Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study.

BACKGROUND: Variants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking. METHODS: We retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111). RESULTS: Average LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN. There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals. CONCLUSIONS: In this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

Cognitive performance among older adults with psychotic depression compared to non-psychotic depression.

It remains unclear whether psychotic depression (PD) compared to non-psychotic depression (non-PD) among older adults is associated with poorer cognitive performance. For inpatients (60+) with a major depressive episode, cognitive performance in PD and non-PD (categorical) were compared as well as the relationship between symptom severity for depression and psychosis (dimensional) and cognition. Of 90 participants (on average 72.7 years old; range 60-92), 64% were female. The severity of depressive- and psychotic symptoms are both negatively associated with cognitive functioning among older adults with depression. This is of relevance for the treatment of this vulnerable group of patients.

Diagnostic yield of genetic testing in heart transplant recipients with prior cardiomyopathy.

BACKGROUND: The importance of genetic testing for cardiomyopathies has increased in the last decade. However, in heart transplant patients with former cardiomyopathy, genetic testing in retrospect is not routinely performed. We hypothesize that the yield of genetic testing in this population is considerable, and will have a major impact for both patients and relatives. METHODS: Patients that underwent heart transplantation (HTx) between 1995 and 2020 and were still in follow-up, were offered genetic testing if the primary etiology was non-ischemic cardiomyopathy. Next generation sequencing (NGS) of known cardiomyopathy genes was performed and variants were classified as variant of unknown significance (class 3), likely pathogenic (class 4) or pathogenic (class 5) variant. RESULTS: Of the 99 HTx patients in active follow-up, only 6 patients had a genetic diagnosis at the time of HTx. In this study, 31 selected patients with prior non-ischemic cardiomyopathy underwent genetic testing post HTx. 23/31 patients (74.2%) carried a variant that was classified as class 3 or higher. In 12/31 patients a class 4/5 variant (38.7%) was identified, and in 11/31 patients (35.5%) a class 3 variant. Class 5 Variants in TTN were the most prevalent (7/31), followed by class 5 variants in MYBPC3 (2/31). A positive family history was present in 21/31 (67.7%) and a second precipitating factor (e.g., alcohol abuse, pregnancy) was present in 17/31 patients (54.8%). Diagnostic yield of genetic testing was similar between patients with or without familial history and/or second hit. Through cascade screening 48 family members were screened for presence of a class 4/5 variant, of whom 19 (39.6%) were genotype positive, of whom 10 (52.6%) showed a cardiac phenotype. Appropriate follow-up was offered. CONCLUSIONS: Genetic testing for cardiomyopathy genes established a molecular diagnosis in 38.7% of patients post HTx. These results highlight the importance of genetic testing in this population as it is still often overlooked in patients that already underwent HTx in the past. Genetic testing is highly recommended, independent of family history or second precipitating factors, as it might identify relatives at risk.

The deleterious effects of smoking resumption after heart transplantation.

AIMS: Smoking is linked to disease and survival in the general and transplant population. We studied the smoking history, disease and survival of patients after heart transplantation. METHODS: A total of 130 patients who underwent heart transplantation between 1995 and 2019 received a questionnaire to document their smoking history. We assessed patient characteristics, comorbidities and survival. RESULTS: Sixty-five per cent of patients were active or former smokers prior to heart transplantation. All patients stopped smoking; 26% of the former smokers resumed smoking after transplantation. Patients who resumed smoking were younger at the time of transplantation, used fewer statins and were more likely to be treated with azathioprine after transplantation. The mean follow-up for all patients was 11 ± 5.5 years. Patients who resumed smoking were more likely to develop solid organ cancers (45%) compared to those who remained abstinent (23%) and those who never smoked (13%) (p 0.014). A Cox proportional hazards regression analysis identified smoking resumption, with a RR of 2.31 (1.14-4.68, p 0.02), and age at transplantation, with a RR of 1.03 (1-1.06, p 0.034), as significant for survival. Patients resuming smoking after transplantation had a significantly higher risk of dying from solid organ cancer, with a RR of 2.54 (1.03, 6.28; p 0.04) with a short median survival time (25th-75th percentile) of (1 (0-5) months, p 0.007). CONCLUSION: Patients who resume smoking after heart transplantation have worse survival and are at higher risk of dying from solid organ cancer. Implementing a smoking cessation plan throughout the post-transplant period is important.

Autochthonous dengue in two Dutch tourists visiting Département Var, southern France, July 2020.

We report dengue virus (DENV) infection in two Dutch tourists who visited Département Var, southern France, in July and August 2020. As some autochthonous dengue cases have occurred in Europe in recent years, awareness among physicians and public health experts about possible intermittent presence of DENV in southern Europe is important to minimise delay in diagnosis and treatment. Quick diagnosis can lead to timely action to contain the spread of vector-borne diseases and minimise transmission.

Performance of the Psychotic Depression Assessment Scale as a Predictor of ECT Outcome.

OBJECTIVES: The presence of psychotic symptoms is an important predictor of responsiveness to electroconvulsive therapy (ECT). This study investigates whether a continuous severity measure, the Psychotic Depression Assessment Scale (PDAS), is a more accurate predictor. METHODS: Depression severity was assessed before and after the ECT course using the Montgomery-Asberg Depression Rating Scale (MADRS) in 31 patients with psychotic depression and 34 depressed patients without psychotic symptoms. Logistic regression models for MADRS response and remission were fitted, with either the PDAS total score or the dichotomous predictors "absence/presence of psychotic symptoms" as the independent variables. Age, episode duration, and treatment resistance were added as covariates. RESULTS: Both the asserted presence of psychotic symptoms and a higher PDAS total score reflected MADRS response (areas under the curve, 0.83 and 0.85, respectively), with MADRS remission also being predicted by the presence of psychotic symptoms and higher PDAS scores (areas under the curves, 0.86 and 0.84, respectively). Age was a contributor to these prediction models, with response and remission rates being highest in the older patients. Psychotic Depression Assessment Scale scores decreased significantly during ECT: at end point, 81.5% of the patients showed significant response and 63.9% had achieved remission. CONCLUSIONS: The PDAS indeed accurately predicts response to and remission after ECT in (psychotic) depression and most pronouncedly so in older patients but seems to have no clear advantage over simply verifying the presence of psychotic symptoms. This could be the consequence of a ceiling effect, as ECT was extremely effective in patients with psychotic depression.ClinicalTrials.gov: Identifier: NCT02562846.

Cognitive Deficits in Older Adults With Psychotic Depression: A Meta-Analysis.

A major depressive disorder with psychotic features, that is, psychotic depression (PD), is often accompanied by cognitive deficits, particularly in older patients. We aimed to assess to what extent various cognitive domains are affected in older patients with PD compared to those with nonpsychotic depression (NPD). Therefore, a systematic search was conducted in Medline, Embase, Web of Science, the Cumulative Index to Nursing and Allied Literature (CINAHL), Google Scholar, and Cochrane for all relevant studies. Hereafter, we conducted a meta-analysis of seven studies on cognitive deficits in older adults (55+ years), comparing patients with PD and patients with NPD. Compared to patients with NPD, those with PD not only showed a significantly poorer performance on overall cognitive function, with a Hedges' g effect size of -0.34 (95% confidence interval: -0.56; -0.12; p = 0.003), but also on nearly all separate cognitive domains, with Hedges' g effect sizes ranging from -0.26 to -0.64 (all p's <0.003), of which attention was most adversely affected. Verbal fluency showed no significant effect, although this analysis may have been underpowered. The funnel plot suggested no significant publication bias (Egger test intercept: -2.47; 95% confidence interval: -5.50; 0.55; p = 0.09). We conclude that older patients with PD show more cognitive deficits on all cognitive domains, except for verbal fluency, compared to patients with NPD. It is crucial that clinicians and researchers take cognitive deficits into consideration in older adults with PD.

Biomarkers and Donor Selection in Heart Transplantation.

BACKGROUND: Previously, we showed that B-type natriuretic peptide (BNP) measured in the donor was related to cardiac performance after cardiac transplantation. The present study assesses the value of 3 biomarkers in the selection of donor hearts in a larger cohort. METHODS: Blood samples were prospectively obtained in 105 brain-dead patients scheduled for heart donation. BNP, soluble suppressor of tumorigenicity 2 (ST2), and troponin of heart donors were correlated with hemodynamic parameters early after transplantation as well as with the mortality of the recipients. RESULTS: A significant inverse relationship was found between donor BNP measured at the time of donation and recipient cardiac index and cardiac output at day 13 post-transplantation (r = -0.31, P = .005, and r = -0.34, P = .0016, respectively). Logistic regression analysis-including BNP, ST2, and troponin-showed that donor BNP was a predictor of a poor cardiac index (< 2.2 L/min/m2) in the recipient (P = .04). A donor BNP > 132 pg/mL has a sensitivity of 56% (95% confidence interval 21-86) and a specificity of 86% (95% confidence interval 77-93) to predict poor cardiac performance in the recipient. When the donor BNP is ≤ 132 pg/mL, the risk of a poor cardiac function in the recipient is very low (negative predictive value 94%). Mortality at 30 days was also correlated to donor BNP (r = 0.29, P = .0029). Long-term survival of the recipient was not correlated to the biomarkers measured in the donor. CONCLUSION: Donor BNP, but not donor ST2 or high-sensitivity troponin, provides information on the donor heart and early post-transplant performance, including 1-month mortality.

[Psychotic depression in older adults: an overview]. / Psychotische depressie bij ouderen: een overzicht.

Psychotic depression is a frequent, severe psychiatric condition in older depressive inpatients aged 60 years and older. Older adults with a psychotic depression exhibit specific symptoms that are different from those in younger adults with psychotic depression. Moreover, the symptoms are also different from those in older adults  with a major depression without psychotic features. The recommended treatment consists of a tricyclic antidepressant, with or without addition of an antipsychotic, or electroconvulsive therapy. These treatments may however produce significant side effects that require intensive monitoring. In this article we present an overview of clinical topics regarding the diagnosis and treatment of older people with a psychotic depression.

Prediction of Electroconvulsive Therapy Response and Remission in Major Depression: Meta-analysis - CORRIGENDUM.

This notice describes a correction to the above mentioned paper.

Clinical validation of the Psychotic Depression Assessment Scale (PDAS) against independent global severity ratings in older adults.

OBJECTIVES: According to a recent study, ratings on the Psychotic Depression Assessment Scale (PDAS) obtained via a dedicated semi-structured interview are valid measures of the severity of psychotic depression. This study aimed to further test the validity, scalability and responsiveness of the PDAS in older adults using independent ratings on the Clinical Global Impression Scale - Severity (CGI-S) and the Montgomery-Asberg Depression Rating Scale (MADRS) as references. METHODS: Ratings were performed at admission and discharge at two old age psychiatric wards in Flanders, Belgium. In total, 62 older adults (mean age: 74.3 years) with psychotic depression were included. The PDAS was rated by trained nurses using the semi-structured PDAS interview. Senior psychiatrists scored the participants on the CGI-S. Psychologists or experienced nurses rated participants on the MADRS. Clinical validity was assessed by correlating the PDAS total scores with CGI-S ratings and MADRS total scores. Mokken analysis was performed to assess the scalability of the PDAS. Responsiveness was assessed by comparing the proportion of participants in remission (PDAS total score <8 at study baseline and endpoint). RESULTS: The Spearman correlation coefficients were 0.76 and 0.79 for the PDAS versus CGI-S and PDAS versus MADRS, respectively. The Mokken analysis yielded a Loevinger coefficient of 0.46, which is indicative of scalability. At admission, no participants met the PDAS remission criterion. At discharge, 54% (95% confidence interval: 47%-60%) of the patients met this criterion. CONCLUSION: The PDAS appears to be a clinically valid, scalable and responsive measure of the severity of psychotic depression in older adults.

Prediction of electroconvulsive therapy response and remission in major depression: meta-analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is considered to be the most effective treatment in severe major depression. The identification of reliable predictors of ECT response could contribute to a more targeted patient selection and consequently increased ECT response rates. Aims To investigate the predictive value of age, depression severity, psychotic and melancholic features for ECT response and remission in major depression. METHOD: A meta-analysis was conducted according to the PRISMA statement. A literature search identified recent studies that reported on at least one of the potential predictors. RESULTS: Of the 2193 articles screened, 34 have been included for meta-analysis. Presence of psychotic features is a predictor of ECT remission (odds ratio (OR) = 1.47, P = 0.001) and response (OR = 1.69, P < 0.001), as is older age (standardised mean difference (SMD) = 0.26 for remission and 0.35 for response (P < 0.001)). The severity of depression predicts response (SMD = 0.19, P = 0.001), but not remission. Data on melancholic symptoms were inconclusive. CONCLUSIONS: ECT is particularly effective in patients with depression with psychotic features and in elderly people with depression. More research on both biological and clinical predictors is needed to further evaluate the position of ECT in treatment protocols for major depression. Declaration of interest None.

Evolution of Functional Mitral Regurgitation and Prognosis in Medically Managed Heart Failure Patients With Reduced Ejection Fraction.

OBJECTIVES: The purpose of this study was to assess whether medical management may alter the severity of functional mitral regurgitation (FMR) and its prognosis in patients who have heart failure with reduced ejection fraction (HFrEF). BACKGROUND: FMR in patients who have HFrEF is associated with a worse prognosis. It is uncertain to what extent medical management may alter the severity of FMR and its prognosis. METHODS: The extent of FMR was assessed at baseline and after a median follow-up period of 50 months in 163 consecutive HFrEF patients (left ventricular ejection fraction <40%). Severe FMR was defined as mitral regurgitation (MR) grade 3-4. All of the patients received the maximal tolerable doses of their heart failure (HF) medications. Major adverse cardiac events were defined as a composite of all-cause death and the need for heart transplantation or hospitalization for HF and/or malignant arrhythmias. RESULTS: A total of 50 (31%) patients had severe MR at baseline. During the follow-up period, 38% of the severe FMR patients showed an improvement to nonsevere FMR (MR grade <3), whereas 18% of the nonsevere FMR patients developed severe FMR despite optimal HF treatment. Cox regression analysis revealed that the presence of sustained severe FMR or worsening of FMR was the most important independent prognostic determinant with an adjusted odds ratio of 2.5 (95% confidence interval: 1.5 to 4.3, major adverse cardiac events 83% vs. 43%). In addition, those patients showed a 13% increase in left ventricular end-diastolic volume index (LVEDVI), whereas the patients with improvement in their severe MR showed a 2% decrease in LVEDVI (p = 0.01). CONCLUSIONS: Severe FMR was successfully treated with medication in almost 40% and was associated with prevention of left ventricular adverse remodeling and with an improved long-term prognosis.

Establishing the cut-off score for remission and severity-ranges on the Psychotic Depression Assessment Scale (PDAS).

BACKGROUND: The Psychotic Depression Assessment Scale (PDAS) is a rating scale dedicated to the measurement of severity in psychotic depression (PD). The aim of this study was to establish the PDAS cut-off for remission of PD as well as PDAS score-ranges for mild, moderate, and severe PD. The secondary aim was to test how remission, as defined by the PDAS, would perform as outcome measure when applied to the data from a large randomized controlled trial (RCT) in PD. METHODS: The study was based on data from the Study of Pharmacotherapy in Psychotic Depression (STOP-PD). The cut-off for remission on the PDAS and the severity-ranges for mild, moderate, and severe PD were defined using the Clinical Global Impression - Severity scale (CGI-S) as reference by means of pair-wise receiver operating characteristic (ROC) analyses. Subsequently, it was tested whether remission on the PDAS could separate the effects of Olanzapine+Sertraline vs. Olanzapine+Placebo through an intention-to-treat, mixed-effects logistic regression of the data from STOP-PD. RESULTS: According to the ROC analyses, the ideal cut-off for remission of PD was a PDAS total score <8, while the severity-ranges for mild, moderate and severe PD were 8-15, 16-23, and >23 respectively. When applying the PDAS total score <8 (remission) as outcome on the STOP-PD data, treatment with Olanzapine+Sertraline performed significantly better than Olanzapine+Placebo (p<0.001). LIMITATIONS: The STOP-PD was not designed specifically to answer the research questions of the present study. CONCLUSIONS: According to this study, a total score <8 on the PDAS corresponds to remission of PD.

Disseminated malignancy after extracorporeal life support and left ventricular assist device, diagnosed by left ventricular apical core biopsy.

The left ventricular apical core biopsy performed during implantation of a left ventricular assist device (VAD) is a well-known diagnostic procedure in confirming cardiomyopathies leading to end-stage heart failure. We describe a patient in whom disseminated malignancy was revealed by means of the apical core biopsy after extracorporeal life support and left ventricular assist device implantation as a bridge to transplantation. This case emphasizes the importance of thorough oncological screening before VAD implantation and the possible consequences of circulating tumour cells in this device-assisted circulation.

Donor B-type natriuretic peptide predicts early cardiac performance after heart transplantation.

BACKGROUND: Decision processes in heart donation remain difficult and are often based on subjective evaluation. We measured B-type natriuretic peptide (BNP) in heart donors and analyzed its value as a discriminator for early post-transplant cardiac performance. METHODS: Blood samples were prospectively obtained in 94 brain-dead patients, among whom 56 were scheduled for heart donation. BNP values were not available prior to donor selection. BNP of heart donors was related to invasively measured cardiac output and hemodynamic parameters, early after transplantation. RESULTS: BNP, expressed as median (interquartile range), was 65 (32 to 149) pg/ml in brain-dead donors scheduled for heart donation. BNP was higher (287 pg/ml, range 65 to 457; p = 0.0001) in donors considered ineligible for heart donation. In 45 heart recipients, cardiac output (CO) of 5.6 (4.8 to 6.2) liters/min was measured at Day 12 (10-15). In the univariate analysis, recipient CO correlated significantly with donor BNP (r = -0.34, p = 0.025). Stepwise multiple regression, including donor variables such as body mass index, age, BNP, norepinephrine dose, gender and total ischemic time, identified donor BNP and age as the best independent predictors of CO in recipients (p = 0.02 and p = 0.005, respectively, R(2) of the model = 0.27). Donor BNP of >160 pg/ml had 89% accuracy to predict poor cardiac performance in the recipient (cardiac index <2.2 liters/min/m(2)). High donor BNP was independently correlated with a longer hospital stay. CONCLUSIONS: Donor BNP was found to be related to cardiac performance, early after cardiac transplantation. BNP measurement in heart donors could become a useful tool in the evaluation of donor hearts.

Endomyocardial fibrosis.

We report the case of a 51-year-old man of central African origin. Medical evaluation revealed severe heart failure. Echocardiography disclosed poor left ventricular function. The apex of the left ventricle showed complete obliteration and retraction. Magnetic resonance imaging revealed subendocardial hyperenhancement of the apex of the left and right ventricle, strongly suggesting endomyocardial fibrosis. For this particular patient a conservative approach (non-surgical) was decided on, and until now--12 months after termination of cardiac rehabilitation--proves successful.

Treating humoral rejection after cardiac transplantation.

Whereas effective strategies are available to treat acute cellular cardiac rejection, humoral rejection, also called vascular or antibody-mediated rejection, is more difficult to manage. Antibody-mediated (non-cellular) rejections (AMR) are rare and few successfully treated cases have been described in the literature. We report on a female patient, diagnosed with humoral rejection, leading to severe ventricular dysfunction and haemodynamic compromise, two months after transplantation. The patient received a combination therapy, consisting of plasmapheresis and immunoglobulins, which resulted in complete resolution of immunohistochemical signs of AMR. In this report, we will overview AMR and discuss several treatment modalities.

Coronary artery-pulmonary artery fistula in a heart-transplanted patient.

A 64-year-old-man underwent routine elective right-left heart catheterization, 1 year after cardiac transplantation for terminal ischaemic cardiomyopathy. Surprisingly, selective coronary angiography disclosed coronary-pulmonary artery fistula with three feeding vessels originating from the proximal right coronary artery, the proximal portion of the left anterior descending artery, the circumflexus artery, and the left main coronary artery, draining into the pulmonary trunk. For this particular patient, without any significant cardiac complaints or symptoms, with normal cardiac dimensions and haemodynamic findings, a conservative approach was decided on.