Rare c.302C>T TTR Variant Associated with Transthyretin Amyloidosis.

Background and Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a rare disease caused by pathogenic variants in the transthyretin (TTR) gene. More than 140 different disease-causing variants in TTR have been reported. Only a few individuals with a rare TTR variant, c.302C>T, p.(Ala101Val) (historically known as p.(Ala81Val)), primarily associated with cardiac ATTRv, have been described. Therefore, our aim was to analyze the clinical characteristics of individuals with the identified c.302C>T TTR variant at our center. Materials and Methods: We analyzed data from individuals with ATTRv who were diagnosed and treated at Vilnius University Hospital Santaros Klinikos. ATTRv was confirmed by negative hematological analysis for monoclonal protein, positive tissue biopsy or bone scintigraphy and a pathogenic TTR variant. Results: During 2018-2021, the TTR NM_000371.3:c.302C>T, NP_000362.1:p.(Ala101Val) variant was found in one individual in a homozygous state and in three individuals in a heterozygous state. The age of onset of symptoms ranged from 44 to 74 years. The earliest onset of symptoms was in the individual with the homozygous variant. A history of carpal tunnel syndrome was identified in two individuals. On ECG, three individuals had low QRS voltage in limb leads. All individuals had elevated NT-proBNP and hsTroponine I levels on baseline laboratory tests and concentric left ventricular hypertrophy on transthoracic echocardiography. The individual with the homozygous c.302C>T TTR variant had the most pronounced polyneuropathy with tetraparesis. Other patients with the heterozygous variant had more significant amyloid cardiomyopathy. When screening family members, the c.302C>T TTR variant was identified in two phenotypically negative relatives at the ages of 33 and 47 years. Conclusions: c.302C>T is a rare TTR variant associated with ATTRv cardiomyopathy. The homozygous state of this variant was not reported before, and is associated with earlier disease onset and neurological involvement compared to the heterozygote state.

Electrocardiographic Markers of Adverse Left Ventricular Remodeling and Myocardial Fibrosis in Severe Aortic Stenosis.

The optimal timing for aortic valve replacement (AVR) in aortic stenosis (AS) is still controversial and may be guided by markers of adverse left ventricular (LV) remodeling. We aim to assess electrocardiographic (ECG) strain in relation to LV remodeling and myocardial fibrosis. 83 severe AS patients underwent surgical AVR, with preoperative 12-lead ECG, cardiovascular magnetic resonance with T1 mapping and echocardiography with global longitudinal strain analysis. Collagen volume fraction (CVF) was measured in myocardial biopsies sampled during AVR. Patients with ECG strain had more severe AS, more advanced LV remodeling and evidence of heart failure. Patients with ECG strain had more diffuse fibrosis, as evident by higher mean native T1 values (974.8 ± 34 ms vs. 946.5 ± 28 ms, p < 0.001). ECG strain was the only predictor of increased LV mass index on multivariate regression analysis (OR = 7.10, 95% CI 1.46-34.48, p = 0.02). Patients with persistent ECG strain at 1 year following AVR had more advanced LV remodeling and more histological fibrosis (CVF 12.5% vs. 7.3%, p = 0.009) at baseline assessment. Therefore, ECG strain is a marker of adverse LV remodeling and interstitial myocardial fibrosis. Lack of improvement in ECG strain following AVR indicates more advanced baseline LV injury and higher levels of myocardial fibrosis.

Type 2 Myocardial Infarction and Long-Term Mortality Risk Factors: A Retrospective Cohort Study.

INTRODUCTION: In-hospital risk factors for type 1 myocardial infarction (MI) have been extensively investigated, but risk factors for type 2 MI are still emerging. Moreover, type 2 MI remains an underdiagnosed and under-researched condition. Our aim was to assess survival rates after type 2 MI and to analyze the risk factors for patient prognosis after hospitalization. METHODS: We conducted a retrospective database analysis of patients with MI diagnosis who were treated in Vilnius University Hospital Santaros Klinikos. A total of 6495 patients with the diagnosis of MI were screened. The primary study endpoint was long-term all-cause mortality. The predictive value of laboratory tests was estimated including blood hemoglobin, D dimer, creatinine, brain natriuretic peptide (BNP), C-reactive protein (CRP), and troponin levels. RESULTS: Out of all the patients diagnosed with MI there were 129 cases of type 2 MI (1.98%). Death rate almost doubled from 19.4% at 6 months to 36.4% after 2 years of follow-up. Higher age and impaired kidney function were risk factors for death both during hospitalization and after 2 years of follow-up. Lower hemoglobin (116.6 vs. 98.9 g/L), higher creatinine (90 vs. 161.9 µmol/L), higher CRP (31.4 vs. 63.3 mg/l), BNP (707.9 vs. 2999.3 ng/L), and lower left ventricle ejection fraction were all predictors of worse survival after 2 years of follow-up. Preventive medication during hospitalization can decrease the mortality risk: angiotensin-converting enzyme inhibitor (ACEi) (HR 0.485, 95% CI 0.286-0.820) and statins (HR 0.549, 95% CI 0.335-0.900). No significant influence was found for beta blockers (HR 0.662, 95% CI 0.371-1.181) or aspirin (HR 0.901, 95% CI 0.527-1.539). CONCLUSIONS: There is significant underdiagnosis of type 2 MI (1.98% out of all MIs). If the patient is prescribed a preventive medication like ACEi or statins, the mortality risk is lower. Increased awareness of elevation of laboratory results could help to improve the treatment of these patients and identify the most vulnerable groups.

Exploring myocardial fibrosis in severe aortic stenosis: echo, CMR and histology data from FIB-AS study.

Myocardial fibrosis in aortic stenosis is associated with worse survival following aortic valve replacement. We assessed myocardial fibrosis in severe AS patients, integrating echocardiographic, cardiovascular magnetic resonance (CMR) and histological data. A total of 83 severe AS patients (age 66.4 ± 8.3, 42% male) who were scheduled for surgical AVR underwent CMR with late gadolinium enhancement and T1 mapping and global longitudinal strain analysis. Collagen volume fraction was measured in myocardial biopsies (71) that were sampled at the time of AVR. Results. CVF correlated with imaging and serum biomarkers of LV systolic dysfunction and left side chamber enlargement and was higher in the sub-endocardium compared with midmyocardium (p<0.001). CVF median values were higher in LGE-positive versus LGE-negative patients [28.7% (19-33) vs 20.7% (15-30), respectively, p=0.040]. GLS was associated with invasively (CVF; r=-0.303, p=0.013) and non-invasively (native T1; r=-0.321, p<0.05) measured myocardial fibrosis. GLS and native T1 correlated with parameters of adverse LV remodelling, systolic and diastolic dysfunction and serum biomarkers of heart failure and myocardial injury. Conclusion. Our data highlight the role of myocardial fibrosis in adverse cardiac remodelling in AS. GLS has potential as a surrogate marker of myocardial fibrosis, and high native T1 and low GLS values differentiated patients with more advanced cardiac remodelling.

Randomized Pilot Trial on Optimal Treatment Strategy, Myocardial Changes, and Prognosis of Patients with Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA).

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) remains an unresolved challenge. Many different diagnostic approaches are often required to diagnose, confirm, and evaluate MINOCA. The prevalence can be as high as 13% of all acute myocardial infarction patients, indicating that this condition is not rare. At this time, there have been no completed randomized clinical trials involving MINOCA patients, and a better understanding of the mechanisms and management of these patients is important. This exploratory analysis seeks to find possible etiologic factors, the value of novel biomarkers, and the effect of different treatment strategies in patients with MINOCA. METHODS: This prospective randomized pilot trial will include 150 patients with MINOCA. A thorough clinical, laboratory, and imaging evaluation will be performed, including novel biomarkers and modern imaging techniques (heart magnetic resonance imaging and noninvasive testing). The duration of the enrollment is 18 months, and duration of the follow-up is 12 months from the enrollment of the first patient. RESULTS: The trial is registered under www.clinicaltrials.gov: NCT04538924. The study is currently recruiting participants. CONCLUSIONS: Because MINOCA is not a benign disease, the results of the current investigation could inform future diagnostic and therapeutic strategies and enhance the understanding of MINOCA patients.

The Impact of the Pandemic on Acute Ischaemic Stroke Endovascular Treatment from a Multidisciplinary Perspective: A Nonsystematic Review.

BACKGROUND: At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, reduced admissions for cerebrovascular events were identified, but acute ischaemic stroke (AIS) has remained one of the leading causes of death and disability for many years. The aim of this article is to review current literature data for multidisciplinary team (MDT) coordination, rational management of resources and facilities, ensuring timely medical care for large vessel occlusion (LVO) AIS patients requiring endovascular treatment during the pandemic. METHODS: A detailed literature search was performed in Google Scholar and PubMed databases using these keywords and their combinations: acute ischaemic stroke, emergency, anaesthesia, airway management, mechanical thrombectomy, endovascular treatment, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19. Published studies and guidelines from inception to April 2021 were screened. The following nonsystematic review is based on a comprehensive literature search of available data, wherein 59 were chosen for detailed analysis. RESULTS: The pandemic has an impact on every aspect of AIS care, including prethrombectomy, intraprocedural and post-thrombectomy issues. Main challenges include institutional preparedness, increased number of AIS patients with multiorgan involvement, different work coordination principles and considerations about preferred anaesthetic technique. Care of these patients is led by MDT and nonoperating room anaesthesia (NORA) principles are applied. CONCLUSIONS: Adequate management of AIS patients requiring mechanical thrombectomy during the pandemic is of paramount importance to maximise the benefit of the endovascular procedure. MDT work and familiarity with NORA principles decrease the negative impact of the disease on the clinical outcomes for AIS patients.

Current Recommendations for Airway Management Techniques in COVID-19 Patients without Respiratory Failure Undergoing General Anaesthesia: A Nonsystematic Literature Review.

SUMMARY BACKGROUND: Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged, many articles have been published on airway management for coronavirus disease 2019 (COVID-19) patients. However, there is a lack of clear and concise conceptual framework for working with infected patients without respiratory failure undergoing general anaesthesia compared to noninfected patients. The aim of this article is to review current literature data on new challenges for anaesthesia providers, compare standard airway management techniques protocols with new data, and discuss optimisation potential. MATERIALS AND METHODS: Literature search was performed in Google Scholar and PubMed databases using these keywords and their combinations: anaesthesia, preoxygenation, airway management, difficult airway, SARS-CoV-2, COVID-19. The following nonsystematic review is based on a comprehensive literature search of available data, wherein 41 articles were chosen for detailed analysis. Summarised and analysed data are presented in the article. RESULTS: SARS-CoV-2 has unique implications for airway management techniques in patients without respiratory failure undergoing general anesthesia. Main differences with the standard practice include: institutional preparedness, team composition principles, necessary skills, equipment, drugs, intubation and extubation strategies. Failed or difficult intubation is managed with predominance of emergency front of neck access (FONA) due to increased aerosol generation. CONCLUSIONS: Airway management techniques in COVID-19 patients without respiratory failure are more challenging than in noninfected patients undergoing general anaesthesia. Safe, accurate and swift actions avoid unnecessary time delay ensuring the best care for patients, and reduce risk of contamination for staff. Appropriate airway strategy, communication, minimisation of time for aerosol generating procedures and ramped-up position aid to achieve these goals. During the pandemic, updated available literature data may change clinical practice as new evidence emerges.

Two Novel Variants in Genes of Arrhythmogenic Right Ventricular Cardiomyopathy - a Case Report.

SUMMARY BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable cardiomyopathy, characterized by fibrofatty replacement of myocytes in the right ventricular, left ventricular or both ventricles. It is caused by pathogenic variants of genes encoding desmosomal (JUP, DSP, PKP2, DSG2, DSC2) and non-desmosomal proteins, and is one of the most common causes of sudden cardiac death in young athletes. Therefore, early identification, correct prevention and treatment can prevent adverse outcomes. CASE REPORT: Our case presents a 65-years-old man with recurrent ventricular tachycardia. The ischemic cause was the first to rule out. Echocardiography revealed right ventricular structural and functional abnormalities. After suspicion of ARVC, magnetic resonance imaging was performed showing reduced right ventricular ejection fraction with local aneurysms, structural changes ir the right and left myocardium. Subsequently performed genetic testing identified a novel ARVC likely pathogenic variant in DSC2 gene and variant of uncertain significance in RYR2 gene. CONCLUSIONS: Diagnostic evaluation of ARVC is challenging and requires multidisciplinary team collaboration. Further functional tests for elucidation of the clinical significance of the two novel variants of ARVC-associated genes could be suggested.

Prognostic value of myocardial fibrosis in severe aortic stenosis: study protocol for a prospective observational multi-center study (FIB-AS).

BACKGROUND: Adverse cardiac remodeling with a myocardial fibrosis as a key pathophysiologic component may be associated to worse survival in aortic stenosis (AS) patients. Therefore, with the application of advanced cardiac imaging we aim to investigate left ventricular myocardial fibrosis in severe AS patients undergoing aortic valve replacement (AVR) and determine its impact with post-intervention clinical outcomes. METHODS: In a prospective, observational, cohort study patients with severe AS scheduled either for surgical or transcatheter AVR will be recruited from two tertiary heart centers in Denmark and Lithuania. All patients will receive standard of care in accordance with the current guidelines and will undergo additional imaging testing before and after AVR: echocardiography with deformation analysis and cardiovascular magnetic resonance (CMR) with T1 parametric mapping. Those undergoing surgical AVR will also have a myocardial biopsy sampled at the time of a surgery for histological validation. Patients will be recruited over a 2-year period and followed up to 2 years to ascertain clinical outcomes. Follow-up CMR will be performed 12 months following AVR, and echocardiography with deformation analysis will be performed 3, 12, and 24 months following AVR. The study primary outcome is a composite of all-cause mortality and major adverse cardiovascular events. DISCUSSION: Despite continuous effort of research community there is still a lack of early predictors of left ventricular decompensation in AS, which could improve patient risk stratification and guide the optimal timing for aortic valve intervention, before irreversible left ventricular damage occurs. Advanced cardiac imaging and CMR derived markers of diffuse myocardial fibrosis could be utilized for this purpose. FIB-AS study is intended to invasively and non-invasively assess diffuse myocardial fibrosis in AS patients and investigate its prognostic significance in post-interventional outcomes. The results of the study will expand the current knowledge of cardiac remodeling in AS and will bring additional data on myocardial fibrosis and its clinical implications following AVR. ETHICS/DISSEMINATION: The study has full ethical approval and is actively recruiting patients. The results will be disseminated through scientific journals and conference presentations. TRIAL REGISTRATION: ClinicalTrials.govNCT03585933. Registered on 02 July 2018.

Correction to: Prevalence and prognostic value of late gadolinium enhancement on CMR in aortic stenosis: meta-analysis.

The original version of this article, published on 12 August 2019, unfortunately contained a mistake. The funding note was incorrect; the correct funding note is given below.

Prevalence and prognostic value of late gadolinium enhancement on CMR in aortic stenosis: meta-analysis.

OBJECTIVES: The aim of this study was to investigate the prevalence and prognostic value of late gadolinium enhancement (LGE), as assessed by cardiovascular magnetic resonance (CMR) imaging, in patients with aortic stenosis. METHODS AND RESULTS: A systematic search of PubMed and EMBASE was performed, and observational cohort studies that analysed the prevalence of LGE and its relation to clinical outcomes in patients with aortic stenosis were included. Odds ratios were used to measure an effect of the presence of LGE on both all-cause and cardiovascular mortality. Nineteen studies were retrieved, accounting for 2032 patients (mean age 69.8 years, mean follow-up 2.8 years). We found that LGE is highly prevalent in aortic stenosis, affecting half of all patients (49.6%), with a non-infarct pattern being the most frequent type (63.6%). The estimated extent of focal fibrosis, expressed in % of LV mass, was equal to 3.83 (95% CI [2.14, 5.52], p < 0.0001). The meta-analysis showed that the presence of LGE was associated with increased all-cause (pooled OR [95% CI] = 3.26 [1.72, 6.18], p = 0.0003) and cardiovascular mortality (pooled OR [95% CI] = 2.89 [1.90, 4.38], p < 0.0001). CONCLUSIONS: LGE by CMR is highly prevalent in aortic stenosis patients and exhibits a substantial value in all-cause and cardiovascular mortality prediction. These results suggest a potential role of LGE in aortic stenosis patient risk stratification. KEY POINTS: • Up to the half of aortic stenosis patients are affected by myocardial focal fibrosis. • Sixty-four percent of focal fibrosis detected by LGE-CMR is non-infarct type. • The presence of focal fibrosis triples all-cause and cardiovascular mortality.

Transthyretin cardiac amyloidosis in aortic stenosis: Prevalence, diagnostic challenges, and clinical implications.

Transthyretin cardiac amyloidosis (ATTR-CA) is a challenging and underdiagnosed cause of heart failure. Advances in cardiac imaging have enabled noninvasive diagnosis of ATTR-CA, causing the recent upsurge in disease awareness and detection. ATTR-CA has been increasingly recognized in patients with degenerative aortic stenosis (AS). With the growing number of elderly patients undergoing aortic valve intervention, the identification of ATTR-CA in this group of patients is of high clinical importance. Timely and correct diagnosis is essential for amyloid-directed therapies, as well as deciding on the AS treatment strategy. This review provides a comprehensive overview of the recent studies investigating coexistence of these two entities. We present the data on the prevalence of ATTR-CA in AS and their prognostic associations. As the diagnosis of ATTR-CA may be challenging, special attention is paid to the diagnostic utility of different imaging modalities, namely, echocardiography, cardiovascular magnetic resonance, nuclear imaging, and distinctive imaging features, in patients with dual pathology. We also present a flowchart summarizing integrated imaging in patients with suspected ATTR-CA.

Epicardial Adipose Tissue Accumulation and Essential Hypertension in Non-Obese Adults.

Background and Objectives: Epicardial adipose tissue (EAT) is shown to be an important factor in the development of coronary artery disease, but numerous pathophysiological mechanisms of its action are still only partially understood. There is a lack of studies on its association with different grades of essential hypertension (EH). Therefore, we aimed to evaluate the association between size of EAT depots and the risk of EH taking into account its grade. Materials and Methods: Non-obese adult patients with various cardiovascular diseases were investigated: 157 of them had essential hypertension and 101 did not. Hypertensive patients were assigned to three groups according to the grade of hypertension. EAT volume and thickness on ventricular free walls (6 locations) and grooves (5 locations) were measured using cardiac magnetic resonance imaging and compared between groups. A regression model for the prediction of EH was constructed. Results: In general, thickness (in all locations) and volume of EAT depots was greater among hypertensive patients than in normotensive (NORM) group. Mean EAT thickness in all 11 locations and EAT volume were lower in NORM than in grade 1 hypertension group; similarly, EAT volume was lower in grade 1 than in grade 2 hypertension group. EAT accumulation did not differ between grade 2 and severe hypertension groups. EAT volume, dyslipidaemia status, body mass index, and age were independent predictors for EH in regression model. Conclusions: EAT accumulation is larger among hypertensive than normotensive individuals. Measurement of EAT depots could be beneficial for identification of hypertensive patients and prediction of hypertension severity.

Use of Magnetic Resonance Imaging in Evaluating Fetal Brain and Abdomen Malformations during Pregnancy.

Magnetic resonance imaging (MRI) is used as a clarifying technique after a high-resolution ultrasound examination during pregnancy. Combining ultrasound with MRI, additional diagnostic information is obtained or ultrasound diagnosis is frequently corrected. High spatial resolution provides accurate radiological imaging of internal organs and widens possibilities for detecting perinatal development disorders. The safety of MRI and the use of intravenous contrast agent gadolinium are discussed in this article. There is no currently available evidence that MRI is harmful to the fetus, although not enough research has been carried out to prove enduring safety. MRI should be performed when the benefit outweighs the potential side effects. The narrative review includes several clinical cases of fetal MRI performed in Vilnius University Hospital Santaros Clinics.

Predictors of ischaemic mitral regurgitation recurrence in patients undergoing combined surgery: additional value of cardiovascular magnetic resonance imaging.

OBJECTIVES: We aimed to evaluate (i) the effectiveness of combined surgery (coronary artery bypass grafting with restrictive mitral valve annuloplasty) and (ii) the late gadolinium enhancement cardiovascular magnetic resonance-based predictors of ischaemic mitral regurgitation (IMR) recurrence. METHODS: The prospective analysis included 40 patients with multivessel coronary artery disease, IMR >II° and left ventricular (LV) dysfunction undergoing combined surgery. The degree of IMR and LV parameters were assessed preoperatively by transthoracic echocardiography, 3D transoesophageal echocardiography and cardiovascular magnetic resonance and postoperatively by transthoracic echocardiography. The effective mitral valve repair group (n = 30) was defined as having recurrent ischaemic mitral regurgitation (RIMR) ≤II° at the end of follow-up (25 ± 11 months). RESULTS: The surgery was effective: freedom from RIMR >II° at 1 and 2 years after surgery was 80% and 75%, respectively. Using multivariable logistic regression, 2 independent predictors of RIMR >II° were identified: ≥3 non-viable LV segments (odds ratio 22, P = 0.027) and ≥1 non-viable segment in the LV posterior wall (odds ratio 11, P = 0.026). Using classification trees, the best combinations of cardiovascular magnetic resonance-based and 3D transoesophageal echocardiography-based predictors for RIMR >II° were (i) posterior mitral valve leaflet angle >40° and LV end-systolic volume index >45 ml/m2 (sensitivity 100%, specificity 89%) and (ii) scar transmurality >68% in the inferior LV wall and EuroSCORE II >8 (sensitivity 83%, specificity 78%). CONCLUSIONS: There is a clear relationship between the amount of non-viable LV segments, especially in the LV posterior and inferior walls, and the recurrence of IMR after the combined surgery.

NMR, Raman, and DFT Study of Lyotropic Chromonic Liquid Crystals of Biomedical Interest: Tautomeric Equilibrium and Slow Self-Assembling in Sunset Yellow Aqueous Solutions.

Temperature and composition effects in Sunset Yellow FCF (SSY) aqueous solutions were studied by the 1H, 15N NMR as well as Raman spectroscopy passing through all phase transitions between isotropic phase (I) and chromonic phases-nematic (N) and columnar (M). It was shown that the tautomeric equilibrium in SSY is strongly shifted toward the hydrazone form. The corresponding equilibrium constant p KT = 2.5 was deduced using the density functional theory solvent model density model. The dominance of the hydrazone form was confirmed experimentally using the long-range 1H-15N correlation, widely known as heteronuclear multiple bond correlation. The peak found in the 1H NMR spectra at ca. 14.5 ppm can be attributed to the proton in the intramolecular N-H···O bond. The existence of this signal shows that (i) the growth of the SSY aggregates is accompanied by the segregation of water in the intercolumnar areas with no access for exchange with the N-H protons in the internal layers of the columnar stacks and that (ii) the lifetime of those aggregates is ≥10-8 s or even longer. The temperature dependences of H2O chemical shift and Raman O-H stretching band shape show that water confined in the intercolumnar areas behaves as in the neat substance. When the sample is heated and the transition from M phase to N phase occurs, the molecular motion of water is seen to change in a manner similar to that when water is melting. The equilibration time for N + M→ M is very long because of slow supramolecular restructuring, i.e., the growing of columnar stacks and building of hexagonal arrays. If the sample is cooled down to the temperature below N → M transition relatively fast, the structural changes are behind, and the system falls into supercooled state. In this case, the system evolves via long-lasting self-assembling from the supercooled state to the equilibrium. This process affects the shape of the 1H NMR signal and is easy to monitor.