Prevalence of transthyretin amyloid cardiomyopathy in pacemaker patients.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by increased wall thickness, diastolic dysfunction and progressive heart failure symptoms. The disease may infiltrate the conduction system leading to conduction disturbances requiring an implantation of permanent cardiac pacemaker (PM), but the extent is unknown. Here, we report the prevalence of ATTR-CM in patients ≥65 years with PM. METHODS AND RESULTS: In this prospective, cross-sectional single-centre study patients were recruited from our out-patient pacemaker clinic. Eligibility criteria were age above 65 years, permanent cardiac pacemaker and competent to give informed consent. Patients underwent echocardiography at the pacemaker visit and were referred to 99mTc-DPD-scintigraphy (DPD) and blood samples if septum thickness was ≥12 mm, defined as left ventricular hypertrophy (LVH). Fifty eight of the 128 patients had LVH on echocardiography. Eleven patients had a DPD-scintigraphy based diagnosis of ATTR-CM, which represent 19% of patients with LVH and 9% of the total cohort. Patients diagnosed with ATTR-CM had higher concentrations of cardiac biomarkers (P < 0.001), higher E/E' (P = 0.001), and lower global longitudinal strain (P = 0.003) on echocardiography and more heart failure symptoms (P = 0.001). CONCLUSIONS: The prevalence of ATTR-CM in elderly patients with PM and LVH on echocardiography was 19%.

A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function.

PPP1R21 acts as a co-factor for protein phosphatase 1 (PP1), an important serine/threonine phosphatase known to be essential for cell division, control of glycogen metabolism, protein synthesis, and muscle contractility. Bi-allelic pathogenic variants in PPP1R21 were linked to a neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) with pediatric onset. Functional studies unraveled impaired vesicular transport as being part of PPP1R21-related pathomechanism. To decipher further the pathophysiological processes leading to the clinical manifestation of NEDHFBA, we investigated the proteomic signature of fibroblasts derived from the first NEDHFBA patient harboring a splice-site mutation in PPP1R21 and presenting with a milder phenotype. Proteomic findings and further functional studies demonstrate a profound activation of the ubiquitin-proteasome system with presence of protein aggregates and impact on cellular fitness and moreover suggest a cross-link between activation of the proteolytic system and cytoskeletal architecture (including filopodia) as exemplified on paradigmatic proteins including actin, thus extending the pathophysiological spectrum of the disease. In addition, the proteomic signature of PPP1R21-mutant fibroblasts displayed a dysregulation of a variety of proteins of neurological relevance. This includes increase proteins which might act toward antagonization of cellular stress burden in terms of pro-survival, a molecular finding which might accord with the presentation of a milder phenotype of our NEDHFBA patient.

ANO5-related muscle diseases: From clinics and genetics to pathology and research strategies.

Anoctamin-5 (ANO5) is a multi-pass membrane protein localized to the sarcolemma and the sarcoplasmic reticulum. Mutations were linked to rare autosomal recessive muscle diseases. Here, we summarize the clinical spectrum, imaging data and molecular research findings as well as results of animal modeling, which significantly moved forward the understanding of mechanisms underlying ANO5-related muscle diseases. Given that precise histological information on inflammatory processes taking place in patient-derived muscle are still lacking, an (immuno)histological study on biopsies derived from six ANO5-patients was performed showing focal accumulation of necrotic fibers, mild fiber-size variances and myophagocytosis. In addition, MRI data of four ANO5-patients (including a 10-year follow-up in one patient) are presented and discussed in the context of previously published MRI-findings. Hence, data presented in this article combining a review of the literature with own myopathological findings address scientific trends and open questions on ANO5-related muscle diseases, which would be of significant interest for a wide neuromuscular diseases community. To conclude, a clear genotype-phenotype correlation does not exist, and ANO5-related muscle disorders might represent the next entity of a clinical continuum with varying degree of muscle cell pathologies. In addition, results of pre-clinical studies allowed the definition of suitable cell and animal models characterized by certain histological and functional pathologies resembling the human phenotype. These models might serve as suitable systems for testing of interventional concepts in future.

Homozygous WASHC4 variant in two sisters causes a syndromic phenotype defined by dysmorphisms, intellectual disability, profound developmental disorder, and skeletal muscle involvement.

Recessive variants in WASHC4 are linked to intellectual disability complicated by poor language skills, short stature, and dysmorphic features. The protein encoded by WASHC4 is part of the Wiskott-Aldrich syndrome protein and SCAR homolog family, co-localizes with actin in cells, and promotes Arp2/3-dependent actin polymerization in vitro. Functional studies in a zebrafish model suggested that WASHC4 knockdown may also affect skeletal muscles by perturbing protein clearance. However, skeletal muscle involvement has not been reported so far in patients, and precise biochemical studies allowing a deeper understanding of the molecular etiology of the disease are still lacking. Here, we report two siblings with a homozygous WASHC4 variant expanding the clinical spectrum of the disease and provide a phenotypical comparison with cases reported in the literature. Proteomic profiling of fibroblasts of the WASHC4-deficient patient revealed dysregulation of proteins relevant for the maintenance of the neuromuscular axis. Immunostaining on a muscle biopsy derived from the same patient confirmed dysregulation of proteins relevant for proper muscle function, thus highlighting an affliction of muscle cells upon loss of functional WASHC4. The results of histological and coherent anti-Stokes Raman scattering microscopic studies support the concept of a functional role of the WASHC4 protein in humans by altering protein processing and clearance. The proteomic analysis confirmed key molecular players in vitro and highlighted, for the first time, the involvement of skeletal muscle in patients. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Utility of Global Longitudinal Strain by Echocardiography to Detect Left Ventricular Dysfunction in Long-Term Adult Survivors of Childhood Lymphoma and Acute Lymphoblastic Leukemia.

Measuring left ventricular (LV) global longitudinal strain (GLS) is recommended in screening of long-term cancer survivors for cardiotoxicity. However, there are limited data on GLS in this setting, in particular in survivors with apparently normal LV function without risk factors of impaired GLS. In the present study, we measured GLS in 191 adult survivors of childhood lymphoma or acute lymphoblastic leukemia, with normal LV ejection fraction and fractional shortening (FS) and without known hypertension, diabetes mellitus, myocardial infarction, or stroke. We compared GLS in the survivors with 180 controls. Mean GLS was -19.0 ± 2.2% in the survivor group and -21.4 ± 2.0% in the controls (p <0.001). Impaired GLS, defined as mean - 1.96 SDs in the control group, occurred in 53 of 191 survivors (28%). We included survivors with impaired LV ejection fraction and/or FS or traditional risk factors (n = 231 in all) in multiple regression analyses to explore associations with previous cancer treatment. Survivors treated with mediastinal radiotherapy had an odds ratio of impaired GLS of 5.2 (95% confidence interval 2.2 to 12) compared with other survivors. Survivors treated with cumulative anthracycline doses >300 mg/m(2) had an odds ratio of 4.8 (95% confidence interval 1.7 to 14) of impaired GLS. In conclusion, this study demonstrates a high proportion of LV dysfunction assessed by GLS in apparently healthy adult survivors of childhood cancer. Impaired GLS was associated with previous exposure to mediastinal radiotherapy and high doses of anthracyclines. The prognostic role of measuring GLS in this specific patient population should be examined in prospective studies.

Right ventricular function in long-term adult survivors of childhood lymphoma and acute lymphoblastic leukaemia.

AIMS: Little is known about right ventricular (RV) function in survivors of childhood cancer, although both anthracyclines and radiotherapy represent potentially cardiotoxic treatment. We hypothesized that adult survivors of childhood malignant lymphoma or acute lymphoblastic leukaemia would have impaired RV function. METHODS AND RESULTS: We examined RV dimensions and function by echocardiography in 246 survivors, mean 21.7 years after diagnosis, and in 211 matched controls. Of the survivors, 84% had been exposed to anthracyclines, mediastinal radiotherapy, or both. Compared with controls, all mean measures of RV function were lower in the survivor group: fractional area change (44.5 vs. 48.6%, P < 0.001), tricuspid annular plane systolic excursion (2.24 vs. 2.49 cm, P < 0.001), peak systolic tricuspid annular velocity (12.1 vs. 13.0 cm/s, P < 0.001), and free wall strain (-26.5 vs. -28.4%, P < 0.001). In contrast, there were little differences in RV diastolic dimensions. Lower measures of RV function were found in all survivor subgroups having received cardiotoxic treatment, but not in the 16% of survivors unexposed to anthracyclines or mediastinal radiotherapy. Signs of RV systolic dysfunction were found in 30% of the survivors, and more than 3 times more often in survivors with left ventricular dysfunction. CONCLUSION: Long-term survivors of childhood lymphoma or acute lymphoblastic leukaemia frequently have impaired RV function compared with controls. As this is associated with increased risk of heart failure and death in many other conditions, we recommend increased attention to RV function in childhood survivors. Whether RV dysfunction impairs prognosis in this patient group should be examined in longitudinal studies.

Impaired exercise capacity and left ventricular function in long-term adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for late cardiotoxic effects of cancer treatment, but conflicting evidence exists on the effects of anthracyclines on left ventricular (LV) diastolic function and exercise capacity. PROCEDURE: We performed a cross-sectional study with comprehensive echocardiography in 138 adult survivors of childhood ALL, median 23.4 years after diagnosis. Pulsed tissue Doppler measurements of early diastolic mitral annular velocities (e') were used for the assessment of diastolic function, and compared to 138 matched controls. Of the survivors, 133 also performed ergospirometry measuring peak oxygen uptake (VO2 max). Associations between cancer treatment, LV function, and VO2 max were analyzed. RESULTS: The survivor group had lower e' values than controls (e' septal 11.0 vs. 12.6 cm/s, P < 0.001), but the difference was confined to the subgroup of anthracycline treated survivors (median cumulative dose 120 mg/m(2) ). Anthracycline exposure was inversely correlated with e' (regression coefficient -1.581, P=0.009). Reduced VO2 max/kg occurred in 47% of the survivors, but more often in anthracycline treated survivors (56%) than anthracycline naïve survivors (17%, P<0.001). Anthracycline exposure was inversely correlated with VO2 max/kg (regression coefficient -3.084, P = 0.05 in multivariate analysis). Furthermore, associations were observed between measures of LV function and VO2 max/kg, and e' was the best predictor of VO2 max/kg (standardized coefficient 0.355, P < 0.001 in multivariate analysis). CONCLUSIONS: Adult survivors of childhood ALL have increased risk for impaired LV diastolic function and impaired exercise capacity, both associated with previous anthracycline exposure. Furthermore, there is an association between LV diastolic function and exercise capacity.

Left ventricular function in long-term survivors of childhood lymphoma.

Survivors of childhood lymphoma (CL) have markedly increased risk of developing heart failure. Echocardiographic studies after cardiotoxic treatment have primarily demonstrated left ventricular (LV) systolic dysfunction. In the present study, we hypothesized that longer follow-up and a more comprehensive echocardiographic examination would reveal more cardiac abnormalities. We conducted a cross-sectional study with echocardiography 20.4 ± 8.6 years after diagnosis in 125 survivors of CL, grouped according to treatment methods, and compared with matched controls. Treatment included mediastinal radiotherapy (median 40.0 Gy) in 66 and anthracyclines (median dose 160 mg/m(2)) in 92 survivors of CL. Abnormal LV function, left-sided valve dysfunction, or both occurred in 62 patients (50%). Diastolic dysfunction occurred in 29%. Compared with control subjects, mitral annular early diastolic velocities (e') were reduced in patients (septal e' 0.09 ± 0.03 vs 0.12 ± 0.03 m/s, p <0.001), and the E/e' ratio was increased, particularly after mediastinal radiotherapy (10.6 ± 6.4 vs 5.6 ± 1.3, p <0.001). Survivors of CL had lower fractional shortening than control subjects (32 ± 6 vs 36 ± 7, p <0.001), but mean ejection fraction was equal and overt systolic dysfunction was infrequent. After mediastinal radiotherapy alone, global longitudinal myocardial strain was lower (p <0.05) compared with other treatment groups. Left-sided valvular dysfunction occurred in 55% of patients after mediastinal radiotherapy. In conclusion, survivors of CL had reduced LV diastolic function assessed by tissue Doppler imaging. This was more pronounced after mediastinal radiotherapy, which also frequently led to valvular disease. Systolic function was normal in most survivors of CL.

Do geographic and educational factors influence the quality of life in rectal cancer patients with a permanent colostomy?

PURPOSE: This study was designed to evaluate possible social and geographic factors that could have an impact on quality of life in patients after abdominoperineal excision of the rectum. Although the number of patients with rectal cancer who need to be treated with abdominoperineal excision of the rectum and construction of permanent colostomy has greatly decreased in the past, there is still controversy about the influence on quality of life caused by this procedure. METHODS: In a prospective trial, patients operated on for low rectal cancer by abdominoperineal excision of the rectum were evaluated by a quality of life questionnaire, modified from The American Society of Colon and Rectal Surgeons questionnaire, to assess fecal incontinence. The results for the four domains of quality of life (lifestyle, coping behavior, embarrassment, depression), as well as for subjective general health, were evaluated with regard to age, gender, education, and geographic origin in univariate and multivariate analyses. RESULTS: Thirteen institutions in 11 countries included data from 257 patients. Although the analysis of general health did not reveal any significant differences, the analysis of the four quality of life domains showed the significant influence of geographic origin. The presence of a permanent colostomy showed a consistently negative impact on patients in southern Europe as well as for patients of Arabic (Islamic) origin. On the other hand, age, gender, and educational status did not reveal a statistically significant influence. CONCLUSIONS: This is the first study to show the influence of geographic origin on quality of life of patients with a permanent colostomy. Possible factors that may influence the outcome of patients after surgical treatment of rectal cancer, such as weather, religion, or culture, should be taken into account when quality of life evaluations are considered.