Diagnostic value of left ventricular layer strain and specific regional strain patterns in cardiac amyloidosis and Fabry disease.

Aims: Layer-specific left ventricular (LV) strain alterations have been suggested as a specific finding in Fabry disease (FD). Our study aimed to assess the diagnostic value of layer-specific radial strain (RS) indices compared to the established LV regional strain pattern in cardiac amyloidosis (CA) and FD, i.e. apical sparing and posterolateral strain deficiency (PLSD). Methods and results: We retrospectively analysed the global, subendocardial, subepicardial LV radial strain, the corresponding strain gradient, as well as the regional and global longitudinal strain. The diagnostic accuracy of the diverse LV strain analyses was comparatively assessed using receiver operating characteristic curve and multivariable regression analyses. In 40 FD and 76 CA patients, CA featured more reduced layer strain values [global RS -12.3 (-15.6 to -9.6) in CA vs. -16.7 (-20.0 to -13.6) in FD; P < 0.001; subendocardial RS -22.3 (-27.4 to -15.9) vs. -28.3 (-31.8 to -23.6), P < 0.001; subepicardial RS -6.6 (-8.6 to -4.7) in CA vs. -8.9 (-11.7 to - 6.5) in FD; P < 0.001]. Global radial and longitudinal strain held an area under the curve (AUC) of 0.75 (0.66-0.84) and AUC 0.73 (0.63-0.83). While the apical sparing and PLSD strain pattern showed the highest accuracy as single parameters [AUC 0.87 (0.79-0.95) and 0.81 (0.72-0.89), P < 0.001], the combination of subendocardial RS and the apical sparing pattern featured the highest diagnostic accuracy [AUC 0.92 (0.87-0.97)]. Conclusion: Combining radial strain-derived parameters to the established strain pattern apical sparing and PLSD improve the diagnostic accuracy in the echocardiographic assessment in suspected storage disease.

Neurological affection and serum neurofilament light chain in wild type transthyretin amyloidosis.

In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Right heart and left atrial strain to differentiate cardiac amyloidosis and Fabry disease.

Echocardiographic differentiation of cardiac amyloidosis (CA) and Fabry disease (FD) is often challenging using standard echocardiographic parameters. We retrospectively analyzed the diagnostic accuracy of right heart and left atrial strain parameters to discriminate CA from FD using receiver operating characteristic curve analyses and logistic regression models. A total of 47 FD and 88 CA patients with left ventricular wall thickening were analyzed. The comparison of both cardiomyopathies revealed significantly reduced global and free wall longitudinal right ventricular strain (RVS; global RVS: CA - 13 ± 4%, n = 67, vs. FD - 18 ± 4%, n = 39, p < 0.001) as well as right atrial strain (RAS; reservoir RAS: CA 12 ± 8%, n = 70, vs. FD 26 ± 9%, n = 40, p < 0.001) and left atrial strain (LAS) in CA patients. Individually, global RVS as well as phasic LAS and RAS showed the highest diagnostic accuracy to distinguish CA and FD. The best diagnostic accuracy was achieved by combining the age, basal RV diameter, global RVS, and reservoir and conduit RAS (area under the curve 0.96 [95% CI 0.90-1.00]). Differential echocardiographic diagnostic work-up of patients with suspected CA or FD can be improved by integrating structural and functional parameters of the right heart and the left atrium.Trial registration: DRKS00027403.

Diagnostic value of papillary muscle hypertrophy and mitral valve thickness to discriminate cardiac amyloidosis and Fabry disease.

BACKGROUND: Cardiac amyloidosis (CA) and Fabry disease (FD) cause myocardial damage but may also affect the valvular and subvalvular apparatus. We aimed to evaluate the diagnostic accuracy of new echocardiographic indices including mitral valve thickness and papillary muscle (PM) hypertrophy to differentiate CA and FD. METHODS: In patients with confirmed CA and FD, a detailed assessment of valvular function, mitral valve leaflet thickness and PM area as well as PM left ventricular area ratio (PM/LV-ratio) was performed in offline analyses. Receiver operating characteristic curve analyses were conducted to determine the diagnostic accuracy of mitral valve thickness, PM hypertrophy, and PM/LV-ratio to distinguish CA from FD. RESULTS: We retrospectively analyzed a cohort of 129 patients (FD n = 49, CA n = 80). CA patients showed significantly more thickened mitral valve leaflets (4.1 ± 1.3 mm vs. 2.9 ± 1.1 mm, p < 0.001) and a higher PM area [4.0 (3.1-4.6) mm2 vs. 2.8 (2.1-4.6) mm2, p = 0.009] with a comparable PM/LV-ratio in both groups. Mitral valve thickness showed the highest diagnostic accuracy to discriminate CA [AUC 0.77 (95% CI 0.67-0.87)]. The prevalence of aortic, tricuspid, and pulmonary valve regurgitation was significantly higher in CA (aortic regurgitation ≥ II° 13% vs. 4%, tricuspid regurgitation≥ II° 19% vs. 8%, p < 0.001). CONCLUSION: Our results suggest that the assessment of mitral valve thickness may be a new useful echocardiographic parameter to differentiate CA and FD, whereas papillary muscle hypertrophy and PM/LV-ratio showed a limited diagnostic performance to discriminate CA. German clinical trials registry: DRKS00027403.

mRNA vaccines for COVID-19 are safe and clinically effective in patients with cardiac amyloidosis.

INTRODUCTION: Amyloidosis is a rare disease in which malformed proteins are deposited in tissues occurring mostly commonly in older age. These deposits can lead to severe organ dysfunction e.g. in the myocardium with great impact on prognosis. The Covid-19 pandemic has caused excess mortality worldwide since 2020. Risk factors for a severe course include pre-existing cardiac diseases like heart failure and advanced age. Therefore, vaccination against Sars-CoV2 viruses is highly recommended for patients with cardiac amyloidosis. However, since there are no specific data on mRNA vaccines in patients with cardiac amyloidosis, some patients have concerns about cardiac adverse events following immunization (AEFI), such as myocarditis. PURPOSE: The purpose of the study is to assess the safety and efficacy of mRNA vaccines in patients with cardiac amyloidosis. METHODS: Patients of the Amyloidosis Center Charité Berlin (ACCB) were assessed about the vaccination, its tolerability and clinical effectiveness. To date, we included 62 patients (54 men) with a median age of 82,5 years (range 37 to 92). 46 patients had wtATTR amyloidosis, ten patients had hATTR amyloidosis, and six patients had AL amyloidosis. The mean systolic left ventricular function was 51% (range 30 to 62) with a mean global strain of -11,5% (range -18,5 to -3,1). The mean NT-pro-BNP was 1145 ng/l (range 24 to 48297). RESULTS: 59 patients were triple vaccinated and three patients so far are double vaccinated. Three of the patients were unvaccinated. 171 of the vaccine doses administered were mRNA vaccines and eight doses were a viral vector-vaccine. None of the patients reported severe side effects. Thirteen patients reported feeling of pressure and pain at the injection site after vaccination and four patients had fever of maximum two days, eight patients reported lower general condition of maximum five days. One patient reported malaise for 14 days after each vaccination, which resolved spontaneously. There was no clinical or laboratory evidence of suspected vaccine-induced myocarditis. Five patients reported of a COVID-19 breakthrough infection, all of which with a mild course of disease. None of the patients had symptoms of worsening heart failure in temporal relation to the vaccination. Most of the vaccinations (103) were performed at an official vaccination center, 59 were performed at a general practitioner. CONCLUSION: In patients with cardiac amyloidosis, mRNA vaccines for COVID-19 are safe with respect to severe cardiac adverse events and show effective protection against clinically relevant SARS-CoV2 infection.

Left atrial strain predicts hemodynamic parameters in cardiovascular patients.

BACKGROUND: We aimed to evaluate the predictive value of left atrial (LA) reservoir, conduit, and contractile function parameters as assessed by speckle tracking echocardiography (STE) for invasively measured hemodynamic parameters in a patient cohort with myocardial and valvular diseases. METHODS: Sixty-nine patients undergoing invasive hemodynamic assessment were enrolled into the study. Invasive hemodynamic parameters were obtained by left and right heart catheterization. Transthoracic echocardiography assessment of LA reservoir, conduit, and contractile function was performed by STE. RESULTS: Forty-nine patients had sinus rhythm (SR) and 20 patients had permanent atrial fibrillation (AF). AF patients had significantly reduced LA reservoir function compared to SR patients. In patients with SR, LA reservoir, conduit, and contractile function inversely correlated with pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure, and mean pulmonary artery pressure (PAP), and showed a moderate association with cardiac index. In AF patients, there were no significant correlations between LA reservoir function and invasively obtained hemodynamic parameters. In SR patients, LA contractile function with a cutoff value of 16.0% had the highest diagnostic accuracy (area under the curve, AUC: 0.895) to predict PCWP ≥18 mm Hg compared to the weaker diagnostic accuracy of average E/E' ratio with an AUC of 0.786 at a cutoff value of 14.3. In multivariate analysis, LA contractile function remained significantly associated with PCWP ≥18 mm Hg. CONCLUSION: In a cohort of patients with a broad spectrum of cardiovascular diseases LA strain shows a valuable prediction of hemodynamic parameters, specifically LV filling pressures, in the presence of SR.

Cardiac and renal function in a large cohort of amateur marathon runners.

BACKGROUND: Participation of amateur runners in endurance races continues to increase. Previous studies of marathon runners have raised concerns about exercise-induced myocardial and renal dysfunction and damage. In our pooled analysis, we aimed to characterize changes of cardiac and renal function after marathon running in a large cohort of mostly elderly amateur marathon runners. METHODS: A total of 167 participants of the Berlin-Marathon (female n = 89, male n = 78; age = 50.3 ± 11.4 years) were included and cardiac and renal function was analyzed prior to, immediately after and 2 weeks following the race by echocardiography and blood tests (including cardiac troponin T, NT-proBNP and cystatin C). RESULTS: Among the runners, 58% exhibited a significant increase in cardiac biomarkers after completion of the marathon. Overall, the changes in echocardiographic parameters for systolic or diastolic left and right ventricular function did not indicate relevant myocardial dysfunction. Notably, 30% of all participants showed >25% decrease in cystatin C-estimated glomerular filtration rate (GFR) from baseline directly after the marathon; in 8%, we observed a decline of more than 50%. All cardiac and renal parameters returned to baseline ranges within 2 weeks after the marathon. CONCLUSIONS: The increase in cardiac biomarkers after completing a marathon was not accompanied by relevant cardiac dysfunction as assessed by echocardiography. After the race, a high proportion of runners experienced a decrease in cystatin C-estimated GFR, which is suggestive of transient, exercise-related alteration of renal function. However, we did not observe persistent detrimental effects on renal function.

Echocardiographic follow-up of patients with systemic sclerosis by 2D speckle tracking echocardiography of the left ventricle.

BACKGROUND: Subclinical myocardial involvement is common in systemic sclerosis (SSc) and associated with poor prognosis. Early detection, particularly during follow-up, is important. Two-dimensional speckle tracking echocardiography (STE) has already been shown to detect early left ventricular systolic impairment in SSc patients with advanced disease. The aim of this study was to assess the ability of STE to diagnose changes in left ventricular function in patients with SSc with preserved LV ejection fraction (LVEF) and normal pulmonary pressure over time. METHODS: This single-center pilot study included nineteen SSc patients without pulmonary hypertension and preserved LVEF (55.2 ± 10.8 years, 13 women, mean modified Rodnan Skin Score of 8.2 ± 6.5, median disease duration 6 ± 4.5 years). We performed STE at baseline and after two years (mean 756.6 ± 8.8 days). Pulmonary hypertension was ruled out in all patients by right heart catheterization (average mean PAP 17.7 ± 3.5 mmHg). RESULTS: The LVEF remained unchanged (63.3 ± 4.2% vs. 63.2 ± 5.0%, P = ns), but the global longitudinal peak systolic strain of the left ventricle was significantly lower: baseline -22.0 ± 2.3% vs. follow-up -20.8 ± 2.1% (P = 0.04). The regional analysis showed a heterogeneous distribution of segmental systolic dysfunction that did not match any particular coronary artery distribution. In contrast, the LV diastolic function remained stable during follow-up. CONCLUSION: STE might be a sensititive and valuable method to detect early LV systolic impairment in patients with SSc and preserved LVEF during two years. Prospective evaluations are needed for prognostic implications of these changes.

Remission of an intracardiac melanoma metastasis after tremelimumab therapy.

Tremelimumab is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte-associated antigen 4. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumour regressions. Our echocardiographic images impressively show the effects of this new antibody in a patient with cardiac metastatic malignant melanoma.

Acute regional improvement of myocardial function after interventional transfemoral aortic valve replacement in aortic stenosis: a speckle tracking echocardiography study.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a promising therapy for patients with severe aortic stenosis (AS) and high perioperative risk. New echocardiographic methods, including 2D Strain analysis, allow the more accurate measurement of left ventricular (LV) systolic function. The goal of this study was to describe the course of LV reverse remodelling immediately after TAVI in a broad spectrum of patients with symptomatic severe aortic valve stenosis. METHODS: Thirty consecutive patients with symptomatic aortic valve stenosis and preserved LVEF underwent transfemoral aortic valve implantation. We performed echocardiography at baseline and one week after TAVI. Echocardiography included standard 2D and Doppler analysis of global systolic and diastolic function as well as 2D Strain measurements of longitudinal, radial and circumferential LV motion and Tissue Doppler echocardiography. RESULTS: The baseline biplane LVEF was 57 ± 8.2%, the mean pressure gradient was 46.8 ± 17.2 mmHg and the mean valve area was 0.73 ± 0.27 cm(2). The average global longitudinal 2D strain of the left ventricle improved significantly from -15.1 (± 3.0) to -17.5 (± 2.4) % (p < .001). This was reflected mainly in improvement in the basal and medial segments while strain in the apex did not change significantly [-11.6 (± 5.2) % to -15.1 (± 5.5) % (p < .001), -13.9 (± 5.1) % to -16.8 (± 5.6) % (p < .001) and -19.2 (± 7.0) % to -20.0 (± 7.2) % (p = .481) respectively]. While circumferential strain [-18.1 (± 5.1) % vs. -18.9 (± 4.2) %, p = .607], radial strain [36.5 (± 13.7) % vs. 39.7 (± 17.2) %, p = .458] and the LVEF remained unchanged after one week [57.0 (± 8.2) % vs. 59.1 (± 8.1) %, p = .116]. CONCLUSION: There is an acute improvement of myocardial longitudinal systolic function of the basal and medial segments measured by 2D Strain analysis immediately after TAVI. The radial, circumferential strain and LVEF does not change significantly in all patients acutely after TAVI. These data suggest that sensitive new echo methods can reliably detect early regional changes of myocardial function after TAVI before benefits in LVEF are detectable.

Nucleic acids from intact epithelial cells as a target for stool-based molecular diagnosis of colorectal cancer.

Stool-based molecular techniques may improve strategies for colorectal cancer screening. Molecular methods have successfully been applied to detect tumour DNA in stool from patients diagnosed for colorectal carcinoma. In these assays human DNA has to be analyzed against a background of excess nucleic acids from bacteria and dietary waste products. More recently a different diagnostic approach has been described characterizing intact cells isolated from stool. In this study we combine both approaches preparing nucleic acids from isolated epithelial cells to evaluate if: a) tumour cell-specific RNA can be analyzed since cellular RNA molecules are prevented from early digestion by an intact cell membrane; and b) specificity or sensitivity of established DNA-based methods can be improved when epithelial cells are separated from other stool components. Comparing different protocols we found cell isolation using epithelium-specific antibodies to be more effective and reproducible than a technique using density gradient centrifugation. A detection limit of 10(4) cells per ml stool was determined when samples from healthy volunteers were spiked with epithelial cells. Amplification of human sequences from total stool DNA was more efficient than a correspondent amplification of DNA extracted from isolated cells, so that an improvement of DNA-based methods cannot be expected by introducing cell isolation procedures. RNA detection was successful in 1 of 5 patients with confirmed diagnosis of colorectal cancer. The authors suggest that low numbers of detectable cells might rather be a biological than an analytical problem limiting a routinely performed method for colorectal cancer diagnosis.