A case report of transthyretin amyloidosis following cardiac transplantation: thick ventricles that look alike.

Background: Transthyretin (ATTR) amyloidosis is more prevalent than initially thought. As much as 13% of patients hospitalized with heart failure with preserved ejection fraction may have ATTR-cardiomyopathy (CM). Conversely, heart transplant patients may manifest left ventricular hypertrophy or diastolic dysfunction, especially late after transplantation. Case summary: We present a case of a 82-year-old male heart transplant patient, 31 years following orthotopic heart transplantation. While he was satisfied with his exercise capacity as an octogenarian, several years before, he required pacemaker implantation due to third-degree atrioventricular block, had bilateral carpal tunnel syndrome treated with carpal tunnel release surgery, and experienced idiopathic sudden deafness. Based on increasing left ventricular wall thickness during routine follow-up, a diagnosis of ATTR amyloidosis was suspected. Ultimately, the diagnosis was confirmed non-invasively with a specific scintigraphic exam, while an additional physicochemical stain on an endomyocardial biopsy taken several years before provided pathological proof. We initiated tafamidis, yet stopped this treatment after 1 month because of gastrointestinal intolerance. Ultimately, our patient died 2 years later due to heart failure. Discussion: Our case shows the long delay between the onset of ATTR deposition, the presence of clinical signs, and the final diagnosis. Echocardiographic findings suggestive for ATTR-CM include left ventricular hypertrophy and diastolic dysfunction, which are both common in heart transplant patients. Yet, ATTR-CM should be considered in the differential diagnosis, especially late after transplantation, in this closely monitored population.

Heart failure patients' perspectives on treatment outcomes and unmet medical needs: A qualitative preference study.

AIMS: Decision-makers still predominantly focus on the perspective of non-patient stakeholders, which may deviate from the unique perspective of heart failure (HF) patients. To enhance patient-centred decision-making, there is a need for more patient-based evidence derived directly from the patients themselves. Hence, this study aimed to understand (i) HF patients' unmet medical needs and preferred treatment outcomes; (ii) patients' risk tolerance; and (iii) their information needs, uncertainties and satisfaction towards HF treatment. METHODS: This qualitative patient preference study consisted of a literature review with a systematic search strategy and semi-structured interviews with HF patients, analysed using the framework method. During the interviews, patients were asked to rank a predefined list of disease and treatment-related characteristics informed by the literature review and were able to spontaneously raise additional characteristics. RESULTS: The study included 14 Belgian HF patients (age range: 58-79, mean age: 72). (i) Regarding their unmet medical needs, HF patients reported that the most important unmet medical needs were shortness of breath and fatigue, as they negatively impact their quality of life (QoL) and independence. In the ranking exercise, patients prioritized improvements in QoL over improvements in life expectancy, whereby the following characteristics received the highest cumulative score: (1) independence, (2) shortness of breath, (3) impaired renal function, (4) survival, (5) fatigue, (6) risk of hospitalization and (7) communication with and between physicians. Patients most often spontaneously raise characteristics related to the general care process. Mechanism of action, route of administration, dose frequency and weight fluctuations scored among the least important characteristics. (ii) Regarding patients' risk tolerance towards HF treatment, some of the patients expressed zero tolerance for side effects, as they had not yet experienced any discomfort caused by the treatment or disease. (iii) Regarding their information needs, patients voiced their desire to receive practical and comprehensible advice orally from their physician because they highly value individualized treatment decision-making. Patients also expressed uncertainties regarding whether the experienced effects were due to their treatment, disease, ageing or other comorbidities. CONCLUSIONS: This study shows that, besides increasing life expectancy, HF patients prioritize improvements in symptoms and side effects reducing their QoL and independence, such as shortness of breath and fatigue. The patient-relevant characteristics identified in this study, from the perspective of HF patients themselves, may be useful to inform clinical trial endpoint selection and guide downstream drug development, evaluation and clinical decision-making towards addressing the unmet medical needs and treatment outcomes of importance to HF patients.

How does age affect outcomes after left ventricular assist device implantation: results from the PCHF-VAD registry.

AIMS: Use of left ventricular assist devices (LVADs) in older patients has increased, and assessing outcomes in older LVAD recipients is important. Therefore, this study aimed to investigate associations between age and outcomes after continuous-flow LVAD (cf-LVAD) implantation. METHODS AND RESULTS: Cf-LVAD patients from the multicentre European PCHF-VAD registry were included and categorized into those <50, 50-64, and ≥65 years old. The primary endpoint was all-cause mortality. Among secondary outcomes were heart failure (HF) hospitalizations, right ventricular (RV) failure, haemocompatibility score, bleeding events, non-fatal thromboembolic events, and device-related infections. Of 562 patients, 184 (32.7%) were <50, 305 (54.3%) were aged 50-64, whereas 73 (13.0%) were ≥65 years old. Median follow-up was 1.1 years. Patients in the oldest age group were significantly more often designated as destination therapy (DT) candidates (61%). A 10 year increase in age was associated with a significantly higher risk of mortality (hazard ratio [HR] 1.34, 95% confidence interval [CI] [1.15-1.57]), intracranial bleeding (HR 1.49, 95% CI [1.10-2.02]), and non-intracranial bleeding (HR 1.30, 95% CI [1.09-1.56]), which was confirmed by a higher mean haemocompatibility score (1.37 vs. 0.77, oldest vs. youngest groups, respectively, P = 0.033). Older patients suffered from less device-related infections requiring systemic antibiotics. No age-related differences were observed in HF-related hospitalizations, ventricular arrhythmias, pump thrombosis, non-fatal thromboembolic events, or RV failure. CONCLUSIONS: In the PCHF-VAD registry, higher age was associated with increased risk of mortality, and especially with increased risk of major bleeding, which is particularly relevant for the DT population. The risks of HF hospitalizations, pump thrombosis, ventricular arrhythmia, or RV failure were comparable. Strikingly, older patients had less device-related infections.

Sex-related differences in left ventricular assist device utilization and outcomes: results from the PCHF-VAD registry.

AIMS: Data on sex and left ventricular assist device (LVAD) utilization and outcomes have been conflicting and mostly confined to US studies incorporating older devices. This study aimed to investigate sex-related differences in LVAD utilization and outcomes in a contemporary European LVAD cohort. METHODS AND RESULTS: This analysis is part of the multicentre PCHF-VAD registry studying continuous-flow LVAD patients. The primary outcome was all-cause mortality. Secondary outcomes included ventricular arrhythmias, right ventricular failure, bleeding, thromboembolism, and the haemocompatibility score. Multivariable Cox regression models were used to assess associations between sex and outcomes. Overall, 457 men (81%) and 105 women (19%) were analysed. At LVAD implant, women were more often in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 or 2 (55% vs. 41%, P = 0.009) and more often required temporary mechanical circulatory support (39% vs. 23%, P = 0.001). Mean age was comparable (52.1 vs. 53.4 years, P = 0.33), and median follow-up duration was 344 [range 147-823] days for women and 435 [range 190-816] days for men (P = 0.40). No significant sex-related differences were found in all-cause mortality (hazard ratio [HR] 0.79 for female vs. male sex, 95% confidence interval [CI] [0.50-1.27]). Female LVAD patients had a lower risk of ventricular arrhythmias (HR 0.56, 95% CI [0.33-0.95]) but more often experienced right ventricular failure. No significant sex-related differences were found in other outcomes. CONCLUSIONS: In this contemporary European cohort of LVAD patients, far fewer women than men underwent LVAD implantation despite similar clinical outcomes. This is important as the proportion of female LVAD patients (19%) was lower than the proportion of females with advanced HF as reported in previous studies, suggesting underutilization. Also, female patients were remarkably more often in INTERMACS profile 1 or 2, suggesting later referral for LVAD therapy. Additional research in female patients is warranted.

Mixed-methods evaluation of a multifaceted heart failure intervention in general practice: the OSCAR-HF pilot study.

AIMS: Heart failure (HF) is an important health problem for which multidisciplinary care is recommended, yet few studies involve primary care practitioners in the multidisciplinary management of HF. We set up a multifaceted prospective observational trial, OSCAR-HF, piloting audit and feedback, natriuretic peptide testing at the point of care, and the assistance of a specialist HF nurse in primary care. The aim was to optimize HF care in general practice. METHODS AND RESULTS: This is an analysis at 6 month follow-up of the study interventions of the OSCAR-HF pilot study, a nonrandomized, noncontrolled prospective observational trial conducted in eight Belgian general practices [51 general practitioners (GPs)]. Patients who were assessed by their GP to have HF constituted the OSCAR-HF study population. We used descriptive statistics and mixed-effects modelling for the quantitative analysis and thematic analysis of the focus group interviews. There was a 10.2% increase in the registered HF population after 6 months of follow-up (n = 593) compared with baseline (n = 538) and a 27% increase in objectified HF diagnoses (baseline n = 359 to 456 at T6 M). Natriuretic peptide testing (with or without referral) accounted for 54% (n = 60/111) of the newly registered HF diagnoses. There was no difference in the proportion of patients with HF with reduced ejection fraction who received their target dosage of renin-angiotensin-aldosterone system inhibitors or beta-blockers at 6 months compared with baseline (P = 0.9). Patients who received an HF nurse intervention (n = 53) had significantly worse quality of life at baseline [difference in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score 9.2 points; 95% confidence interval (CI) 4.0, 14] and had a significantly greater improvement in quality-of-life scores at the 6 month follow-up [change in MLHFQ score -9.8 points; 95% CI -15, -4.5] than patients without an HF nurse intervention. GPs found audit and feedback valuable but time intensive. Natriuretic peptides were useful, but the point-of-care test was impractical, and the assistance of an HF nurse was a useful addition to routine HF care. CONCLUSIONS: The use of audit and feedback combined with natriuretic peptide testing was a successful strategy to increase the number of registered and objectified HF diagnoses at 6 months. GPs and HF nurses selected patients with worse quality-of-life scores at baseline for the HF nurse intervention, which led to a significantly greater improvement in quality-of-life scores at the 6 month follow-up compared with patients without an HF nurse intervention. The interventions were deemed feasible and useful by the participating GPs with some specific remarks that can be used for optimization. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02905786), registered on 14 September 2016 at https://clinicaltrials.gov/.

Combination prophylaxis in CMV high risk heart transplant recipients: A single center experience.

INTRODUCTION: Cytomegalovirus (CMV) is the most clinically relevant infectious agent following heart transplantation (HTX). Data on the beneficial effects of prophylactic use of CMV immunoglobulins (CMVIG) are scarce. METHODS: In this single-center, retrospective study, we reported patient outcomes following cardiac transplantation using prophylactic CMV treatment, including CMVIG. Distinct clinically relevant outcomes were compared across different CMV risk groups (CMV D-/R-, CMV D-/R+, CMV D+/R+, and CMV D+/R- or CMV high risk group). RESULTS: We included 272 heart transplant procedures, performed between 1/1/2009 and 1/11/2020. Sixty-one (22%) procedures belonged to the CMV high risk group, while 96 (35%), 50 (18%), and 65 (24%) were CMV D-/R-, CMV D-/R+, and CMV D+/R+, respectively. Baseline donor and recipient characteristics (sex, age, body mass index, cause of death, indication for HTX), ischemia times and baseline immunosuppressive regimens were similar across the different CMV risk groups, yet fewer patients were bridged with a mechanical circulatory support in the CMV D+/R- group. CMV disease following cardiac transplantation was more common in the CMV D+/R- risk group (n = 40 or 66.7%; p < .001), yet mortality and re-transplantation rates, cardiac allograft vasculopathy (CAV) severity, rejection episodes, and development of donor-specific antibodies (DSA), post-transplant lymphoproliferative diseases (PTLD), and EBV infections were similar across all four CMV risk groups. CONCLUSION: High risk CMV D+/R- patients had a similar survival compared to low and intermediate CMV risk groups using a prophylactic strategy combining CMVIG and viral DNA polymerase inhibitors. This may be related to a number of factors unrelated to prophylaxis strategy as two out of three CMV D+/R- recipients developed CMV primary infection after prophylaxis was discontinued.

Consensus validation of a screening tool for cardiovascular pharmacotherapy in geriatric patients: the RASP_CARDIO list (Rationalization of Home Medication by an Adjusted STOPP list in Older Patients).

PURPOSE: Cardiovascular agents commonly used in geriatric patients, are linked to potentially avoidable harm and might hence be a suitable substrate for medication review practices. Therefore, we sought to update and validate the content of the cardiovascular segment of the previously published Rationalization of Home Medication by an Adjusted STOPP list in Older Patients (RASP) List. METHODS: A three-step study was conducted by the pharmacy department in collaboration with the geriatric medicine and cardiology department at the University Hospitals Leuven, Belgium. First, the cardiovascular segment of the RASP list version 2014 was updated taking into account published research, other screening tools and the input of end-users. Secondly, this draft was reviewed during three panel discussions with five expert cardiologists and three clinical pharmacists, all of whom had relevant expertise in geriatric pharmacotherapy. Thirdly, the content was validated using a modified Delphi Technique by a panel of European hospital pharmacists, cardiologists, geriatricians and an internal medicine physician. RESULTS: After the first and second step, the RASP_CARDIO list comprised 94 statements. Consensus (≥ 80% agreement) of all statements and one new statement about gliflozins in heart failure was achieved by a panel of seventeen experts across four European countries after two validation rounds. The final construct comprised a list of 95 statements related to potentially inappropriate prescribing of cardiovascular agents. CONCLUSION: The RASP_CARDIO list is an updated and validated explicit screening tool to optimize cardiovascular pharmacotherapy in geriatric patients.

Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.

BACKGROUND: Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed. RESULTS: A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups. CONCLUSIONS: The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).

Impact of progressive aortic regurgitation on outcomes after left ventricular assist device implantation.

Aortic regurgitation (AR) following continuous flow left ventricular assist device implantation (cf-LVAD) may adversely impact outcomes. We aimed to assess the incidence and impact of progressive AR after cf-LVAD on prognosis, biomarkers, functional capacity and echocardiographic findings. In an analysis of the PCHF-VAD database encompassing 12 European heart failure centers, patients were dichotomized according to the progression of AR following LVAD implantation. Patients with de-novo AR or AR progression (AR_1) were compared to patients without worsening AR (AR_0). Among 396 patients (mean age 53 ± 12 years, 82% male), 153 (39%) experienced progression of AR over a median of 1.4 years on LVAD support. Before LVAD implantation, AR_1 patients were less frequently diabetic, had lower body mass indices and higher baseline NT-proBNP values. Progressive AR did not adversely impact mortality (26% in both groups, HR 0.91 [95% CI 0.61-1.36]; P = 0.65). No intergroup variability was observed in NT-proBNP values and 6-minute walk test results at index hospitalization discharge and at 6-month follow-up. However, AR_1 patients were more likely to remain in NYHA class III and had worse right ventricular function at 6-month follow-up. Lack of aortic valve opening was related to de-novo or worsening AR (P < 0.001), irrespective of systolic blood pressure (P = 0.67). Patients commonly experience de-novo or worsening AR when exposed to continuous flow of contemporary LVADs. While reducing effective forward flow, worsening AR did not influence survival. However, less complete functional recovery and worse RV performance among AR_1 patients were observed. Lack of aortic valve opening was associated with progressive AR.

Acetazolamide in Decompensated Heart Failure with Volume Overload trial (ADVOR): baseline characteristics.

AIMS: To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with other contemporary diuretic trials in acute heart failure (AHF). METHODS AND RESULTS: ADVOR recruited 519 patients with AHF, clinically evident volume overload, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) and maintenance loop diuretic therapy prior to admission. All participants received standardized loop diuretics and were randomized towards once daily intravenous acetazolamide (500 mg) versus placebo, stratified according to study centre and left ventricular ejection fraction (LVEF) (≤40% vs. >40%). The primary endpoint was successful decongestion assessed by a dedicated score indicating no more than trace oedema and no other signs of congestion after three consecutive days of treatment without need for escalating treatment. Mean age was 78 years, 63% were men, mean LVEF was 43%, and median NT-proBNP 6173 pg/ml. The median clinical congestion score was 4 with an EuroQol-5 dimensions health utility index of 0.6. Patients with LVEF ≤40% were more often male, had more ischaemic heart disease, higher levels of NT-proBNP and less atrial fibrillation. Compared with diuretic trials in AHF, patients enrolled in ADVOR were considerably older with higher NT-proBNP levels, reflecting the real-world clinical situation. CONCLUSION: ADVOR is the largest randomized diuretic trial in AHF, investigating acetazolamide to improve decongestion on top of standardized loop diuretics. The elderly enrolled population with poor quality of life provides a good representation of the real-world AHF population. The pragmatic design will provide novel insights in the diuretic treatment of patients with AHF.

Improved survival of left ventricular assist device carriers in Europe according to implantation eras: results from the PCHF-VAD registry.

AIMS: Temporal changes in patient selection and major technological developments have occurred in the field of left ventricular assist devices (LVADs), yet analyses depicting this trend are lacking for Europe. We describe the advances of European LVAD programmes from the PCHF-VAD registry across device implantation eras. METHODS AND RESULTS: Of 583 patients from 13 European centres in the registry, 556 patients (mean age 53 ± 12 years, 82% male) were eligible for this analysis. Patients were divided into eras (E) by date of LVAD implantation: E1 from December 2006 to December 2012 (6 years), E2 from January 2013 to January 2020 (7 years). Patients implanted more recently were older with more comorbidities, but less acutely ill. Receiving an LVAD in E2 was associated with improved 1-year survival in adjusted analysis (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.35-0.98; p = 0.043). LVAD implantation in E2 was associated with a significantly lower chance of heart transplantation (adjusted HR 0.40, 95% CI 0.23-0.67; p = 0.001), and lower risk of LVAD-related infections (adjusted HR 0.64, 95% CI 0.43-0.95; p = 0.027), both in unadjusted and adjusted analyses. The adjusted risk of haemocompatibility-related events decreased (HR 0.60, 95% CI 0.39-0.91; p = 0.016), while heart failure-related events increased in E2 (HR 1.67, 95% CI 1.02-2.75; p = 0.043). CONCLUSION: In an analysis depicting the evolving landscape of continuous-flow LVAD carriers in Europe over 13 years, a trend towards better survival was seen in recent years, despite older recipients with more comorbidities, potentially attributable to increasing expertise of LVAD centres, improved patient selection and pump technology. However, a smaller chance of undergoing heart transplantation was noted in the second era, underscoring the relevance of improved outcomes on LVAD support.

Impaired biventricular contractile reserve in patients with diastolic dysfunction: insights from exercise stress echocardiography.

AIMS: Cardiac output limitation is a fundamental feature of heart failure with preserved ejection fraction (HFpEF) but the relative contribution of its determinants in symptomatic vs. asymptomatic stages are not well characterized. We aimed to gain insight into disease mechanisms by performing comprehensive comparative non-invasive exercise imaging in patients across the disease spectrum. METHODS AND RESULTS: We performed bicycle stress echocardiography in 10 healthy controls, 13 patients with hypertensive left ventricular (LV) concentric remodelling and asymptomatic diastolic dysfunction (HTDD), 15 HFpEF patients, and 15 subjects with isolated right ventricular (RV) dysfunction secondary to chronic thromboembolic pulmonary hypertension (CTEPH). During exercise, ventricular performance differed across the groups (all P ≤ 0.01 for interaction). Notably in controls, LV and RV function significantly increased (all P < 0.05) while both LV systolic and diastolic reserve were significantly reduced in HFpEF patients. Likewise, RV systolic reserve was also impaired in HFpEF but not to the extent of CTEPH patients (P < 0.001 between groups). HTDD patients behaved as an intermediary group with borderline LV systolic and diastolic reserve and reduced RV systolic reserve. The increased pulmonary vascular (PV) load in HFpEF and CTEPH patients in combination with impaired RV reserve resulted in RV-pulmonary artery uncoupling during exercise. CONCLUSION: The multifaceted decline of cardiac and PV function accompanying disease progression in HFpEF is unmasked by exercise and already emerges in preclinical disease. The revelation of these subtle abnormalities during exercise illustrates the benefit of exercise imaging and creates new prospects for early diagnosis and management.

Long-term evolution of N-terminal pro-brain natriuretic peptide levels and exercise capacity in 132 left ventricular assist device recipients.

OBJECTIVES: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a widely used biomarker in clinical practice in the context of heart failure. Little is known about the long-term evolution of NT-proBNP levels in left ventricular assist device (LVAD) recipients. Besides this, the potential correlation of NT-proBNP with exercise capacity on the long term after LVAD implantation has not been previously studied. METHODS: We retrospectively analysed 132 single-centre LVAD recipient records (HeartMate II/III; HeartWare; between March 2007 and January 2018; mean follow-up 559 days). Blood samples, 6-min walking test (6MWT) and maximal cardiopulmonary exercise test were performed in a standardized way. RESULTS: Pre-LVAD NT-proBNP levels were increased (9736 ± 1072 ng/l) and dropped significantly after implantation [14 days: 4360 ± 545 ng/l (P < 0.0001), 6 months: 1485 ± 139 ng/l (P < 0.0001)]. Afterwards a steady state was reached during follow-up (after 1 year: 1592 ± 214 ng/l, after 5 years: 1679 ± 311 ng/l). Submaximal exercise capacity significantly improved postoperatively [percentage of the predicted distance walked during the 6MWT 50 ± 2% (0-3 months); 61 ± 2% (3-6 months, P < 0.001)], with a steady state afterwards [66 ± 2% (6-12 months, P = 0.08); 64 ± 3%, P = 0.70 later on]. We found a gradual increment of percentage of the expected peak oxygen consumption postoperatively [44 ± 2% (0-3 months); 49 ± 2% (3-6 months); 52 ± 2% (6-12 months); 53 ± 1% (after 12 months)] with a significant improvement between 0 and 3 months versus after the first year on LVAD. Furthermore, we showed a significant moderate correlation between NT-proBNP levels and results at both the 6MWT (correlation coefficient: -0.31, P < 0.0001) and cardiopulmonary exercise testing (correlation coefficient: -0.28, P < 0.0001). CONCLUSIONS: NT-proBNP decreased on LVAD support. We showed that submaximal (6MWT) and maximal exercise capacity (cardiopulmonary exercise testing) improve after LVAD implantation and demonstrated an inverse correlation of both tests with NT-proBNP levels.

Machine learning optimization of an electronic health record audit for heart failure in primary care.

AIMS: The diagnosis of heart failure (HF) is an important problem in primary care. We previously demonstrated a 74% increase in registered HF diagnoses in primary care electronic health records (EHRs) following an extended audit procedure. What remains unclear is the accuracy of registered HF pre-audit and which EHR variables are most important in the extended audit strategy. This study aims to describe the diagnostic HF classification sequence at different stages, assess general practitioner (GP) HF misclassification, and test the predictive performance of an optimized audit. METHODS AND RESULTS: This is a secondary analysis of the OSCAR-HF study, a prospective observational trial including 51 participating GPs. OSCAR used an extended audit based on typical HF risk factors, signs, symptoms, and medications in GPs' EHR. This resulted in a list of possible HF patients, which participating GPs had to classify as HF or non-HF. We compared registered HF diagnoses before and after GPs' assessment. For our analysis of audit performance, we used GPs' assessment of HF as primary outcome and audit queries as dichotomous predictor variables for a gradient boosted machine (GBM) decision tree algorithm and logistic regression model. Of the 18 011 patients eligible for the audit intervention, 4678 (26.0%) were identified as possible HF patients and submitted for GPs' assessment in the audit stage. There were 310 patients with registered HF before GP assessment, of whom 146 (47.1%) were judged not to have HF by their GP (over-registration). There were 538 patients with registered HF after GP assessment, of whom 374 (69.5%) did not have registered HF before GP assessment (under-registration). The GBM and logistic regression model had a comparable predictive performance (area under the curve of 0.70 [95% confidence interval 0.65-0.77] and 0.69 [95% confidence interval 0.64-0.75], respectively). This was not significantly impacted by reducing the set of predictor variables to the 10 most important variables identified in the GBM model (free-text and coded cardiomyopathy, ischaemic heart disease and atrial fibrillation, digoxin, mineralocorticoid receptor antagonists, and combinations of renin-angiotensin system inhibitors and beta-blockers with diuretics). This optimized query set was enough to identify 86% (n = 461/538) of GPs' self-assessed HF population with a 33% reduction (n = 1537/4678) in screening caseload. CONCLUSIONS: Diagnostic coding of HF in primary care health records is inaccurate with a high degree of under-registration and over-registration. An optimized query set enabled identification of more than 80% of GPs' self-assessed HF population.

Speckle-tracking-based global longitudinal and circumferential strain detect early signs of antibody-mediated rejection in heart transplant patients.

AIMS: Acute rejection is an important cause of mortality after heart transplant (HTx), but symptoms develop only when myocardial damage is already extensive. We sought to investigate if echocardiographic parameters can detect and predict an acute cellular rejection (ACR) or antibody-mediated rejection (AMR) episode in HTx patients. METHODS AND RESULTS: Data of 403 consecutive HTx recipients between 2003 and 2020 from our centre were reviewed. Patients with severe ACR (n = 10) and AMR (n = 7) were identified. Each HTx patient presenting with rejection was matched to a control HTx patient. Echocardiographic variables from the moment of rejection and 3, 6, and 12 months before were analysed and compared among groups. At acute rejection episode, patients with rejection had lower values of global longitudinal strain (GLS), global circumferential strain (GCS), and left ventricular ejection fraction (LVEF) compared to controls. HTx patients with AMR showed a progressive decline of GLS and GCS in the months preceding acute rejection, while controls and ACR patients had stable strain values except for the moment of rejection. In our cohort, a GLS cut-off lower than 15.5% and a GCS cut-off lower than 15.2% could distinguish with a sensitivity and specificity of 100.0% AMR from controls 3 months before rejection. LVEF and other conventional echo parameters could not differentiate among groups. CONCLUSION: GLS and GCS show a progressive decrease months before AMR becomes clinically apparent. Our data suggest that global strain assessment by echocardiography allows an early detection of a developing AMR, which could improve the clinical management of HTx patients.

Potential of Medical Management to Mitigate Suction Events in Ventricular Assist Device Patients.

Ventricular suction is a common adverse event in ventricular assist device (VAD) patients and can be due to multiple underlying causes. The aim of this study is to analyze the potential of different therapeutic interventions to mitigate suction events induced by different pathophysiological conditions. To do so, a suction module was embedded in a cardiovascular hybrid (hydraulic-computational) simulator reproducing the entire cardiovascular system. An HVAD system (Medtronic) was connected between a compliant ventricular apex and a simulated aorta. Starting from a patient profile with severe dilated cardiomyopathy, four different pathophysiological conditions leading to suction were simulated: hypovolemia (blood volume: -900 ml), right ventricular failure (contractility -70%), hypotension (systemic vascular resistance: 8.3 Wood Units), and tachycardia (heart rate:185 bpm). Different therapeutic interventions such as volume infusion, ventricular contractility increase, vasoconstriction, heart rate increase, and pump speed reduction were simulated. Their effects were compared in terms of general hemodynamics and suction mitigation. Each intervention elicited a different effect on the hemodynamics for every pathophysiological condition. Pump speed reduction mitigated suction but did not ameliorate the hemodynamics. Administering volume and inducing a systemic vasoconstriction were the most efficient interventions in both improving the hemodynamics and mitigating suction. When simulating volume infusion, the cardiac powers increased, respectively, by 38%, 25%, 42%, and 43% in the case of hypovolemia, right ventricular failure, hypotension, and tachycardia. Finally, a management algorithm is proposed to identify a therapeutic intervention suited for the underlying physiologic condition causing suction.

Exercise capacity, muscle strength and objectively measured physical activity in patients after heart transplantation.

Maximal exercise capacity of patients after heart transplantation (HTX) remains limited, affecting their quality of life. Evidence on the evolution of muscle strength and physical activity (PA) post-HTX is lacking, but a prerequisite to tailor cardiac rehabilitation programmes. Forty-five consecutive patients were evaluated every 3 months during the first year post-HTX. Functional exercise capacity (Six minutes walking distance test (6MWD)), peripheral (Quadriceps strength (QF)) and respiratory (Maximal inspiratory strength (MIP)) muscle strength were evaluated. PA (number of steps (PAsteps), active time (PAactive) and sedentary time (PAsed)) was objectively measured. 6MWD, QF, MIP, PAsteps and PAactive significantly improved over time (P < 0.001). No change in PAsed was noticed (P = 0.129). Despite improvements in 6MWD and QF, results remained substantially below those of age-and gender-matched healthy subjects. One year post-HTX, 30% of patients presented with peripheral muscle weakness. Baseline levels of 6MWD and QF were significantly higher in patients with pretransplant LVAD-implantation and this difference was maintained during follow-up. cardiac rehabilitation, combining aerobic exercise training and peripheral muscle strength training, is mandatory in patients post-HTX. Inspiratory muscle training should be implemented when respiratory muscle weakness is present. Programmes improving physical activity and reducing sedentary time post-HTX are essential.

Right ventricular and cyclic guanosine monophosphate signalling abnormalities in stages B and C of heart failure with preserved ejection fraction.

AIMS: Identifying early right ventricular (RV) dysfunction and impaired vasodilator reserve is challenging in heart failure with preserved ejection fraction (HFpEF). We hypothesized that cardiac magnetic resonance (CMR)-based exercise imaging and serial cyclic guanosine monophosphate (cGMP) measurements can identify dynamic RV-arterial uncoupling and responsiveness to pulmonary vasodilators at early stages of the HFpEF syndrome. METHODS AND RESULTS: Patients with HFpEF (n = 16), impaired left ventricular relaxation due to concentric remodelling (LVCR, n = 7), and healthy controls (n = 8) underwent CMR at rest and during supine bicycle exercise with simultaneous measurements of central haemodynamics and circulating cGMP levels, before and after oral administration of 50 mg sildenafil. At rest, mean pulmonary artery pressures (mPAP) were higher in HFpEF, compared with LVCR and controls (27 ± 2, 18 ± 1, and 11 ± 1, respectively; P = 0.01), whereas biventricular volumes, heart rate, and stroke volume were similar. During exercise, LVCR and HFpEF had a greater increase in the ratio of mPAP over cardiac output than controls (5.50 ± 0.77 and 6.34 ± 0.86 vs. 2.24 ± 0.55 in controls, P = 0.005). The ratio of peak exercise to rest RV end-systolic pressure-volume, a surrogate of RV contractility, was significantly reduced in LVCR and HFpEF (2.32 ± 0.17 and 1.56 ± 0.08 vs. 3.49 ± 0.35 in controls, P < 0.001) and correlated with peak exercise VO2 (R2  = 0.648, P < 0.001). cGMP levels increased with exercise across the HFpEF spectrum (P < 0.05 vs. baseline), except when postcapillary pulmonary hypertension was present at rest (P = 0.73 vs. baseline). A single sildenafil administration failed to increase circulating cGMP levels and did not improve RV performance. CONCLUSION: Exercise CMR identifies impaired RV-arterial coupling at an early stage of HFpEF. Circulating cGMP levels phenocopy the haemodynamic spectrum in HFpEF but fail to increase after phosphodiesterase type 5 inhibition, endorsing the need for alternative interventions to increase cGMP signalling in HFpEF.

Heart failure related to adult congenital heart disease: prevalence, outcome and risk factors.

AIMS: Information on the prevalence, outcome and factors associated with heart failure in patients with adult congenital heart disease (CHD) (ACHD-HF) is lacking. We aimed at assessing the prevalence and outcome of ACHD-HF, the variables associated with ACHD-HF, and the differences between major anatomical/pathophysiological ACHD subgroups. METHODS AND RESULTS: We included 3905 patients (age 35.4 ± 13.2 years) under active follow-up in our institution (last visit >2010). Outcome of ACHD-HF cases was compared with sex- and age-matched cases. Univariable and multivariable binary logistic regression with ACHD-HF diagnosis as a dependent variable was performed. Overall prevalence of ACHD-HF was 6.4% (mean age 49.5 ± 16.7 years), but was higher in patients with cyanotic CHD (41%), Fontan circulation (30%), and a systemic right ventricle (25%). All-cause mortality was higher in ACHD-HF cases when compared with controls (mortality rate ratio 4.67 (2.36-9.27); P = 0.0001). In multivariable logistic regression analysis, age at latest follow-up [per 10 years; odds ratio (OR) 1.52; 95% confidence interval (CI) 1.31-1.77], infective endocarditis (OR 4.11; 95%CI 1.80-9.38), history of atrial arrhythmia (OR 3.52; 95%CI 2.17-5.74), pacemaker implantation (OR 2.66; 95% CI 1.50-4.72), end-organ dysfunction (OR 2.41; 95% CI 1.03-5.63), New York Heart Association class (OR 9.28; 95% CI 6.04-14.25), heart rate (per 10 bpm; OR 1.27; 95% CI 1.08-1.50), ventricular dysfunction (OR 3.62; 95% CI 2.54-5.17), and pulmonary hypertension severity (OR 1.66; 95% CI 1.21-2.30) were independently related to the presence of ACHD-HF. Some variables (age, atrial arrhythmia, pacemaker, New York Heart Association, and ventricular dysfunction) were related to ACHD-HF in all anatomical/physiological subgroups, whereas others were not. CONCLUSIONS: ACHD-HF is prevalent especially in complex CHD and is associated with poor prognosis. Our data provide insight in the factors related to ACHD-HF including differences between specific anatomical and physiological subgroups.