plaque composition and has demonstrated an association between some atherosclerotic risk factors (RF) and markers of plaque vulnerability in naive patients. We aimed at investigating this association in medically treated asymptomatic patients. This is a cross-sectional interim analysis (August 2013-September 2016) of a single center prospective study on carotid plaque vulnerability (MAGNETIC study). We recruited patients with asymptomatic carotid atherosclerosis (US stenosis > 30%, ECST criteria), receiving medical treatments at a tertiary cardiac rehabilitation. Atherosclerotic burden and plaque composition were quantified with 3.0 T MRI. The association between baseline characteristics and extent of lipid-rich necrotic core (LRNC), fibrous cap (CAP) and intraplaque hemorrhage (IPH) was studied with multiple regression analysis. We enrolled 260 patients (198 male, 76%) with median age of 71-y (interquartile range: 65-76). Patients were on antiplatelet therapy, ACE-inhibitors/angiotensin receptor blockers and statins (196-229, 75-88%). Median LDL-cholesterol was 78 mg/dl (59-106), blood pressure 130/70 mmHg (111-140/65-80), glycosylated hemoglobin 46 mmol/mol (39-51) and BMI 25 kg/m2 (23-28); moreover, 125 out of 187 (67%) patients were ex-smokers. Multivariate analysis of a data-set of 487 (94%) carotid arteries showed that a history of hypercholesterolemia, diabetes, hypertension or smoking did not correlate with LRNC, CAP or IPH. Conversely, maximum stenosis was the strongest independent predictor of LRNC, CAP and IPH (p < 0.001). MRI assessment of plaque composition in patients on treatment for asymptomatic carotid atherosclerosis shows no correlation between plaque vulnerability and the most well-controlled modifiable RF. Conversely, maximum stenosis exhibits a strong correlation with vulnerable features despite treatment.

Cardiac Magnetic Resonance in Stable Coronary Artery Disease: Added Prognostic Value to Conventional Risk Profiling.

AIMS: Cardiovascular magnetic resonance (CMR) permits a comprehensive evaluation of stable coronary artery disease (CAD). We sought to assess whether, in a large contemporaneous population receiving optimal medical therapy, CMR independently predicts prognosis beyond conventional cardiovascular risk factors (RF). METHODS: We performed a single centre, observational prospective study that enrolled 465 CAD patients (80% males; 63±11 years), optimally treated with ACE-inhibitors/ARB, aspirin, and statins (76-85%). Assessments included conventional evaluation (clinical history, atherosclerosis RF, electrocardiography, and echocardiography) and a comprehensive CMR with LV dimensions/function, late gadolinium enhancement (LGE), and stress perfusion CMR (SPCMR). RESULTS: During a median follow-up of 62 months (IQR 23-74) there were 50 deaths and 92 major adverse cardiovascular events (MACE). CMR variables improved multivariate model prediction power of mortality and MACE over traditional RF alone (F-test p<0.05 and p<0.001, respectively). LGE was an independent prognostic factor of mortality (hazard ratio [95% CI]: 3.4 [1.3-8.8]); moreover, LGE (3.3 [1.7-6.3]) and SPCMR (2.1 [1.4-3.2]) were the best predictors of MACE. CONCLUSION: LGE is an independent noninvasive marker of mortality in the long term in patients with stable CAD and optimized medical therapy. Furthermore, LGE and SPCMR independently predict MACE beyond conventional risk stratification.

Arrhythmogenic Right Ventricular Cardiomyopathy: Clinical Course and Predictors of Arrhythmic Risk.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined. OBJECTIVES: This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy. METHODS: We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals. RESULTS: A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p < 0.001), participation in strenuous exercise after the diagnosis (HR: 2.98; p = 0.028), hemodynamically tolerated sustained monomorphic ventricular tachycardia (HR: 2.19; p = 0.023), and male sex (HR: 2.49; p = 0.012). No difference was observed in the occurrence of LAE before and after treatment with amiodarone, beta-blockers, sotalol, or ablation. A total of 81 patients received an implantable cardioverter-defibrillator, 34 were successfully defibrillated. CONCLUSIONS: The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management.

Late gadolinium enhancement by cardiovascular magnetic resonance is complementary to left ventricle ejection fraction in predicting prognosis of patients with stable coronary artery disease.

BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) predicts adverse prognosis in patients with stable coronary artery disease (CAD). However, the interaction with conventional risk factors remains uncertain. Our aim was to assess whether the extent of LGE is an independent predictor of adverse cardiac outcome beyond conventional risk factors, including left ventricle ejection fraction (LVEF). METHODS: We enrolled 376 patients (88% males, 64 ± 11 years) with stable CAD, who underwent LGE assessment and a detailed conventional evaluation (clinical and pharmacological history, risk factors, ECG, Echocardiography). During a follow-up of 38 ± 21 months, 56 events occurred (32 deaths, 24 hospitalizations for heart failure). RESULTS: LGE and LVEF showed the strongest univariate associations with end-points (HR: 13.61 [95%C.I.: 7.32-25.31] for LGE ≥ 45% of LV mass; and 12.34 [6.80-22.38] for LVEF ≤ 30%; p < 0.0001). Multivariate analysis identified baseline LVEF, loop diuretic therapy, moderate-severe mitral regurgitation and pulmonary hypertension as significant predictors among conventional risk factors. According to a step-wise approach, LGE showed strong association with prognosis as well (5.25 [2.64-10.43]; p < 0.0001). LGE significantly improved the model predictability (chi-square 239 vs 221, F-test p < 0.0001) with an additive effect on the prognostic power of LVEF, which however retained its prognostic power (4.89 [2.50-09.56]; p < 0.0001). Patients with LGE ≥ 45% and/or LVEF ≤ 30% had much worse prognosis compared to patients without risk factors (annual event rates of 43% vs 3%; p < 0.0001). Interestingly LGE was a significant predictor when all cause mortality was analyzed as the only endpoint. CONCLUSIONS: This study demonstrates that LGE assessed by CMR is a robust independent non-invasive marker of prognosis in stable CAD patients. LGE can integrate the available metrics to substantially improve risk stratification.

Predicting and preventing cardiotoxicity in the era of breast cancer targeted therapies. Novel molecular tools for clinical issues.

Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists.

Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities.

AIMS: Recent data suggest that sub-clinical structural abnormalities may be part of the Brugada syndrome (BrS) phenotype, a disease traditionally thought to occur in the structurally normal heart. In this study, we carried out detailed assessment of cardiac morphology and function using cardiac magnetic resonance imaging (CMRI). METHODS AND RESULTS: Thirty consecutive patients with BrS were compared with 30 sex- (26/4 male/female), body surface area- (+/-0.2 m(2)), and age-matched (+/-5 years) normal volunteers. CMRI exam included long- and short-axis ECG-gated breath-hold morphological T1-TSE sequences for fatty infiltration and cine-SSFP sequences for kinetic assessment. Fatty infiltration was not found in any subject. Patients with BrS compared with normal subjects showed higher incidence of mild right ventricle (RV) wall-motion abnormalities [15 (50%) vs. 5 (17%) subjects (P = 0.006) with reduced radial fractional shortening in more than two segments], reduction of outflow tract ejection fraction (49 +/- 11% vs. 55 +/- 10%; P = 0.032), enlargement of the inflow tract diameter (46 +/- 4 vs. 41 +/- 5 mm, P < 0.001 in short-axis; 46 +/- 4 vs. 42 +/- 5 mm, P = 0.001 in four-chamber long-axis view) and area (22 +/- 2 vs. 20 +/- 3 cm(2); P = 0.050), and of global RV end-systolic volume (34 +/- 10 vs. 30 +/- 6 mL/m(2); P = 0.031) but comparable outflow tract dimensions, global RV end-diastolic volume, left ventricle parameters, and atria areas. CONCLUSION: CMRI detects a high prevalence of mild structural changes of the RV, and suggests further pathophysiological complexity in BrS. Prospective studies to assess the long-term evolution of such abnormalities are warranted.

Intra-observer and interobserver reproducibility of right ventricle volumes, function and mass by cardiac magnetic resonance.

OBJECTIVES: Cardiac magnetic resonance (CMR) allows quick and non-invasive evaluation both of right ventricle (RV) volume and function, which are important in many heart diseases. We have evaluated CMR intra- and interobserver reproducibility in different conditions of RV dimension and function. METHODS: We have analysed CMR exams of 45 subjects, randomly selected from our database according to RV end-diastolic volume (EDV; 15-subject groups with EDV < 25th, 25-75th and > 75th percentiles of a normal control population). Selected subjects were of both sexes (male/female 33/12) and of variable age (8-83 years) and body surface (0.9-2.3 m). RV end-diastolic and end-systolic volumes (ESV), ejection fraction (EF) and mass were blindly evaluated by two operators. Bland-Altman bias and coefficient of variability (CoV) were used to assess intra- and interobserver reproducibility. RESULTS: A wide range of EDV (range = 46-239 ml), ESV (20-129 ml) and EF (6-64%) was observed. The intra-observer bias was -5 ml for EDV, -2 ml for ESV, -1% for EF and 5 g for mass, with a CoV of 7-12%. The interobserver bias was 5 ml for EDV, 2 ml for ESV, 2% for EF and 6 g for mass, with a CoV of 8-13%. Analysis by tertiles showed EF assessment variability to be higher in the lower tertiles at intra-observer (P < 0.036) and, above all, at interobserver (P < 0.000) analysis. Mass assessment variability was higher in the upper tertile (P < 0.004) at intra-observer analysis. CONCLUSIONS: Intra- and interobserver reproducibility of RV parameters assessed by CMR are adequate in a wide range of RV dimensions and function. However, caution is required with respect to the significance of small changes of EF and mass in the case of poor function and hypertrophy of the RV, respectively.

Contrast-enhanced cardiac magnetic resonance in a patient with chemotoxic cardiomyopathy.

Gadolinium-enhanced cardiac magnetic resonance was performed in a patient with chemotoxic cardiomyopathy. Intramyocardial midwall linear delayed hyperenhancement was found. Such a finding is consistent with midwall fibrosis and/or myocardial cell loss due to cardiotoxic effect of chemotherapy.

Improved reproducibility of right ventricular volumes and function estimation from cardiac magnetic resonance images using level-set models.

This study aims to assess whether an alternative method, that is based on volumetric surface detection (VoSD) without tracing and is totally free of geometric assumptions, can improve the reproducibility of right ventricular (RV) volume quantification from cardiac magnetic resonance (CMR) images, in comparison with a conventional disk-area technique. In a sample of 23 patients, with wide variability of RV end-diastolic volume (EDV: 47-131 ml), end-systolic volume (ESV: 20-76 ml), and ejection fraction (EF: 29-73%), using the standard method (Argus, Siemens) as the reference, the VoSD method showed good agreement for EDV, ESV, and EF estimations (correlation coefficient: 0.91, 0.94, and 0.94; Bland-Altman biases: 1 ml, 1 ml, and 0%; limits of agreement: +/-16 ml, +/-11 ml, and +/-11%, respectively). An analysis of the reproducibility of the two methods showed lower intraobserver variability for the VoSD method than for the conventional method, as evidenced by the coefficient of variability (CoV) values (2-6% vs. 8-15%; P < 0.05). In addition, the VoSD method showed improved interobserver reproducibility (7-10% vs. 8-15%), but the difference was statistically significant only for EF estimation variability (8 vs. 15%, P < 0.05). In conclusion, the newly developed VoSD technique allows accurate measurements of RV volumes and function, and appears to be more reproducible than the conventional methodology.

Scar detection by contrast-enhanced magnetic resonance imaging in chronic coronary artery disease: a comparison with nuclear imaging and echocardiography.

We compared contrast-enhanced MRI (CeMRI) with the most widely used imaging techniques for myocardial infarct (MI) diagnosis, SPECT and Echo, in unselected patients with chronic coronary artery disease (CAD). Two blinded operators assessed scars on MRI, SPECT and Echo images using a 16-segments LV model. We studied 105 consecutive patients: 50 had Q-wave MI (Q-MI), 19 non Q-wave MI or rest angina (nonQ-MI/RA) and 36 effort angina (EA) history. CeMRI was positive, respectively, in 96%, 37%, and 6%, SPECT in 90%, 53%, and 44%, and Echo in 84%, 32%, and 28% of patients (within Q-MI: CeMRI vs. SPECT p < 0.03, vs. Echo p < 0.001; within EA CeMRI vs. SPECT and ECHO p < 0.001; all trends p < 0.001, pseudo r-square: 0.56-0.75 for CeMRI, 0.18-0.28 for SPECT and 0.23-0.37 for Echo). CeMRI and SPECT agreed in 83 patients (79%); negative SPECT with 1 +/- 0 segments subendocardial delayed enhancement (DE) was found in 4 (4%); negative CeMRI with 4 +/- 3 segments perfusion defects in 18 (17%), 16 of whom were obese or showed LBB or sub-occlusion of related coronary. CeMRI and Echo agreed in 78 patients (75%); negative Echo with 2 +/- 1 segments subendocardial DE was found in 13 (12%) and negative CeMRI with 11 +/- 7 segments kinetic abnormalities in 14 (13%), in 10 confirmed by Cine-MRI. In Q-MI, CeMRI detects DE more frequently than perfusion defects and, especially, kinetic abnormalities are found by SPECT and Echo, respectively. CeMRI identifies small areas of DE also in some patients with nonQ-MI or RA but usually not in patients with EA. This biologically plausible decreasing trend is shown by CeMRI more clearly than by SPECT and Echo. Disagreement between CeMRI and SPECT or Echo may be reduced, but perhaps not fully eluded, performing dobutamine Echo and SPECT after maximal epicardial coronary dilatation.

Improved quantification of left ventricular volumes and mass based on endocardial and epicardial surface detection from cardiac MR images using level set models.

PURPOSE: The reproducibility of left ventricular (LV) volume and mass measurements based on subjective slice-by-slice tracing of LV borders is affected by image quality, and volume estimates are biased by geometric modeling. The authors developed a technique for volumetric surface detection (VoSD) and quantification of LV volumes and mass without tracing and geometric approximations. The authors hypothesized that this technique is accurate and more reproducible than the conventional methodology. METHODS: Images were obtained in 24 patients in 6 to 10 slices from LV base to apex (GE 1.5 T, FIESTA). Volumetric data were reconstructed, and endocardial and epicardial surfaces were detected using the level set approach. LV volumes were obtained from voxel counts and used to compute ejection fraction (EF) and mass. Conventional measurements (MASS Analysis) were used as a reference to test the accuracy of VoSD technique (linear regression, Bland-Altman). For both techniques, measurements were repeated to compute inter- and intra-observer variability. RESULTS: VoSD values resulted in high correlation with the reference values (EDV: r = 0.98; ESV: r = 0.99; EF: r = 0.91; mass: r = 0.98), with no significant biases (8 ml, 5 ml, 0.2% and -9 g) and narrow limits of agreement (SD: 13 ml, 10 ml, 6% and 9 g). Inter-observer variability of the VoSD technique was lower (range 3 to 5%) than that of the reference technique (5 to 11%; p < 0.05). Intra-observer variability was also lower (1 to 3% vs. 7 to 10%; p < 0.05). CONCLUSION: VoSD technique allows accurate measurements of LV volumes, EF, and mass, which are more reproducible than the conventional methodology.

Contrast-enhanced magnetic resonance imaging assessment of scar size in patients with chronic myocardial infarction.

BACKGROUND: In the assessment of myocardial infarction (MI) mass, contrast-enhanced magnetic resonance imaging (CE-MRI) is comparable to single-photon emission computed tomography (SPECT). The aim of the present study was to determine whether the MI area, as assessed at CE-MRI and SPECT, is comparable to mass evaluation. We also compared CE-MRI and SPECT estimates of the MI area with functional evaluations made at echocardiography and kinetic MRI (cine-MRI). METHODS: We used a 1.0 Tesla MRI scanner and an inversion-recovery turboFLASH sequence, a tomographic gamma-camera and second-harmonic ultrasound systems. Two blinded operators assessed the extent of scarring, expressed as a percentage of the whole left ventricle (LV), using a 16-segment model. We studied 55 consecutive patients with a clinically stable healed MI (50 Q wave, 5 non-Q wave). RESULTS: The scar mass was 19+/-23% of the LV at CE-MRI and 21+/-25% at SPECT; the scar area was 29+/-23% of the LV at CE-MRI, 41+/-28% at SPECT, 29+/-31% at cine-MRI, and 32+/-29% at echocardiography. The Bland-Altman bias between CE-MRI and SPECT mass estimations was -2% of the LV with a+/-23% limit of agreement (LOA), while the bias between the area assessments was -12% with a+/-42% LOA. Bias between CE-MRI and functional evaluation by cine-MRI and echocardiography was 0% with a+/-39% LOA and -3% with a+/-36% LOA respectively. Comparing SPECT with cine-MRI and echocardiography the bias was 12% with a+/-52% LOA and 9% with a+/-56% LOA respectively. CONCLUSIONS: CE-MRI has proved to be comparable to SPECT in the assessment of the healed MI mass. Conversely, a high systematic error (high bias and LOA) renders CE-MRI and SPECT assessments of the MI area incomparable. Similarly (high bias and/or LOA) CE-MRI and SPECT estimations of the MI area cannot be compared with functional evaluation by echocardiography or cine-MRI.