Diagnosis and treatment of transthyretin amyloidosis cardiomyopathy: A position statement of the Polish Cardiac Society.

Considering the rare incidence of transthyretin amyloidosis cardiomyopathy (ATTR-CM) in Poland, patients encounter difficulties at the stages of diagnosis and treatment. For successful diagnosis, it is vital to raise the suspicion of ATTR-CM, that is, to identify typical clinical scenarios such as heart failure with preserved ejection fraction or the red flags of amyloidosis. In most cases, it is possible to establish the diagnosis on the basis of noninvasive tests. This article presents the recommended diagnostic algorithms including laboratory workup, imaging tests (in particular, isotope scanning), and genetic tests. Since ATTR-CM should be differentiated from light chain amyloidosis, we also discuss aspects related to hematological manifestations and invasive diagnosis. We describe neurological signs and symptoms in patients with amyloidosis and present therapeutic options, including the causative treatment of ATTR-CM with the only currently approved drug, tafamidis. We also discuss drugs that are being assessed in ongoing clinical trials. We outline differences in the symptomatic treatment of heart failure in ATTR-CM and recommendations for nonpharmacological treatment and monitoring of the disease. Finally, we underline the need for providing access to the causative treatment with tafamidis as part of a drug program, as in other rare diseases, so that patients with ATTR-CM can be treated according to the European Society of Cardiology guidelines on heart failure and cardiomyopathy.

Comparison of Regadenoson and Dipyridamole Safety Profiles During Stress Myocardial Perfusion Imaging.

Objectives: The pharmacological stress test with vasodilator agents is an alternative cardiological diagnostic tool for patients with contraindications to the classical stress test provided by physical activity during single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The study compared the frequency of the side effects of regadenoson and dipyridamole during a SPECT MPI. Methods: This retrospective study included data of 283 consecutive patients who underwent pharmacological stress tests in years 2015-2020. The study group consisted of 240 patients who had received dipyridamole and 43 patients who had received regadenoson. The collected data included the patients' characteristics, the occurrence of side effects (divided into mild: headache, vertigo, nausea, vomiting, dyspnea, chest discomfort, hot flushes, general weakness and severe: bradycardia, hypotension, loss of consciousness), and blood pressure values/measurements. Results: Overall, complications occurred relatively often (regadenoson: 23.2%, dipirydamol: 26.7%, p=0.639). Procedure discontinuation was necessary in 0.7% of examinations, whereas pharmacological support was necessary in 4.7%. There was no difference in the prevalence of mild (regadenoson: 16.2%, dipirydamol: 18.3%, p=0.747) and severe complications (regadenoson: 11.6%, dipyridamole: 15.0%, p=0.563). However, regadenoson has been found to cause a significantly smaller mean decrease of systolic blood pressure (SBP) (regadenoson: -2.6±10.0 mmHg, dipyridamole: -8.7±9.6 mmHg, p=0.002), diastolic blood pressure (DBP) (regadenoson: -0.9±5.4 mmHg, dipyridamole: -3.6±6.2 mmHg, p=0.032), as well as mean arterial pressure (MAP) (regadenoson: -1.5±5.6 mmHg, dipyridamole: -5.4±6.5 mmHg, p=0.001). Conclusion: Regadenoson and dipyridamole presented a similar safety profile during SPECT MPI. However, regadenoson has been found to cause significantly smaller decreases in SBP, DBP, and MAP.

Advances in Molecular Imaging in Infective Endocarditis.

Infective endocarditis (IE) is a growing epidemiological challenge. Appropriate diagnosis remains difficult due to heterogenous etiopathogenesis and clinical presentation. The disease may be followed by increased mortality and numerous diverse complications. Developing molecular imaging modalities may provide additional insights into ongoing infection and support an accurate diagnosis. We present the current evidence for the diagnostic performance and indications for utilization in current guidelines of the hybrid modalities: single photon emission tomography with technetium99m-hexamethylpropyleneamine oxime-labeled autologous leukocytes (99mTc-HMPAO-SPECT/CT) along with positron emission tomography with fluorodeoxyglucose (18F-FDG PET/CT). The role of molecular imaging in IE diagnostic work-up has been constantly growing due to technical improvements and the increasing evidence supporting its added diagnostic and prognostic value. The various underlying molecular processes of 99mTc-HMPAO-SPECT/CT as well as 18F-FDG PET/CT translate to different imaging properties, which should be considered in clinical practice. Both techniques provide additional diagnostic value in the assessment of patients at risk of IE. Nuclear imaging should be considered in the IE diagnostic algorithm, not only for the insights gained into ongoing infection at a molecular level, but also for the determination of the optimal clinical therapeutic strategies.

Mechanical extraction of implantable cardioverter-defibrillator leads with a dwell time of more than 10 years: insights from a single high-volume centre.

AIMS: To analyze and compare the effectiveness and safety of transvenous lead extraction (TLE) of implantable cardioverter-defibrillator (ICD) leads with a dwell time of >10 years (Group A) vs. younger leads (Group B) using mechanical extraction systems. METHODS AND RESULTS: Between October 2011 and July 2022, we performed TLE in 318 patients. Forty-six (14.4%) extracted ICD leads in 46 (14.5%) patients that had been implanted for >10 years. The median dwell time of all extracted ICD leads was 5.9 years. Cardiovascular implantable electronic device-related infection was an indication for TLE in 31.8% of patients. Complete ICD leads removal and complete procedural success in both groups were similar (95.7% in Group A vs. 99.6% in Group B, P = 0.056% and 95.6% in Group A vs. 99.6% in Group B, P = 0.056, respectively). We did not find a significant difference between major and minor complication rates in both groups (6.5% in Group A vs. 1.5% in Group B and 2.2% in Group A vs. 1.8% in Group B, P = 0.082, respectively). One death associated with the TLE procedure was recorded in Group B. CONCLUSION: The TLE procedures involving the extraction of old ICD leads were effective and safe. The outcomes of ICD lead removal with a dwell time of >10 years did not differ significantly compared with younger ICD leads. However, extraction of older ICD leads required more frequent necessity for utilizing multiple extraction tools, more experience and versatility of the operator, and increased surgery costs.

To what extent does prior antimicrobial therapy affect the diagnostic performance of radiolabeled leukocyte scintigraphy in infective endocarditis?

AIMS: This prospective, single-center study sought to assess to what extent there is interference between the hybrid technique of single-photon emission tomography-computed tomography with technetium99m-hexamethylpropyleneamine oxime-labeled leukocytes (99mTc-HMPAO-SPECT/CT) and antimicrobial therapy in patients with infective endocarditis (IE). METHODS AND RESULTS: During the years 2015-2019, we enrolled 205 consecutive adults with suspected IE, all underwent 99mTc-HMPAO-SPECT/CT. The study population was divided into those who had received antimicrobial therapy up to 30 days prior to 99mTc-HMPAO-SPECT/CT (group 1, n = 96) and those who had not (group 2, n = 109). Patients were prospectively observed for 12 ± 10 months. Group 1 presented higher positive predictive values (91.89% vs. 60.00%, = 0.001), and decreased negative predictive values (77.97% vs. 90.54%, P = 0.04). Patients treated with antimicrobial therapy displayed false-negative 99mTc-HMPAO-SPECT/CT results more often [odds ratio (OR), 4.63; 95% confidence interval (CI), 1.41-15.23, P = .01], particularly when intravenous (OR 5.37; 95% CI 1.73-16.62, P = .004), definite (OR 9.43; 95% CI 2.65-33.51, P = .001), and combination antibiotic regimens (OR 8.1; 95% CI 2.57-25.64, P = .001) had been administered. CONCLUSION: Prior antibiotic therapy affects 99mTc-HMPAO-SPECT/CT diagnostic properties. Patients treated with antimicrobial therapy display false-negative 99mTc-HMPAO-SPECT/CT results more often, especially if intravenous, definite, or combination regimens are administered.

Reduction in radioactive internal contamination by 99mTc among medical personnel in nuclear medicine facilities with the use of respiratory tract protection measures.

The main objective of the present publication was to assess the reduction of internal radioactive contamination with 99mTc among medical personnel of nuclear medicine facilities using generally available respiratory tract protection systems. During the current research project, four respiratory tract protection systems were tested by estimation of 99mTc activity levels in blood samples collected from medical personnel. Medical staff were equipped with a disposable surgical mask, a half mask with gas absorbers, a half mask with aerosol absorbers and a half mask with gas absorbers with added Petryanov filter. The presented results indicate that wearing only a disposable surgical mask may significantly reduce radioactive internal contamination among medical personnel and improve their safety in the workplace. The best results of reduced 99mTc concentration in the blood were achieved by the use of a half mask with gas absorbers with added Pertryanov filters and a half mask with aerosol absorbers, where the reduction factors were estimated at 90% and 80%, respectively. Respiratory tract protection systems should become standard equipment for medical personnel performing ventilation-perfusion SPECT lung scans.

The scintigraphic diagnosis of cardiac amyloidosis. An expert opinion endorsed by the Section of Nuclear Medicine of the Polish Cardiac Society and the Polish Nuclear Medicine Society.

Amyloid transthyretin cardiomyopathy is a progressive disease that confers significant mortality. While it is relatively rare, the frequency of diagnoses has risen with the increased contribution of novel diagnostic approach over the last decade. Traditionally tissue biopsy was considered to be a gold standard for amyloidosis diagnosis. However, there are significant limitations in the wide application of this approach. A noninvasive imaging-based diagnostic algorithm has been substantially developed in recent years. Establishing radionuclide imaging standards may translate into a further enhancement of disease detection and improving prognosis in the group of patients. Therefore we present in the following document current evidence on the scintigraphic diagnosis of cardiac transthyretin amyloidosis. Moreover, we present standardized protocol for the acquisition and interpretation criteria in the scintigraphic evaluation of cardiac amyloidosis.

Genotoxicity Associated with 131I and 99mTc Exposure in Nuclear Medicine Staff: A Physical and Biological Monitoring Study.

Nuclear medicine staff are constantly exposed to low doses of ionizing radiation. This study investigated the level of genotoxic effects in hospital employees exposed to routinely used 131I and 99mTc in comparison with a control group. The study compared the results of physical and biological monitoring in peripheral blood lymphocytes. The effects of confounding factors, such as smoking status and physical activity, were also considered. Physical dosimetry monitoring revealed differences in the individual annual effective dose as measured by finger ring dosimeter and whole-body dosimeter between the 131I- and 99mTc-exposed groups. The DNA damage studies revealed differences between the groups in terms of excess premature chromosome condensation (PCC) fragments and tail DNA. Physical activity and smoking status differentiated the investigated groups. When assessed by the level of physical activity, the highest mean values of tail DNA were observed for the 99mTc group. When assessed by work-related physical effort, excess PCC fragments were significantly higher in the 131I group than in the control group. In the investigated groups, the tail DNA values were significantly different between non-smokers and past or current smokers, but excess PCC fragments did not significantly differ by smoking status. It is important to measure exposure to low doses of ionizing radiation and assess the potential risk from this exposure. Such investigations support the need to continue epidemiological and experimental studies to improve our understanding of the mechanisms of the health effects of radionuclides and to develop predictive models of the behavior of these complex systems in response to low-dose radiation.

The Relationship between Cardiac Magnetic Resonance-Assessed Replacement and Interstitial Fibrosis and Ventricular Arrhythmias in Hypertrophic Cardiomyopathy.

Non-sustained ventricular tachycardia (nsVT) creates the electrical basis for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). We aimed to evaluate the relationship between interstitial fibrosis on cardiac magnetic resonance (CMR) and nsVT in HCM. A total of 50 HCM patients underwent CMR with a 3 T scanner to determine the presence of replacement fibrosis expressed by late gadolinium enhancement (LGE), and interstitial fibrosis expressed by native T1, post-contrast T1, and extracellular volume (ECV). The incidence of nsVT was assessed by Holter monitoring. We detected nsVT in 14 (28%) out of 50 HCM patients. Replacement fibrosis expressed by LGE was present in 37 (74%) patients and only showed a trend towards a differentiation between the groups with and without nsVT (p = 0.07). However, the extent of LGE was clearly higher in the nsVT group (3.8 ± 4.9% vs. 7.94 ± 4.5%, p = 0.002) and was an independent predictor of nsVT in a multivariable regression analysis (OR 1.2; 95%CI 1.02-1.4; p = 0.02). No relationship was observed between interstitial fibrosis and nsVT. To conclude, it was found that it is not the mere presence but the actual extent of LGE that determines the occurrence of nsVT in HCM patients; the role of interstitial fibrosis remains unclear.

Updates for the diagnosis and management of cardiac amyloidosis.

A substantial increase in the interest in transthyretin cardiac amyloidosis (ATTR-CA) is a result of the constantly growing number of patients, the use of clear diagnostic protocols and the availability of the first selective drug for these patients. This has also raised the awareness of the disease among physicians of all specialties. The topic is particularly relevant to cardiologists, who use non-invasive multimodal imaging in their daily practice. The differential diagnosis of the causes of myocardial hypertrophy includes arterial hypertension, hypertrophic cardiomyopathy, aortic stenosis (AS), athletic heart syndrome, Fabry disease, and cardiac amyloidosis (CA). It turns out that in patients with myocardial hypertrophy >15 mm, amyloidosis is the most common cause of left ventricular (LV) hypertrophy. In parallel, CA is one of the most common infiltrative diseases leading to a clinical picture that may mimic heart failure with preserved ejection fraction (HFpEF). The accumulation of amyloid in the extracellular space impairs the diastolic function of the myocardium, which is observed as the restrictive cardiomyopathy phenotype. In advanced cases, the LV systolic function is also impaired. Moreover, protein deposits contribute to the disturbances of calcium metabolism and cell metabolism as well as to cardiotoxicity, leading to edema and damage to cardiomyocytes.

Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis.

BACKGROUND: Transthyretin amyloidosis (ATTR) is a rare, life-threatening systemic disorder. We present first findings on the cardiac hereditary ATTR in Poland. METHODS: Sixty-eight consecutive patients with suspected or known cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography (ECG) and transthoracic echocardiography. ATTR was confirmed histologically or non-invasively using 99mTc-DPD scintigraphy. Transthyretin (TTR) gene sequencing was performed. RESULTS: In 2017-2019, 10 unrelated male patients were diagnosed with hereditary ATTR. All patients had very uncommon TTR gene mutations: 7 patients had p.Phe53Leu mutation, 2 patients had p.Glu109Lys mutation and 1 patient had p.Ala101Val mutation. The age of onset ranged from 49 to 67 years (mean [SD] age, 58.7 [6.4] years). On ECG, most patients (70%) had pseudoinfarct pattern and/or low QRS voltage. The maximal wall thickness (MWT) on echocardiography varied considerably among the patients from moderate (16 mm) to massively increased (30 mm). Most patients (90%) had decreased left ventricular ejection fraction (mean [SD], 43 [11] %). On follow-up, we observed progressive heart failure in almost all cases. The first patient with p.Phe53Leu mutation died of heart failure, the second died suddenly, the third successfully underwent combined heart and liver transplant with 15 months survival from the surgery. The patient with p.Ala101Val mutation died of stroke. CONCLUSIONS: According to available data, this is the first time that the types of TTR mutations and the clinical characteristics of Polish patients with cardiac hereditary ATTR have been described. Previous literature data about Polish background in families with p.Phe53Leu mutation and the present results, suggest that this TTR mutation might be endemic in the Polish population.

Single-photon emission computed tomography as a fundamental tool in evaluation of myocardial reparation and regeneration therapies.

Despite unquestionable progress in interventional and pharmacologic therapies of ischemic heart disease, the number of patients with chronic ischemic heart failure is increasing and the prognosis remains poor. Repair/restoration of functional myocardium through progenitor cell-mediated (PCs) healing and renovation of injured myocardium is one of the pivotal directions in biomedical research. PCs release numerous pro-angiogenic and anti-apoptotic factors. Moreover, they have self-renewal capability and may differentiate into specialized cells that include endothelial cells and cardiomyocytes. Uptake and homing of PCs in the zone(s) of ischaemic injury (i.e., their effective transplantation to the target zone) is an essential pre-requisite for any potential therapeutic effect; thus effective cell tracking is fundamental in pre-clinical and early clinical studies. Another crucial requirement in rigorous research is quantification of the infarct zone, including the amount of non-perfused and hypo-perfused myocardium. Quantitative and reproducible evaluation of global and regional myocardial contractility and left ventricular remodeling is particularly relevant in clinical studies. Using SPECT, our earlier work has addressed several critical questions in cardiac regenerative medicine including optimizing transcoronary cell delivery, determination of the zone(s) of myocardial cell uptake, and late functional improvement in relation to the magnitude of cell uptake. Here, we review the role of single-photon emission computed tomography (SPECT), a technique that offers high-sensitivity, quantitative cell tracking on top of its ability to evaluate myocardial perfusion and function on both cross-sectional and longitudinal bases. SPECT, with its direct relevance to routine clinical practice, is a fundamental tool in evaluation of myocardial reparation and regeneration therapies.

Acute myocardial infarction reparation/regeneration strategy using Wharton's jelly multipotent stem cells as an 'unlimited' therapeutic agent: 3-year outcomes in a pilot cohort of the CIRCULATE-AMI trial.

Introduction: CIRCULATE-AMI (NCT03404063), a cardiac magnetic resonance imaging (cMRI) infarct size-reduction-powered double-blind randomized controlled trial (RCT) of standardized Wharton jelly multipotent stem cells (WJMSCs, CardioCell Investigational Medical Product) vs. placebo (2 : 1) transcoronary transfer on acute myocardial infarction (AMI) day ~5-7, is preceded by safety and feasibility evaluation in a pilot study cohort (CIRCULATE-AMI PSC). Aim: To evaluate WJMSC transplantation safety and evolution of left ventricular (LV) remodeling in CIRCULATE-AMI PSC. Material and methods: In 10 consecutive patients (32-65 years, peak CK-MB 533 ±89 U/l, cMRI-LVEF 40.3 ±2.7%, cMRI-infarct size 20.1 ±2.8%), 30 × 106 WJMSCs were administered using a novel cell delivery-dedicated, coronary-non-occlusive method (CIRCULATE catheter). Other treatment was guideline-based. Results: WJMSC transfer was safe and occurred in the absence of coronary (TIMI-3 in all) or myocardial (corrected TIMI frame count (cTFC) 45 ±8 vs. 44 ±9, p = 0.51) flow deterioration or troponin elevation. By 3 years, 1 patient died from a new, non-index territory AMI; there were no other major adverse cardiovascular and cerebrovascular events (MACCE) and no adverse events that might be related to WJMSCs. cMRI infarct size was reduced from 33.2 ±7.6 g to 25.5 ±6.4 g at 1 year and 23.1 ±5.6 g at 3 years (p = 0.03 vs. baseline). cMRI, SPECT, and echo showed a consistent, statistically significant increase in LVEF at 6-12 months (41.9 ±2.6% vs. 51.0 ±3.3%, 36.0 ±3.9% vs. 44.9 ±5.0%, and 38.4 ±2.5% vs. 48.0 ±2.1% respectively, p < 0.01 for all); the effect was sustained at 3 years. Conclusions: CIRCULATE-AMI PSC data suggest that WJMSC transcoronary application ~5-7 days after large AMI in humans is feasible and safe and it may be associated with a durable LVEF improvement. CIRCULATE-AMI RCT will quantify the magnitude of LV adverse remodeling attenuation with CardioCell/placebo administration.

Objective, observer-independent evaluation of myocardial perfusion and function: role of SPECT.

The number of patients with coronary artery disease and ischaemic heart failure - and those with terminal heart failure - is increasing despite improvements in medical and interventional therapies of ischaemic heart disease - and, over the next decades, it is projected to continue to increase further. Observer-independent, reproducible imaging techniques play a fundamental role in objective evaluation of both conventional (such as surgical or percutaneous) myocardial revascularization and novel therapeutic approaches to reduce myocardial ischaemia, improve contractility and prevent adverse myocardial remodelling. To be applicable to clinical practice, the clinical study design and data should best be rooted in everyday clinical practice. Accurate and reproducible assessment of left ventricular ejection fraction, left ventricular volumes, myocardial perfusion and function is one of the most important objectives of cardiac imaging. Current techniques used both in clinical studies and in everyday clinical practice include 2- and 3-dimensional echocardiography, magnetic resonance imaging, single-photon emission computed tomography and positron emission tomography; each of these has its strengths and limitations. We review present evidence on the role of single-photon emission computed tomography as a technique that may offer, through being observer-independent, the most objective evaluation of evolution of left ventricular perfusion, volumes and ejection fraction.

The Diagnostic Value of 99mTc-HMPAO-Labelled White Blood Cell Scintigraphy and 18F-FDG PET/CT in Cardiac Device-Related Infective Endocarditis-A Systematic Review.

(1) Background: Treatment of cardiac arrhythmias and conduction disorders with the implantation of a cardiac implantable electronic device (CIED) may lead to complications. Cardiac device-related infective endocarditis (CDRIE) stands out as being one of the most challenging in terms of its diagnosis and management. Developing molecular imaging modalities may provide additional insights into CDRIE diagnosis. (2) Methods: We performed a systematic literature review to critically appraise the evidence for the diagnostic performance of the following hybrid techniques: single photon emission tomography with technetium99m-hexamethylpropyleneamine oxime-labeled autologous leukocytes (99mTc-HMPAO-SPECT/CT) and positron emission tomography with fluorodeoxyglucose (18F-FDG PET/CT). An analysis was performed in accordance with PRISMA and GRADE criteria and included articles from PubMed, Embase and Cochrane databases. (3) Results: Initially, there were 2131 records identified which had been published between 1971-2021. Finally, 18 studies were included presenting original data on the diagnostic value of 99mTc-HMPAO-SPECT/CT or 18F-FDG PET/CT in CDRIE. Analysis showed that these molecular imaging modalities provide high diagnostic accuracy and their inclusion in diagnostic criteria improves CDRIE work-up. (4) Conclusions: 99mTc-HMPAO-SPECT/CT and 18F-FDG PET/CT provide high diagnostic value in the identification of patients at risk of CDRIE and should be considered for inclusion in the CDRIE diagnostic process.

Relationships between Pulmonary Hypertension Risk, Clinical Profiles, and Outcomes in Dilated Cardiomyopathy.

Pulmonary hypertension (PH) in patients with heart failure (HF) contributes to a poorer prognosis. However, in those with dilated cardiomyopathy (DCM), the true prevalence and role of PH is unclear. Therefore, this study aimed to analyze the profile of DCM patients at various levels of PH risk, determined via echocardiography, and its impact on outcomes. The 502 DCM in- and out-patient records were retrospectively analyzed. Information on patient status was gathered after 45.9 ± 31.3 months. Patients were divided into 3 PH-risk groups based on results from echocardiography measurements: low (L, n = 239, 47.6%), intermediate (I, n = 153, 30.5%), and high (H, n = 110, 21.9%). Symptom duration, atrial fibrillation, ventricular tachyarrhythmia, ejection fraction, right atrial area, and moderate or severe mitral regurgitation were found to be independently associated with PH risk. During the follow-up period, 83 (16.5%) DCM patients died: 29 (12.1%) in L, 31 (20.3%) in I, and 23 (20.9%) in H. L-patients had a significantly lower risk of all-cause death (L to H: HR 0.55 (95%CI 0.32-0.98), p = 0.01), while no differences in prognosis were found between I and H. In conclusion, over one in five DCM patients had a high PH risk, and low PH risk was associated with better prognoses.