Genome silencer therapy leading to 'regression' of cardiac amyloid load on cardiovascular magnetic resonance: a case report.

BACKGROUND: Hereditary or variant transthyretin amyloidosis (ATTRv) is a progressive disease manifesting with neuropathy and/or cardiomyopathy. An early and accurate diagnosis of cardiac amyloidosis is a pre-requisite for timely and appropriate patient management, including anti-amyloid therapies, as it is associated with heart failure, conduction disease, and arrhythmias, leading to reduced quality of life and early death. CASE SUMMARY: We present the case of an ATTRv male patient presenting with a mixed amyloidosis phenotype (neuropathy and cardiomyopathy). Cardiac disease manifestation comprised tachyarrhythmias (atrial fibrillation) and conduction abnormalities (atrio-ventricular block) in addition to segmental left ventricular (LV) hypertrophy (septal wall) due to regionally pronounced amyloid deposits in the basal LV myocardium. Interestingly, by means of serial cardiovascular magnetic resonance (CMR) studies, we were able to demonstrate an impressive and unexpected improvement of cardiomyopathy findings within a relatively short period-of-time after the implementation of genome-silencer therapies. DISCUSSION: This is our second case report that showed ATTRv cardiomyopathy reversal under anti-amyloid therapy-documented by multi-parametric CMR. Our findings support the hypothesis that amyloid infiltration leading to cardiomyopathy is not an irreversible pathological process-but rather a dynamic one, that cannot only be stopped but even reversed (to a certain degree) by currently emerging anti-amyloid therapies. Moreover, the role of serial multi-parametric CMR imaging for surveillance of cardiomyopathy dynamics under these therapies is nicely illustrated.

Diagnostic value of the novel CMR parameter "myocardial transit-time" (MyoTT) for the assessment of microvascular changes in cardiac amyloidosis and hypertrophic cardiomyopathy.

BACKGROUND: Coronary microvascular dysfunction (CMD) is present in various non-ischemic cardiomyopathies and in particular in those with left-ventricular hypertrophy. This study evaluated the diagnostic value of the novel cardiovascular magnetic resonance (CMR) parameter "myocardial transit-time" (MyoTT) in distinguishing cardiac amyloidosis from other hypertrophic cardiomyopathies. METHODS: N = 20 patients with biopsy-proven cardiac amyloidosis (CA), N = 20 patients with known hypertrophic cardiomyopathy (HCM), and N = 20 control patients without relevant cardiac disease underwent dedicated CMR studies on a 1.5-T MR scanner. The CMR protocol comprised cine and late-gadolinium-enhancement (LGE) imaging as well as first-pass perfusion acquisitions at rest for MyoTT measurement. MyoTT was defined as the blood circulation time from the orifice of the coronary arteries to the pooling in the coronary sinus (CS) reflecting the transit-time of gadolinium in the myocardial microvasculature. RESULTS: MyoTT was significantly prolonged in patients with CA compared to both groups: 14.8 ± 4.1 s in CA vs. 12.2 ± 2.5 s in HCM (p = 0.043) vs. 7.2 ± 2.6 s in controls (p < 0.001). Native T1 and extracellular volume (ECV) were significantly higher in CA compared to HCM and controls (p < 0.001). Both parameters were associated with a higher diagnostic accuracy in predicting the presence of CA compared to MyoTT: area under the curve (AUC) for native T1 = 0.93 (95% confidence interval (CI) = 0.83-1.00; p < 0.001) and AUC for ECV = 0.95 (95% CI = 0.88-1.00; p < 0.001)-compared to the AUC for MyoTT = 0.76 (95% CI = 0.60-0.92; p = 0.008). In contrast, MyoTT performed better than all other CMR parameters in differentiating HCM from controls (AUC for MyoTT = 0.93; 95% CI = 0.81-1.00; p = 0.003 vs. AUC for native T1 = 0.69; 95% CI = 0.44-0.93; p = 0.20 vs. AUC for ECV = 0.85; 95% CI = 0.66-1.00; p = 0.017). CONCLUSION: The relative severity of CMD (measured by MyoTT) in relationship to extracellular changes (measured by native T1 and/or ECV) is more pronounced in HCM compared to CA-in spite of a higher absolute MyoTT value in CA patients. Hence, MyoTT may improve our understanding of the interplay between extracellular/intracellular and intravasal changes that occur in the myocardium during the disease course of different cardiomyopathies.

Immune Checkpoint Inhibitor-Associated Myocarditis: A Run of Bad Luck or Rather Deficient-Monitoring Protocol?

Immune checkpoint inhibitors (ICIs) can induce immunity-related adverse events. We demonstrate the clinical use of cardiac magnetic resonance and endomyocardial biopsy in the diagnosis and subsequent monitoring of ICI-associated myocarditis, suggesting the need to establish and evaluate a cardiac monitoring protocol for patients under ICI therapy. (Level of Difficulty: Intermediate.).

Reduced global myocardial perfusion reserve in DCM and HCM patients assessed by CMR-based velocity-encoded coronary sinus flow measurements and first-pass perfusion imaging.

BACKGROUND: Coronary microvascular dysfunction (CMD) is an independent predictor of poor prognosis in patients suffering from dilative or hypertrophic cardiomyopathy (DCM/HCM). To assess CMD, quantitative myocardial first-pass perfusion (1P) cardiovascular magnetic resonance (CMR) can be performed. Coronary sinus flow (CSF) measurements at rest and during maximal vasodilatation are an alternative and well-validated approach for the quantification of global myocardial blood flow (MBF) in CMR. METHODS: Global myocardial perfusion reserve (MPR) was used to compare both methods, 1P and CSF. This measure reflects the ratio of myocardial blood flow during maximal coronary vasodilatation over rest. 1P-MPR and CSF-MPR were calculated in 17 HCM patients, 14 DCM patients and 16 controls, who underwent a stress CMR study to rule out obstructive coronary artery disease. All patients were examined on a 1.5-T system and the study protocol comprised both, first-pass myocardial perfusion imaging (MPI) and velocity-encoded (VENC) phase-contrast imaging of CSF during rest and adenosine stress. RESULTS: 1P-MPR was significantly decreased only in HCM patients compared to controls (1.14 vs. 1.43, p = 0.045) whereas CSF-MPR was significantly reduced in both patient groups, HCM and DCM, compared to controls (2.38 and 2.07 vs. 3.18, p = 0.041 and p = 0.032). CSF-MBF at maximal stress was significantly lower in HCM and DCM patients compared to the control group (0.11 and 1.23 vs. 1.58 ml/min/g, p = 0.008 and p = 0.040). A moderate but significant correlation between CSF-MPR and 1P-MPR was observed (r = 0.39, p = 0.011). A negative correlation between LV wall thickness and CSF-MBF at rest and stress was found in the DCM group using VENC-based CSF measurements (r = - 0.64, p = 0.013 and r = - 0.69, p = 0.006)-but not using 1P-MPI. Post-proceeding analysis regarding 1P-MPR and CSF-MPR measurements required 20.1 and 6.5 min, respectively (p < 0.001). CONCLUSION: The presence of microvascular disease can be non-invasively and quickly detected by VENC-based CSF-MPR measurements during routine stress perfusion CMR in both HCM and DCM patients. Compared to conventional 1P-MPI, VENC-based CSF-MPR is particularly useful in DCM patients with thinned ventricular walls.

Diagnostic value of global myocardial perfusion reserve assessment based on coronary sinus flow measurements using cardiovascular magnetic resonance in addition to myocardial stress perfusion imaging.

AIMS: Myocardial perfusion reserve (MPR) is defined as the maximal possible increase in myocardial blood flow (MBF) above baseline conditions. Global MBF can be measured non-invasively by means of coronary sinus flow velocity encoded cine (VENC) cardiovascular magnetic resonance (CMR). We aimed to explore the relationship between global MBF/MPR and the extent and severity of coronary artery disease (CAD) in patients referred for CAD work-up by adenosine-stress CMR. METHODS AND RESULTS: Fifty-eight patients with suspected obstructive CAD underwent both adenosine-stress CMR and invasive coronary angiography. In addition to standard cine- and late gadolinium enhancement (LGE)-imaging, first-pass myocardial perfusion imaging (MPI) and coronary sinus flow measurements (VENC) were performed at rest and during peak stress (after 140 µg/kg/min adenosine), respectively. Nineteen young patients with a very low CAD pre-test probability and normal adenosine-stress CMR formed the control group. Fifty-nine percent (n = 34) of the study group showed segmental, adenosine-induced myocardial perfusion defects compared to none of the control group (P < 0.001). Global MPR was lower in the study group compared to the control group: 2.3 (1.5-3.1) vs. 3.1 (2.0-4.3), P = 0.016. The SYNTAX score was higher in the study group patients with an impaired MPR (<2) compared to those with a preserved MPR (3.0 vs. 16.0, P = 0.01)-mainly due to higher prevalence of proximal epicardial stenoses (60% vs. 27%, P = 0.02) and multi-vessel disease (56% vs. 24%, P = 0.017). The diagnostic yield of stress CMR for the diagnosis of CAD (>50% stenosis) increased from 65to 88% when global MPR assessment was considered in addition to MPI (P = 0.025). CONCLUSIONS: Global MBF and MPR values correlate with the anatomical extent and complexity of CAD and increase the diagnostic yield of non-invasive stress CMR in the work-up of CAD. CMR-based MBF and MPR measurements may play a future role in the evaluation of the total ischaemic burden-particularly in patients with multi-vessel disease.

Remote magnetic targeting of iron oxide nanoparticles for cardiovascular diagnosis and therapeutic drug delivery: where are we now?

Magnetic resonance imaging (MRI) allows for an accurate assessment of both functional and structural cardiac parameters, and thereby appropriate diagnosis and validation of cardiovascular diseases. The diagnostic yield of cardiovascular MRI examinations is often increased by the use of contrast agents that are almost exclusively based on gadolinium compounds. Another clinically approved contrast medium is composed of superparamagnetic iron oxide nanoparticles (IONs). These particles may expand the field of contrast-enhanced cardiovascular MRI as recently shown in clinical studies focusing on acute myocardial infarction (AMI) and atherosclerosis. Furthermore, IONs open up new research opportunities such as remote magnetic drug targeting (MDT). The approach of MDT relies on the coupling of bioactive molecules and magnetic nanoparticles to form an injectable complex. This complex, in turn, can be attracted to and retained at a desired target inside the body with the help of applied magnetic fields. In comparison to common systemic drug applications, MDT techniques promise both higher concentrations at the target site and lower concentrations elsewhere in the body. Moreover, concurrent or subsequent MRI can be used for noninvasive monitoring of drug distribution and successful delivery to the desired organ in vivo. This review does not only illustrate the basic conceptual and biophysical principles of IONs, but also focuses on new research activities and achievements in the cardiovascular field, mainly in the management of AMI. Based on the presentation of successful MDT applications in preclinical models of AMI, novel approaches and the translational potential of MDT are discussed.

The diagnostic value of iron oxide nanoparticles for imaging of myocardial inflammation--quo vadis?

Cardiovascular magnetic resonance (CMR) is an integral part in the diagnostic work-up of cardiac inflammatory diseases. In this context, superparamagnetic iron oxide-based contrast agents can provide additional diagnostic information regarding the assessment of myocardial infarction and myocarditis. After intravenous administration, these nanoparticles are taken up by activated monocytes and macrophages, which predominantly accumulate in regions associated with inflammation as was successfully shown in recent preclinical studies. Furthermore, first clinical studies with a new iron oxide-complex that was clinically approved for the treatment of iron deficiency anaemia recently demonstrated a superior diagnostic value of iron oxide nanoparticles compared to gadolinium-based compounds for imaging of myocardial inflammation in patients with acute myocardial infarction. In this article, we outline the basic features of superparamagnetic iron oxide-based contrast agents and review recent studies using such nanoparticles for cardiac imaging in case of acute myocardial infarction as well as acute myocarditis. Moreover, we highlight the translational potential of these agents and possible research applications with regard to imaging and therapy.

Positive effect of intravenous iron-oxide administration on left ventricular remodelling in patients with acute ST-elevation myocardial infarction - a cardiovascular magnetic resonance (CMR) study.

OBJECTIVES: This study investigated the safety profile and potential "therapeutic" effect of intravenous ultrasmall superparamagnetic iron-oxide (USPIO)-based iron administration regarding infarct healing in patients with ST-elevation myocardial infarction (STEMI). USPIO-administration was recently shown to enable an improved characterization of myocardial infarct pathology in acute STEMI patients. MATERIALS AND METHODS: Seventeen study patients (IRON, 54 ± 9 yrs, 88% male) and 22 matched controls (CONTROL, 57 ± 9 yrs, 77% male) both with primary reperfused STEMI underwent multi-parametric CMR studies in the first week and three months after acute MI. Only IRON patients received a single intravenous bolus of 510 mg elemental iron as ferumoxytol (Feraheme(TM)) within four days following acute MI. RESULTS: Three months later, all patients were alive and there were no adverse cardiac events. Significant improvement in left ventricular (LV) ejection fraction (IRON: 53 ± 10% to 59 ± 9%, p=0.002; CONTROL: 54 ± 6% to 57 ± 10%, p=0.005) as well as shrinkage of infarct size were seen in both groups at follow-up. There was a more pronounced decrease in infarct size in the IRON group (IRON: -10.3 ± 5.4% vs. CONTROL: -7.0 ± 8.4%, p=0.050) in addition to a significant decrease in both endocardial extent and prevalence of transmural infarctions in IRON but not in CONTROL patients. A significant decrease in LV end systolic volume was only seen in the IRON group (71 ± 25 mL to 59 ± 25 mL, p=0.002). CONCLUSIONS: Intravenous iron administration in acute STEMI patients seems to be associated with an improved infarct healing and a beneficial global left ventricular remodelling. These findings together with the good safety profile make USPIO-based iron administration a promising future candidate as a "diagnostic" and "therapeutic" adjunctive solution in acute MI management.

Subclinical cardiotoxicity detected by strain rate imaging up to 14 months after breast radiation therapy.

PURPOSE: Strain rate imaging (SRI) is a new echocardiographic modality that enables accurate measurement of regional myocardial function. We investigated the role of SRI and troponin I (TnI) in the detection of subclinical radiation therapy (RT)-induced cardiotoxicity in breast cancer patients. METHODS AND MATERIALS: This study prospectively included 75 women (51 left-sided and 24 right-sided) receiving adjuvant RT to the breast/chest wall and regional lymph nodes. Sequential echocardiographs with SRI were obtained before RT, immediately after RT, and 8 and 14 months after RT. TnI levels were measured on the first and last day of RT. RESULTS: Mean heart and left ventricle (LV) doses were both 9 ± 4 Gy for the left-sided patients and 4 ± 4 Gy and 1 ± 0.4 Gy, respectively, for the right-sided patients. A decrease in strain was observed at all post-RT time points for left-sided patients (-17.5% ± 1.9% immediately after RT, -16.6% ± 1.4% at 8 months, and -17.7% ± 1.9% at 14 months vs -19.4% ± 2.4% before RT, P<.01) but not for right-sided patients. When we considered left-sided patients only, the highest mean dose was given to the anterior left ventricular (LV) wall (25 ± 14 Gy) and the lowest to the inferior LV wall (3 ± 3 Gy). Strain of the anterior wall was reduced after RT (-16.6% ± 2.3% immediately after RT, -16% ± 2.6% at 8 months, and -16.8% ± 3% at 14 months vs -19% ± 3.5% before RT, P<.05), whereas strain of the inferior wall showed no significant change. No changes were observed with conventional echocardiography. Furthermore, mean TnI levels for the left-sided patients were significantly elevated after RT compared with before RT, whereas TnI levels of the right-sided patients remained unaffected. CONCLUSIONS: In contrast to conventional echocardiography, SRI detected a regional, subclinical decline in cardiac function up to 14 months after breast RT. It remains to be determined whether these changes are related to clinical outcome. In the meantime, we encourage the use of radiation techniques that minimize the exposure of the anterior LV wall in left-sided patients.

Electrocardiographic Q-wave "remodeling" in reperfused ST-segment elevation myocardial infarction: validation study with CMR.

OBJECTIVES: The aim of this study was to evaluate the evolution in Q-wave expression during the first 5 years after a primary, successfully reperfused ST-segment elevation myocardial infarction (MI), using cardiac magnetic resonance (CMR) for infarct location, and to depict changes in infarct size and left ventricular remodeling over time. BACKGROUND: In the absence of QRS confounders, abnormal Q waves are usually diagnostic of myocardial necrosis. It is hypothesized that Q-wave regression after MI could be related to smaller infarct sizes. Late gadolinium enhancement accurately depicts MI of any age. METHODS: Forty-six MI patients underwent electrocardiography and CMR at 1 week (baseline), 4 months, 1 year, and 5 years post-infarction. Conventional CMR parameters were analyzed, and infarct presence, location, and size were assessed using late gadolinium enhancement CMR. Infarct locations were anterior or nonanterior (inferior and/or lateral), using late gadolinium enhancement CMR as a reference. For each time point, patients were classified as having a diagnostic/nondiagnostic electrocardiogram (ECG) using the European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation consensus criteria for previous Q-wave infarct. RESULTS: At baseline, 11 patients (23%) did not meet the criteria for Q-wave MI. Non-Q-wave infarcts were significantly smaller than Q-wave infarcts (p < 0.0001). All anterior Q-wave infarcts (n = 17) were correctly localized, whereas in 7 of 19 nonanterior Q-wave infarcts, the location or extent of the infarct was misjudged by electrocardiography. At 4-month/1-year follow-up, in 10 patients (3 anterior/7 nonanterior), the ECG became nondiagnostic. The ECG remained nondiagnostic at 5-year follow-up. A cutoff infarct size of 6.2% at 1 year yielded a sensitivity of 89% and a specificity of 74% to predict the presence or absence of Q waves. CONCLUSIONS: The incidence of nondiagnostic ECGs for previous MI using the current European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation criteria is substantial and increases with time post-infarction from 23% immediately post-infarction to 44% at 5-year follow-up.

Mesenteric ischemia--a complex disease requiring an interdisciplinary approach. A review of the current literature.

Mesenteric ischemia is caused by a reduction in intestinal blood flow with potential catastrophic clinical consequences: sepsis, bowel infarction, and death. In the recent years, the incidence of mesenteric ischemia increased, now accounting for 0.1% of hospital admissions. Among the multiple factors responsible for this change is the heightened awareness for the diagnoses, the advanced mean age of the population and the increasing number of critically ill patients. Acute mesenteric ischemia is a potentially fatal vascular emergency, with overall mortality of 60-80%; prompt diagnosis and treatment are paramount. A high index of suspicion in the setting of a compatible history and physical examination serves as the cornerstone to early diagnosis of mesenteric ischemia. Restoration of intestinal blood flow, as rapidly as possible, is the main goal of treatment in patients with acute mesenteric ischemia. This may be achieved by medical means, endovascular procedures and by surgery. Chronic mesenteric ischemia is an uncommon process that occurs only when severe atherosclerotic narrowing of a major splanchnic vessel exists in association with occlusion of one or two of the remaining vessels. Its diagnosis is mainly based on the characteristic clinical picture, on the presence of an occlusive lesion in the splanchnic vessels and on the absence of other common causes of abdominal pain. The means available for mesenteric revascularization are the surgical techniques of flow restoration and the more recently developed percutaneous transluminal procedures.

Calcific aortic valve disease and aortic atherosclerosis--two faces of the same disease?

Calcific (degenerative) aortic valve disease is the most common etiology of acquired aortic valve stenosis. Historically, it was seen as a degenerative, "senile-like" process, resulting from aging--"wearing and tearing"--of the aortic valve. However, several lines of evidence suggest that calcific valve disease is not simply due to age-related degeneration but, rather, it is an active disease process with identifiable initiating factors, clinical and genetic risk factors, and cellular and molecular pathways that mediate disease progression. Histopathologically, the early lesions of aortic valve sclerosis resemble arterial atherosclerotic plaques. Furthermore, atherosclerotic risk factors and clinical atherosclerotic cardiovascular disease are independently associated with aortic sclerosis suggesting that it represents an atherosclerosis-like process involving the aortic valve. Until now, the only established treatment for symptomatic aortic valve stenosis has been valve replacement. Newer therapies that may modify or reduce the likelihood of developing aortic valve disease are highly desirable and are currently under investigation. In this article we tried to review the available data on calcific aortic valve disease, starting from histological and pathogenic aspects and finishing with therapeutic implications, in order to characterize its relationship with the atherosclerotic process.