State-of-the-Art of Myocardial Perfusion by CMR: A Practical View.

Ischemic heart disease (IHD) outstands among diseases threatening public health. Essential for its management are the continuous advances in medical and interventional therapies, although a prompt and accurate diagnosis and prognostic stratification are equally important. Besides information on the anatomy of coronary arteries, well covered nowadays by invasive and non-invasive angiographic techniques, there are also other components of the disease with clinical impact, as the presence of myocardial necrosis, the extent of pump function impairment, and the presence and extent of inducible myocardial ischemia, that must be considered in every patient. Cardiovascular Magnetic Resonance (CMR) is a multiparametric diagnostic imaging technique that provides reliable information on these issues. Regarding the detection and grading of inducible ischemia in particular, the technique has been widely adopted in the form of myocardial perfusion sequences under vasodilator stress, which is the subject of this review. While the analysis of images is conventionally performed by visual inspection of dynamic first-pass studies, with the inherent dependency on the operator capability, the recent introduction of a reliable application of quantitative perfusion (QP) represents a significant advance in the field. QP is based on a dual-sequence strategy for conversion of signal intensities into contrast agent concentration units and includes a full automatization of processes such as myocardial blood flow (MBF) calculation (in mL/min/g), generation of a pixel-wise flow mapping, myocardial segmentation, based on machine learning, and allocation of MBF values to myocardial segments. The acquisition of this protocol during induced vasodilation and at rest gives values of stress/rest MBF (in mL/min/g) and myocardial perfusion reserve (MPR), both global and per segment. Dual-sequence QP has been successfully validated against different reference methods, and its prognostic value has been shown in large longitudinal studies. The fact of the whole process being automated, without operator interaction, permits to conceive new interesting scenarios of integration of CMR into systems of entirely automated diagnostic workflow in patients with IHD.

Case 270.

History A 54-year-old woman presented with typical chest pain during physical training at the gym. She had a history of hypertension controlled with hydrochlorothiazide, without any other cardiovascular risk factor and with neither personal nor family history of ischemic heart disease. She was postmenopausal and had a long-standing history of migraine headaches without hormonal or drug therapy. The patient had no history of clinically important thoracic trauma or invasive chest interventions. Initial electrocardiography (ECG) showed signs of ongoing anterior ST segment elevation myocardial infarction, and emergent coronary angiography with angioplasty and intravascular US were performed ( Fig 1 ). Maximal level of high-sensitive T troponins was 820 ng/L (normal, <13 ng/L), while echocardiography showed a normal left ventricular ejection fraction, with no apparent regional wall motion abnormalities. General physical examination findings were unremarkable, excluding ligamentous hyperlaxity and joint instability. C-reactive protein, rheumatoid factor, antinuclear antibody, cytoplasmic antineutrophil cytoplasmic antibody, and angiotensin-converting enzyme blood test results were negative. For further evaluation, arterial phase ECG-synchronized CT angiography from the skull base to the pubis symphysis was performed ( Fig 2 ). Figure 1a: Coronary angiography of the left anterior descending (LAD) and left circumflex (LCX) arteries (30° right anterior oblique and 20° caudally angulated projection) and intravascular US of the LCX artery were performed. (a) Initial coronary angiography projection. (b) Coronary angiography projection after LAD stent placement. (c, d) Intravenous US images of the distal (c) and proximal (d) LCX artery obtained after b. Figure 1b: Coronary angiography of the left anterior descending (LAD) and left circumflex (LCX) arteries (30° right anterior oblique and 20° caudally angulated projection) and intravascular US of the LCX artery were performed. (a) Initial coronary angiography projection. (b) Coronary angiography projection after LAD stent placement. (c, d) Intravenous US images of the distal (c) and proximal (d) LCX artery obtained after b. Figure 1c: Coronary angiography of the left anterior descending (LAD) and left circumflex (LCX) arteries (30° right anterior oblique and 20° caudally angulated projection) and intravascular US of the LCX artery were performed. (a) Initial coronary angiography projection. (b) Coronary angiography projection after LAD stent placement. (c, d) Intravenous US images of the distal (c) and proximal (d) LCX artery obtained after b. Figure 1d: Coronary angiography of the left anterior descending (LAD) and left circumflex (LCX) arteries (30° right anterior oblique and 20° caudally angulated projection) and intravascular US of the LCX artery were performed. (a) Initial coronary angiography projection. (b) Coronary angiography projection after LAD stent placement. (c, d) Intravenous US images of the distal (c) and proximal (d) LCX artery obtained after b. Figure 2a: Arterial phase electrocardiography-synchronized CT angiography from the skull base to the pubis symphysis was performed after coronary angiography, subsequent interventional procedures, and intravenous US. (a, b) Axial oblique slab maximum intensity projection image at the level of the left (a) and right (b) renal arteries. (c) Coronal volume-rendering image shows an anterior view of the renal arteries. Figure 2b: Arterial phase electrocardiography-synchronized CT angiography from the skull base to the pubis symphysis was performed after coronary angiography, subsequent interventional procedures, and intravenous US. (a, b) Axial oblique slab maximum intensity projection image at the level of the left (a) and right (b) renal arteries. (c) Coronal volume-rendering image shows an anterior view of the renal arteries. Figure 2c: Arterial phase electrocardiography-synchronized CT angiography from the skull base to the pubis symphysis was performed after coronary angiography, subsequent interventional procedures, and intravenous US. (a, b) Axial oblique slab maximum intensity projection image at the level of the left (a) and right (b) renal arteries. (c) Coronal volume-rendering image shows an anterior view of the renal arteries.

Case 270: Spontaneous Coronary Artery Dissection Associated with Fibromuscular Dysplasia.

HistoryA 54-year-old woman presented with typical chest pain during physical training at the gym. She had a history of hypertension controlled with hydrochlorothiazide, without any other cardiovascular risk factor and with neither personal nor family history of ischemic heart disease. She was postmenopausal and had a long-standing history of migraine headaches without hormonal or drug therapy. The patient had no history of clinically important thoracic trauma or invasive chest interventions. Initial electrocardiography (ECG) showed signs of ongoing anterior ST segment elevation myocardial infarction, and emergent coronary angiography with angioplasty and intravascular US were performed. Maximal level of high-sensitive T troponins was 820 ng/L (normal, <13 ng/L), while echocardiography showed a normal left ventricular ejection fraction, with no apparent regional wall motion abnormalities. General physical examination findings were unremarkable, excluding ligamentous hyperlaxity and joint instability. C-reactive protein, rheumatoid factor, antinuclear antibody, cytoplasmic antineutrophil cytoplasmic antibody, and angiotensin-converting enzyme blood test results were negative. For further evaluation, arterial phase ECG-synchronized CT angiography from the skull base to the pubis symphysis was performed.

Prognostic value of a new semiquantitative score system for adenosine stress myocardial perfusion by CMR.

OBJECTIVES: Cardiovascular magnetic resonance (CMR) provides information on myocardial ischemia through stress perfusion studies. In clinical practice, the grading of induced perfusion defects is performed by visual estimation of their extension. The aim of our study is to devise a score of the degree of ischemia and to test its prognostic value. METHODS: Between 2009 and 2011, patients with diagnosed or suspected coronary artery disease underwent stress perfusion CMR. A score of ischemic burden was calculated on the basis of (1) stress-induced perfusion defect, (2) persistence, (3) transmurality, and (4) stress-induced contractile defect. Follow-up was censored after 4 years and primary end-point was defined by a composite of death, heart failure episode, acute coronary syndrome, and ventricular arrhythmias. Univariate and multivariate logistic regressions were used to assess the strength of the association between the CMR ischemic variables, and the composite outcome. RESULTS: Forty-four of the 128 patients (34%) presented with adverse events, while 84 (66%) did not. Sixty-one patients (48%) had negative perfusion studies while 67 (52%) showed perfusion defect. Patients with positive perfusion studies and adverse events (n = 39) had higher number of segments with persistent defect (3.3 vs 1.3, p = 0.001) and highest score (19.6 vs 13.3 p = 0.012) than patients with positive perfusion studies and absence of events (n = 28). The number of segments with persistent defect showed the strongest predictive value of adverse events (OR 1.54; CI 1.19-2.00; p < 0.001). CONCLUSIONS: The score of ischemic burden proposed herein has prognostic value. Persistence of a perfusion defect has the strongest impact on prognosis. KEY POINTS: • Cardiovascular magnetic resonance provides information on myocardial ischemia by visual estimation of the presence of perfusion defects induced by stress. • There is not a standardized method for grading perfusion defects which, in practice, is performed by visual estimation of their extension. • As proven in this study, the integration of several parameters of perfusion defects (in addition to extension) into a semiquantitative score has prognostic value.

Protective Effects of Ticagrelor on Myocardial Injury After Infarction.

BACKGROUND: The P2Y12 receptor antagonist ticagrelor has been shown to be clinically superior to clopidogrel. Although the underlying mechanisms remain elusive, ticagrelor may exert off-target effects through adenosine-related mechanisms. We aimed to investigate whether ticagrelor reduces myocardial injury to a greater extent than clopidogrel after myocardial infarction (MI) at a similar level of platelet inhibition and to determine the underlying mechanisms. METHODS: Pigs received the following before MI induction: (1) placebo-control; (2) a loading dose of clopidogrel (600 mg); (3) a loading dose of ticagrelor (180 mg); or (4) a loading dose of ticagrelor followed by an adenosine A1/A2-receptor antagonist [8-(p-sulfophenyl)theophylline, 4 mg/kg intravenous] to determine the potential contribution of adenosine in ticagrelor-related cardioprotection. Animals received the corresponding maintenance doses of the antiplatelet agents during the following 24 hours and underwent 3T-cardiac MRI analysis. Platelet inhibition was monitored by ADP-induced platelet aggregation. In the myocardium, we assessed the expression and activation of proteins known to modulate edema formation, including aquaporin-4 and AMP-activated protein kinase and its downstream effectors CD36 and endothelial nitric oxide synthase and cyclooxygenase-2 activity. RESULTS: Clopidogrel and ticagrelor exerted a high and consistent antiplatelet effect (68.2% and 62.2% of platelet inhibition, respectively, on challenge with 20 µmol/L ADP) that persisted up to 24 hours post-MI (P<0.05). All groups showed comparable myocardial area-at-risk and cardiac worsening after MI induction. 3T-Cardiac MRI analysis revealed that clopidogrel- and ticagrelor-treated animals had a significantly smaller extent of MI than placebo-control animals (15.7 g left ventricle and 12.0 g left ventricle versus 22.8 g left ventricle, respectively). Yet, ticagrelor reduced infarct size to a significantly greater extent than clopidogrel (further 23.5% reduction; P=0.0026), an effect supported by troponin-I assessment and histopathologic analysis (P=0.0021). Furthermore, in comparison with clopidogrel, ticagrelor significantly diminished myocardial edema by 24.5% (P=0.004), which correlated with infarct mass (r=0.73; P<0.001). 8-(p-Sulfophenyl)theophylline administration abolished the cardioprotective effects of ticagrelor over clopidogrel. At a molecular level, aquaporin-4 expression decreased and the expression and activation of AMP-activated protein kinase signaling and cyclooxygenase-2 increased in the ischemic myocardium of ticagrelor- versus clopidogrel-treated animals (P<0.05). These protein changes were not observed in those animals administered the adenosine receptor blocker 8-(p-sulfophenyl)theophylline. CONCLUSIONS: Ticagrelor, beyond its antiplatelet efficacy, exerts cardioprotective effects by reducing necrotic injury and edema formation via adenosine-dependent mechanisms.

Reliability of a new method for coronary artery calcium or metal subtraction by 320-row cardiac CT.

PURPOSE: To investigate the feasibility and diagnostic accuracy of subtraction CTA on patients with highly calcified coronary artery disease (CAD) or previous implanted stents, in comparison with invasive coronary angiography (ICA). MATERIALS AND METHODS: Twenty-three patients were recruited. All conventional and subtraction CTA exams were performed using a 320-row CT. Subjective image quality score was assessed for each segment using a 4-point scale: 1-uninterpretable to 4-good image quality. RESULTS: A total of 129 calcified or stented coronary segments were studied. Mean coronary image quality with conventional CTA was 2.73 ± 0.97 and in subtracted CTA 3.3 ± 0.92 (p < 0.01). After metal subtraction, image quality in stented coronary segments with >3 mm of diameter improved from 2.69 ± 0.97 to 3.34 ± 0.89 (p = 0.01) and in those with <3 mm of diameter from 2.11 ± 0.78 to 2.67 ± 0.87 (p = 0.17). There was an improvement in diagnostic accuracy to detect ICA stenosis >50 % by subtraction CTA compared with conventional CTA (AUC 0.93 to 0.87; p = 0.02). CONCLUSION: Subtraction CTA is promising in overcoming limitations of conventional CTA due to calcium or metal artefacts, especially if no motion artefact is present or when stents > 3 mm are studied. KEY POINTS: • Calcium and metal artefacts are still a limitation for conventional coronary CTA • Diagnostic accuracy is improved by subtraction as compared with conventional CTA • Subtraction CTA is a promising tool to overcome limitations of conventional CTA.

Soluble TNFα-receptor 1 as a predictor of coronary calcifications in patients after long-term cure of Cushing's syndrome.

PURPOSE: Increased cardiovascular (CV) risk persists in Cushing's syndrome (CS), despite remission of hypercortisolism. The aim of this study was to evaluate prevalence of coronary artery disease in CS patients and its correlation with classical CV risk factors and inflammatory markers. METHODS: Cardiac multidetector computed tomography (MDCT) was performed in 41 patients (7 men, 31 of pituitary origin, 29 cured, mean age: 48.6 ± 13 years), using 64-slice Toshiba Aquilion systems. Coronary atherosclerotic plaques were detected and coronary calcifications quantified by the Agatston score (AS). Clinical and biochemical parameters were correlated with the AS to identify possible surrogate markers of coronary disease. Normal values for clinical and biochemical parameters were obtained from a gender- and age-matched normal reference population (n = 82). RESULTS: CS patients with calcifications (AS > 0) (N = 13, 32%) had higher levels of sTNF-R1, homocysteine, triglycerides, blood pressure and body mass index than patients without calcifications (AS = 0) and those of normal reference population. Both groups of CS patients (AS > 0 and AS = 0) had elevated trunk fat mass and IL-6 compared to reference values. Patients with AS > 0 had less adiponectin and higher insulin, HOMA and fibrinogen than those found in normal reference population. sTNF-R1 correlated positively with AS and remained significant after adjusting for confounding factors. The same result was observed when we considered only cured CS patients. CONCLUSION: In our cohort of CS patients sTNF-R1 was a predictor of coronary calcifications. Since MDCT is an expensive technique not readily available in daily clinical practice, increased sTNF-R1 could be a marker of CV risk even in cured CS.

Lateral MI Explains the Presence of Prominent R Wave (R ≥ S) in V1.

AIMS: It is necessary to clarify if the presence of a prominent R wave in V1, in post-myocardial infarction (MI) patients, is due to the involvement of the posterior wall (currently inferobasal segment) or the lateral wall (as has been demonstrated recently by electrocardiographic contrast-enhanced cardiac magnetic resonance [ECG-CE-CMR] correlations studies). METHODS: In 155 patients with inferolateral zone MI, as detected by CE-CMR, the following ECG parameters were evaluated and correlated with MI location according to CE-CMR: R/S ratio in V1 ≥ 1 (classic criteria for posterior MI), R/S ratio in V1 ≥ 0.5, and R in V1 ≥ 3 mm. RESULTS: R/S ≥ 1 criterion: Present in 20 cases: 3 of lateral MI, 17 of inferolateral MI, 0 of inferior MI. Absent in 135 cases, 81 of lateral/inferolateral MI (28/53), 54 of inferior MI (SE 19.8%, SP 100%). R/S ≥ 0.5 criterion: Present in 47 cases: 6 of lateral MI, 39 of inferolateral MI, 2 of inferior MI. Absent in 108 cases, 56 of lateral/inferolateral MI (25/31), 52 of inferior MI (SE 44.6%, SP 96.4%). R ≥ 3 mm criterion: Present in 30 cases: 5 of IM lateral, 23 of inferolateral MI, 2 of inferior MI. Absent in 125 cases, 73 lateral/inferolateral MI (26/47), 52 inferior MI (SE 27.7%, SP 96.4%). CONCLUSIONS: The presence of prominent the R wave in V1 is due to the lateral MI and not to the involvement of inferobasal segment of inferior wall (old posterior wall).

Ruling out coronary artery disease with noninvasive coronary multidetector CT angiography before noncoronary cardiovascular surgery.

PURPOSE: To assess the usefulness of preoperative coronary computed tomographic (CT) angiography in the detection of coronary artery disease (CAD) in nonselected patients scheduled to undergo noncoronary cardiovascular surgery to avoid unnecessary invasive coronary angiography (ICA). MATERIALS AND METHODS: The institutional review board approved the study protocol; informed consent was given. This prospective study involved 161 consecutive patients who underwent coronary calcium scoring and coronary CT angiography before undergoing noncoronary cardiovascular surgery. Seven patients were excluded because of contraindications to CT angiography. The major indication of noncoronary cardiovascular surgery was valvular heart disease (121 patients). Follow-up was performed at a median of 20 months to define ischemic events described as acute coronary syndrome or death secondary to acute coronary syndrome, arrhythmias, or cardiac failure. Multivariate analysis was performed to determine predictors of nondiagnostic coronary CT angiography. Kaplan-Meier analysis was performed to evaluate outcome at follow-up. RESULTS: Twenty-one patients did not undergo surgery, which left 133 patients as the study group. Atrial fibrillation was present in 45 of 133 patients. The interquartile range of the Agatston coronary calcium score was 0-471. Coronary CT angiography was diagnostic in 108 of 133 patients. Of these, 93 of 108 had no significant CAD (≤ 50% stenosis), and noncoronary cardiovascular surgery was performed in them without preoperative ICA. No patients in this group had postoperative ischemic events at follow-up. Coronary CT angiography was nondiagnostic in 25 of 133 patients who were referred for preoperative ICA. Multivariate analysis showed Agatston score to be the only independent predictor of nondiagnostic coronary CT angiography (odds ratio = 1.002; 95% confidence interval: 1.001, 1.003; P = .001). The best Agatston score cutoff for diagnostic coronary CT angiography was 579. CONCLUSION: In nonselected patients scheduled to undergo noncoronary cardiovascular surgery, preoperative coronary CT angiography was diagnostic in 81% of cases. Preoperative ICA could be safely avoided in patients without significant CAD by using coronary CT angiography. The Agatston score, but not the presence of atrial fibrillation, was an independent predictor of nondiagnostic coronary CT angiography. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100384/-/DC1.

Differentiation of athlete's heart and hypertrophic cardiomyopathy by the fractal dimension of left ventricular trabeculae.

BACKGROUND: Differentiation between exercise induced adaptive myocardial hypertrophy (athlete's heart) and hypertrophic cardiomyopathy (HCM) is currently based on echocardiographic and cardiac magnetic resonance (CMR) criteria, but these may be insufficient in patients with subtle phenotype expression. This study aimed to assess whether left ventricular (LV) fractal pattern could permit to differentiate athlete's heart from HCM. METHODS: We recruited retrospectively 61 elite marathon runners, 67 patients with HCM, and 33 healthy subjects. A CMR study was performed in all subjects and the LV trabeculae fractal dimension (FD) was measured in end-diastolic frames of each short-axis cine sequence. For group comparison, the ratio of maximal myocardial wall thickness (mMWT)/indexed LV end-diastolic volume (LVED) was determined. RESULTS: As compared with athletes, patients with HCM had significantly (p < 0.001) greater FD in the LV basal (1.30 ± 0.07 vs. 1.23 ± 0.05) and apical (1.38 ± 0.06 vs. 1.30 ± 0.07) regions and in the whole heart (1.34 ± 0.05 vs. 1.27 ± 0.05). FD increased with age, left atrial area and indexed left ventricular mass (p < 0.05 for all) and correlated negatively with LV and RV end-diastolic volumes (p < 0.05 each). The addition of whole heart FD to the ratio of maximal myocardial wall thickness/indexed LVEDV lead to an improvement in the ability to discriminate HCM with a net reclassification index (NRI) of 71%. CONCLUSIONS: The FD regional distribution of the LV trabeculae differentiates patients with athlete's heart from patients with HCM. The addition of whole heart FD to the mMWT/indexed LVEDV ratio improves the predictive capacity of the model to differentiate both entities.

[Noninvasive coronary angiography using multidetector computed tomography in patients with suspected coronary artery disease and a non-diagnostic exercise treadmill test result]. / Coronariografía no invasiva mediante tomografía computarizada con multidetectores en pacientes con sospecha de enfermedad coronaria y ergometría no diagnóstica.

BACKGROUND AND OBJECTIVE: We aimed to establish the diagnostic and prognostic usefulness of noninvasive coronary angiography using multidetector computer tomography (MDCT) in patients with clinical suspicion of coronary artery disease (CAD) and a non-diagnostic exercise treadmill test result. PATIENTS AND METHOD: Retrospective analysis in 33 patients evaluating the incidence of revascularization and hospitalization due to myocardial infarction or angina, and death. RESULTS: There were obstructive lesions in 7 (21%), non-obstructive lesions in 18 (55%), absence of lesions in 6 (18%), and, finally, 2 patients (6%) had an MDCT deemed as non-evaluable. The follow-up was extended up to 21 (10) months. Events appeared in 5 (15%) patients: 4 myocardial revascularizations in the group with obstructive coronary stenosis, and 1 cardiovascular death in the group with non-obstructive coronary lesions. No events were recorded among those 6 patients without coronary lesions nor in those 2 with non-evaluable MDCT studies. CONCLUSIONS: Patients with suspected CAD and a non-diagnostic exercise test present with a high prevalence of CAD when studied by MDCT and have a high incidence of cardiovascular events. The severity of stenosis as assessed by MDCT relates to cardiovascular events during the follow-up.

New electrocardiographic diagnostic criteria for the pathologic R waves in leads V1 and V2 of anatomically lateral myocardial infarction.

AIMS: To study the different QRS patterns in leads V1 and V2 in first inferior, lateral, and combined inferolateral myocardial infarction (MI) to recognize which are the ECG criteria that best define the presence of lesions isolated to the anatomically lateral wall of the left ventricle. METHODS AND RESULTS: We studied consecutive patients with first inferior (15), lateral (9), or inferolateral (21) MI with reference to contrast enhanced cardiac magnetic resonance (CE-CRM). We measured the R-wave amplitude and duration, the R/S ratio, and the T-wave amplitude and polarity in leads V1 and V2. The specificity of the V1 criteria for lateral MI, that is, R/S amplitude ratio 1 or greater and R duration 40 milliseconds or longer, is very high but its sensitivity is low. We defined 2 new criteria, R/S of 0.5 or greater and R amplitude in V1 greater than 3 mm, with each achieving a sensitivity of 73.3% and specificity of 93.3% for lateral/inferolateral MI location. CONCLUSIONS: (1) New ECG criteria for lateral MI (R/S ratio in V1 > or =0.5 and R amplitude in V1 >3 mm) present very high specificity and lower but very acceptable sensitivity for lateral MI. (2) New criteria based on R waves in V2 or T waves in V1 to V2 do not discriminate between inferior and lateral MI. (3) The classical criteria (R/S amplitude ratio > or =1 and R duration > or =40 ms in V1) attain very high specificity but much lower sensitivity than the new criteria.

Myocardial remodelling and tissue characterisation by cardiovascular magnetic resonance (CMR) in endurance athletes.

There is still some controversy about the benignity of structural changes observed in athlete's heart, especially regarding the observation of increased biomarkers and the presence of myocardial fibrosis (MF). AIM: Our purpose was to evaluate by cardiovascular magnetic resonance (CMR) the presence of diffuse as well as focal MF in a series of high-performance veteran endurance athletes. METHODS: Thirty-four veteran healthy male endurance athletes, still being in regular training, with more than 10 years of training underwent a CMR. A cardiopulmonary exercise test was also performed to assess their maximal physical performance. The control group consisted in 12 non-trained normal individuals. RESULTS: We found an increase in both, right and left ventricular (LV) volumes in the athlete's group when compared with controls. There was no increase in indexed LV myocardial mass despite of a significantly increased maximal myocardial wall thickness in comparison to controls. Native T1 values and extracellular volume (ECV) were normal in all cases. We did not find differences in native T1 values and ECV between both groups. In three athletes (9%), non-ischaemic late gadolinium enhancement (LGE) was observed. We did not find a correlation between total training volume and presence of LGE or with the ECV value. CONCLUSIONS: Our results show that the majority of veteran endurance athletes present with myocardial remodelling without MF as a physiological adaptive phenomenon. In the only three athletes with focal MF, the LGE pattern observed suggests an intercurrent event not related with the remodelling phenomenon.

P2Y12 antagonists and cardiac repair post-myocardial infarction: global and regional heart function analysis and molecular assessments in pigs.

Aims: P2Y12 antagonists are the standard in antiplatelet therapy but their potential effects on functional myocardial recovery and cardioprotection post-myocardial infarction (MI) are unknown. We investigated in a preclinical model of MI whether ticagrelor and clopidogrel differently affect cardiac repair post-MI. Methods and results: Pigs either received: (i) clopidogrel (600 mg; 75 mg/qd); (ii) ticagrelor (180 mg; 90 mg/bid); and (iii) placebo control. MI was induced by mid-left anterior descending coronary artery balloon occlusion (60 min) and animals received the maintenance doses for the following 42 days. Serial cardiac magnetic resonance was performed at Day 3 and Day 42 for the assessment of global and regional cardiac parameters. We determined cardiac AMP-activated protein kinase (AMPK), Akt/PKB, aquaporin-4, vascular density, and fibrosis. In comparison to controls, both P2Y12 antagonists limited infarct expansion at Day 3, although ticagrelor induced a further 5% reduction (P < 0.05 vs. clopidogrel) whereas oedema was only reduced by ticagrelor (≈23% P < 0.05). Scar size decreased at Day 42 in ticagrelor-treated pigs vs. controls but not in clopidogrel-treated pigs. Left ventricular ejection fraction was higher 3 days post-MI in ticagrelor-treated pigs and persisted up to Day 42 (P < 0.05 vs. post-MI). Regional analysis revealed that control and clopidogrel-treated pigs had severe and extensive wall motion abnormalities in the jeopardized myocardium and a reduced myocardial viability that was not as evident in ticagrelor-treated pigs (χ2P < 0.05 vs. ticagrelor). Only ticagrelor enhanced myocardial AMPK and Akt/PKB activation and reduced aquaporin-4 levels (P < 0.05 vs. control and clopidogrel). No differences were observed in vessel density and fibrosis markers among groups. Conclusions: Ticagrelor is more efficient than clopidogrel in attenuating myocardial structural and functional alterations post-MI and in improving cardiac healing. These benefits are associated with persistent AMPK and Akt/PKB activation.

Idiopathic dilated cardiomyopathy exhibits defective vascularization and vessel formation.

BACKGROUND: Ultrastructural findings of idiopathic dilated cardiomyopathy (IDCM) include myocyte atrophy and myofilament loss, yet little is known about the vascular abnormalities present in IDCM. METHODS AND RESULTS: Patients with IDCM and controls underwent multi-slice CT to examine length and diameter of epicardial vasculature. The levels of mobilizing cytokines and circulating EPCs were assessed by endothelial colony formation assay and flow cytometry. Immunohistochemistry and Western blot were used to examine microvessel density and expression of HIF-1alpha and beta-catenin. Main epicardial coronary arteries were shorter and smaller, and microvascular density was reduced in the epicardium in IDCM. Epicardial vessel paucity was associated with increased numbers of HIF-1alpha(+) cells (46.8+/-13.1% vs. 19.4+/-9.4%, p=0.006) indicating local epicardial hypoxia and elevation of circulating VEGF-A (394 pg/mL vs. 22 pg/mL, p=0.001). The number of mobilized progenitors CD133(+)/VEGF-R2(+) was 21-fold higher in IDCM compared with controls (6.5+/-3.3% vs. 0.3+/-0.2%; p<0.001). Moreover, this defective vascularization was associated with reduced myocardial expression of vascular beta-catenin, an important angiogenic regulator. CONCLUSIONS: This study shows defective vascularization and impaired vasculogenesis (the de novo vascular organization of mobilized endothelial progenitors) and angiogenesis (by which new blood vessels are formed from pre-existing mature endothelial cells) in human IDCM.

Electrocardiographic findings in patients with cryptogenic ischemic stroke and patent foramen ovale.

BACKGROUND: A characteristic electrocardiogram (ECG) pattern called crochetage has been described in patients with atrial septal defects. Nevertheless, there are discrepancies regarding its frequency in patients with patent foramen ovale (PFO). OBJECTIVE: We analyzed the ECGs of patients who had cryptogenic stroke to study crochetage and other possible patterns in relation to PFO. METHODS: We prospectively included consecutive patients who have had a cryptogenic stroke and are undergoing a right-to-left shunt (RLS) study with transesophageal echocardiography and simultaneous transcranial Doppler. Two blinded and independent cardiologists analyzed the ECGs for crochetage, defined as a notch near the apex of the R wave in inferior limb leads, P wave abnormalities, and right bundle branch block (RBBB). RESULTS: We studied 104 patients whose mean age was 55.1 +/- 12.7 years; 60.6% were men. PFO was detected in 40.4% of patients. Cardiologists recorded crochetage in 26.2% of patients with PFO and 14.5% of patients without PFO (P = .204) and RBBB in 19% and 8% of patients, respectively (P = .132). P wave abnormalities were also detected in 54.8% of patients with PFO and 35.5% of patients without PFO (P = .070). In patients with PFO, biphasic P waves were more frequent in small RLS (P = .006). Although higher frequencies of crochetage in small RLS and RBBB in moderate RLS were detected, these differences did not reach statistical significance (P = .067 and P = .05, respectively). CONCLUSION: There is no characteristic ECG pattern to identify the patients with cryptogenic stroke.

Allogenic adipose-derived stem cell therapy overcomes ischemia-induced microvessel rarefaction in the myocardium: systems biology study.

BACKGROUND: Myocardial microvascular loss after myocardial infarction (MI) remains a therapeutic challenge. Autologous stem cell therapy was considered as an alternative; however, it has shown modest benefits due to the impairing effects of cardiovascular risk factors on stem cells. Allogenic adipose-derived stem cells (ASCs) may overcome such limitations, and because of their low immunogenicity and paracrine potential may be good candidates for cell therapy. In the present study we investigated the effects of allogenic ASCs and their released products on cardiac rarefaction post MI. METHODS: Pig subcutaneous adipose tissue ASCs were isolated, expanded and GFP-labeled. ASC angiogenic function was assessed by the in-vivo chick chorioallantoic membrane (CAM) model. Pigs underwent MI induction and 7 days after were randomized to receive: allogenic ASCs (intracoronary infusion); conditioned media (CM; intravenous infusion); ASCs + CM; or PBS/placebo (control). Cardiac damage and function were monitored by 3-T cardiac magnetic resonance imaging upon infusion (baseline CMR) and 1 and 3 weeks thereafter. We assessed in the myocardium: microvessel density; angiogenic markers (CD105, CD31, TF, VEGFR2, VEGFR1, vWF, eNOS, CD62); collagen deposition; and reparative fibrosis (TGFß/TßRII/collagen). Differential proteomics of ASCs and CM was performed to characterize the ASC protein signature. RESULTS: CAM indicated a significant ASC proangiogenic capacity. In pigs after MI, only PBS/placebo animals displayed an impaired cardiac function 3 weeks after infusion (p < 0.05 vs baseline). Administration of ASCs + CM significantly enhanced neovessel formation and favored cardiac repair post MI (p < 0.05 vs the other groups). Molecular markers of angiogenesis were significantly upregulated both at transcriptional and protein levels (p < 0.05). The in-silico bioinformatics analysis of the ASC and CM proteome (interactome) indicated activation of a coordinated protein network involved in the formation of microvessels and the resolution of rarefaction. CONCLUSION: Coadministration of allogenic ASCs and their CM synergistically contribute to the neovascularization of the infarcted myocardium through a coordinated upregulation of the proangiogenic protein interactome.

Concordance of electrocardiographic patterns and healed myocardial infarction location detected by cardiovascular magnetic resonance.

Q-wave myocardial infarction (MI) location is generally based on a pathologic correlation first proposed >50 years ago. Despite the proved reliability of contrast-enhanced cardiovascular magnetic resonance (CE-CMR) imaging to detect and locate infarcted areas, no global study has been conducted with the aim of correlating the electrocardiographic (ECG) patterns of Q-wave MI with infarct location. We studied this correlation in 51 patients with ST-elevation acute coronary syndrome who presented with Q waves or equivalents during MI. Seven preestablished ECG patterns that matched with high specificity to 7 different MI locations as detected by CE-CMR imaging were used to assess its value in clinical practice to locate an infarcted area. There were 4 ECG patterns in the anteroseptal zone (23 patients; septal, apical, and/or anteroseptal, extensive anterior, and limited anterolateral) and 3 ECG patterns in the inferolateral zone (28 patients; lateral, inferior, and inferolateral). In conclusion, (1) the predefined ECG patterns we used matched well (86% global concordance) with their corresponding infarction areas as detected by CE-CMR imaging and have real value in clinical practice, and (2) the RS morphology in lead V(1) is due to lateral MI and the QS morphology in lead aVL is due to mid-anterior and mid-lateral MI. Therefore, the terms posterior and high lateral infarction are incorrect and should be changed to lateral wall and limited anterolateral wall MI.