Circadian rhythms in pump parameters of patients on contemporary left ventricular assist device support.

BACKGROUND: Algorithms to monitor pump parameters are needed to further improve outcomes after left ventricular assist device (LVAD) implantation. Previous research showed a restored circadian rhythm in pump parameters in patients on HeartWare (HVAD) support. Circadian patterns in HeartMate3 (HM3) were not studied before, but this is important for the development of LVAD monitoring algorithms. Hence, we aimed to describe circadian patterns in HM3 parameters and their relation to patterns in heart rate (HR). METHODS: 18 HM3 patients were included in this study. HM3 data were retrieved at a high frequency (one sample per 1 or 2 h) for 1-2 weeks. HR was measured using a wearable biosensor. To study overall patterns in HM3 parameters and HR, a heatmap was created. A 24-h cosine was fitted on power and HR separately. The relationship between the amplitude of the fitted cosines of power and HR was calculated using Spearman correlation. RESULTS: A lower between patient variability was found in power compared with flow and PI. 83% of the patients showed a significant circadian rhythmicity in power (p < 0.001-0.04), with a clear morning increase. All patients showed significant circadian rhythmicity in HR (p < 0.001-0.02). The amplitudes of the circadian rhythm in power and HR were not correlated (Spearman correlation of 0.32, p = 0.19). CONCLUSIONS: A circadian rhythm of pump parameters is present in the majority of HM3 patients. Higher frequency pump parameter data should be collected, to enable early detection of complications in the future development of predictive algorithms.

Yield of family screening in dilated cardiomyopathy within low-income setting: Tanzanian experience.

BACKGROUND: Dilated cardiomyopathy (DCM) is often familial and screening of relatives is recommended. However, studies on the yield of screening are scarce in developing countries. AIM: The aim of the study was to identify and characterise First-degree relatives of patients with DCM in Tanzania. METHODS: We recruited first-degree relatives of 57 DCM patients. DCM in the relatives was diagnosed using the 2016 revised definition by the European Society of Cardiology working group on myocardial and pericardial diseases. RESULTS: We screened 120 first-degree relatives. All were asymptomatic (100%) with a median age of 39.0 years (29.5-49.0), slightly over a half (53.3%) were females and 17 (14.1%) were found to have previously unknown DCM. The mean (± SD) indexed left ventricular end-diastolic volume was significantly higher in relatives with DCM (71 ± 11.5 ml) compared to relatives without DCM (50 ± 11.5) (p = 0.001). CONCLUSION: First-degree relatives of patients with DCM are at risk of developing asymptomatic DCM at a young age.

Risk Factors and Prevalence of Dilated Cardiomyopathy in Sub-Saharan Africa: A Systematic Review.

Highlights  Prevalence of DCM varies widely in SSA.Cardiovascular risk factors are important in patients with DCM.The role of genetics in idiopathic DCM is not studied in major part of SSA.

Characteristics and outcomes of COVID-19 in heart transplantation recipients in the Netherlands.

BACKGROUND: Immunocompromised patients are at high risk of complicated severe acute respiratory coronavirus 2 infection. The aim of this retrospective study was to describe the characteristics and outcomes of heart transplantation (HTx) recipients with coronavirus disease 2019 (COVID-19) in the Netherlands. METHODS: HTx patients from one of the three HTx centres in the Netherlands with COVID-19 (proven by positive reverse-transcription polymerase chain reaction or serology test result) between February 2020 and June 2021 were included. The primary endpoint was all-cause mortality and the secondary endpoint was disease severity. RESULTS: COVID-19 was diagnosed in 54/665 HTx patients (8%), with a mean (±â€¯standard deviation (SD)) time after HTx of 11 ± 8 years. Mean (±â€¯SD) age was 53 ± 14 years and 39% were female. Immunosuppressive therapy dosage was reduced in 37% patients (20/54). Hospitalisation was required in 39% patients (21/54), and 13% patients (7/54) had severe COVID-19 (leading to intensive care unit (ICU) admission or death). In-hospital mortality was 14% (3/21), and all-cause mortality was 6%. Compared with patients with moderate COVID-19 (hospitalised without ICU indication), severe COVID-19 patients tended to be transplanted earlier and had a significantly higher mean (±â€¯SD) body mass index (26 ± 3 vs 30 ± 3 kg/m2, p = 0.01). Myocardial infarction, cellular rejection and pulmonary embolism were observed once in three different HTx patients. CONCLUSION: HTx patients were at increased risk of complicated COVID-19 with frequent hospitalisation, but the all-cause mortality was substantially lower than previously described (7-33%).

Initiation of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock during out of hours versus working hours is not associated with increased mortality.

BACKGROUND: Initiation of veno-arterial (VA) Extracorporeal Membrane Oxygenator (ECMO) is associated with severe complications. It is unknown whether these adverse consequences occur more often after initiations during out of hours service compared to working hours. METHODS: All patients receiving VA-ECMO for cardiogenic shock between 2009 and 2020 were categorized into a working hours group (between 8 am and 5 pm on weekdays) and an out of hours service group (between 5 pm and 8 am, or between Friday 5 pm and Monday 8 am). Primary outcome was all-cause mortality at 30 days. Secondary outcomes included vascular complications (including limb ischemia and/or bleeding), bloodstream infections and length of ICU stay. Propensity scores were used to adjust for potential confounding effects. RESULTS: Among 250 patients (median (IQR) age 56 (42-64) years) receiving VA-ECMO (median duration 3.5 (1.0-9.0) days), 160 (64%) runs were initiated between 5 pm and 8 am whereas the remainder (36%) started during working hours. Characteristic did not differ between the working hours- and out of hours-group. By day 30, 37 (41.1%), and 68 (42.5%) patients in either group had died, respectively (p = 0.831). VA-ECMO support duration and length of stay on the ICU did not differ significantly in both crude and adjusted analyses. More complications occurred during out of hours service (p = 0.039). CONCLUSIONS: Out of hours- versus working hours-initiation of VA-ECMO for cardiogenic shock was not associated with higher mortality, longer VA-ECMO support duration, or longer length of stay on the intensive care. Vascular complications were more common in the out of hours group.

Listing criteria for heart transplantation in the Netherlands.

The updated listing criteria for heart transplantation are presented on behalf of the three heart transplant centres in the Netherlands. Given the shortage of donor hearts, selection of those patients who may expect to have the greatest benefit from a scarce societal resource in terms of life expectancy and quality of life is inevitable. The indication for heart transplantation includes end-stage heart disease not remediable by more conservative measures, accompanied by severe physical limitation while on optimal medical therapy, including ICD/CRT­D. Assessment of this condition requires cardiopulmonary stress testing, prognostic stratification and invasive haemodynamic measurements. Timely referral to a tertiary centre is essential for an optimal outcome. Chronic mechanical circulatory support is being used more and more as an alternative to heart transplantation and to bridge the progressively longer waiting time for heart transplantation and, thus, has become an important treatment option for patients with advanced heart failure.

Morning pulmonary artery pressure measurements by CardioMEMS are most stable and recommended for pressure trends monitoring.

AIMS: The CardioMEMS HF system is used to measure pulmonary artery (PA) pressures of patients with heart failure (HF). The goal of this study was to determine the impact of time in the daily PA pressure measurements, considering variance and influence of circadian rhythms on cardiovascular pathophysiology. METHODS AND RESULTS: The study included 10 patients with HF with reduced ejection fraction (LVEF < 40%; New York Heart Association class III). Individual daily PA pressures were obtained by CardioMEMS sensors, per protocol, measured up to six times throughout the day, for a period of 5 days. Differences between variation of morning versus evening PA pressures were compared with Wilcoxon signed-rank test. Mean PA pressures (mPAP) increased from a morning value of 19.1 ± 2 mm Hg (8 am; mean ± standard error of the mean [SEM]) to 21.3 ± 2 mm Hg late in the evening (11 pm; mean ± SEM). Over the course of 5 days, evening mPAP exhibited a significantly higher median coefficient of variation than morning mPAP (14.9 (interquartile range [IQR] 7.6-21.0) and 7.0 (IQR 5.0-12.8) respectively; p = 0.01). The same daily pattern of pressure variability was observed in diastolic (p = 0.01) and systolic (p = 0.04) pressures, with diastolic pressures being more variable than systolic at all time points. CONCLUSIONS: Morning PA pressure measurements yield more stable values for observing PA trends. Patients should thus be advised to consistently perform their daily PA pressure measurements early in the morning. This will improve reliability and interpretation of the CardioMEMS management, indicating true alterations in the patient's health status, rather than time-of-day-dependent variations.

Waiting list mortality and the potential of donation after circulatory death heart transplantations in the Netherlands.

BACKGROUND: With more patients qualifying for heart transplantation (HT) and fewer hearts being transplanted, it is vital to look for other options. To date, only organs from brain-dead donors have been used for HT in the Netherlands. We investigated waiting list mortality in all Dutch HT centres and the potential of donation after circulatory death (DCD) HT in the Netherlands. METHODS: Two different cohorts were evaluated. One cohort was defined as patients who were newly listed or were already on the waiting list for HT between January 2013 and December 2017. Follow-up continued until September 2018 and waiting list mortality was calculated. A second cohort of all DCD donors in the Netherlands (lung, liver, kidney and pancreas) between January 2013 and December 2017 was used to calculate the potential of DCD HT. RESULTS: Out of 395 patients on the waiting list for HT, 196 (50%) received transplants after a median waiting time of 2.6 years. In total, 15% died while on the waiting list before a suitable donor heart became available. We identified 1006 DCD donors. After applying exclusion criteria and an age limit of 50 years, 122 potential heart donors remained. This number increased to 220 when the age limit was extended to 57 years. CONCLUSION: Waiting list mortality in the Netherlands is high. HT using organs from DCD donors has great potential in the Netherlands and could lead to a reduction in waiting list mortality. Cardiac screening will eventually determine the true potential.

Outcome of mechanical circulatory support at the University Medical Centre Utrecht.

BACKGROUND: The prevalence of heart failure (HF) is increasing substantially and, despite improvements in medical therapy, HF still carries a poor prognosis. Mechanical circulatory support (MCS) by a continuous-flow left ventricular assist device (cf-LVAD) improves survival and quality of life in selected patients. This holds especially for the short-term outcome, but experience regarding long-term outcome is growing as the waiting time for heart transplantation is increasing due to the shortage of donor hearts. Here we present our results from the University Medical Centre Utrecht. METHODS: Data of all patients with a cf-LVAD implant between March 2006 and January 2018 were collected. The primary outcome was survival. Secondary outcomes included adverse events defined according to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definitions, described per patient year. RESULTS: A total of 268 patients (69% male, mean age 50 ± 13 years) received a cf-LVAD. After a median follow-up of 542 (interquartile range 205-1044) days, heart transplantation had been performed in 82 (31%) patients, the cf-LVAD had been explanted in 8 (3%) and 71 (26%) had died. Survival at 1, 3 and 5 years was 83%, 72% and 57%, respectively, with heart transplantation, cf-LVAD explantation or death as the end-point. Death was most often caused by neurological complications (31%) or infection (20%). Major bleeding occurred 0.51 times and stroke 0.15 times per patient year. CONCLUSION: Not only short-term results but also 5­year survival after cf-LVAD support demonstrate that MCS is a promising therapy as an extended bridge to heart transplantation. However, the incidence of several major complications still has to be addressed.

UNRAVEL: big data analytics research data platform to improve care of patients with cardiomyopathies using routine electronic health records and standardised biobanking.

INTRODUCTION: Despite major advances in our understanding of genetic cardiomyopathies, they remain the leading cause of premature sudden cardiac death and end-stage heart failure in persons under the age of 60 years. Integrated research databases based on a large number of patients may provide a scaffold for future research. Using routine electronic health records and standardised biobanking, big data analysis on a larger number of patients and investigations are possible. In this article, we describe the UNRAVEL research data platform embedded in routine practice to facilitate research in genetic cardiomyopathies. DESIGN: Eligible participants with proven or suspected cardiac disease and their relatives are asked for permission to use their data and to draw blood for biobanking. Routinely collected clinical data are included in a research database by weekly extraction. A text-mining tool has been developed to enrich UNRAVEL with unstructured data in clinical notes. PRELIMINARY RESULTS: Thus far, 828 individuals with a median age of 57 years have been included, 58% of whom are male. All data are captured in a temporal sequence amounting to a total of 18,565 electrocardiograms, 3619 echocardiograms, data from over 20,000 radiological examinations and 650,000 individual laboratory measurements. CONCLUSION: Integration of routine electronic health care in a research data platform allows efficient data collection, including all investigations in chronological sequence. Trials embedded in the electronic health record are now possible, providing cost-effective ways to answer clinical questions. We explicitly welcome national and international collaboration and have provided our protocols and other materials on www.unravelrdp.nl .

Suppression of T cells by mesenchymal and cardiac progenitor cells is partly mediated via extracellular vesicles.

Adverse remodeling after myocardial infarction (MI) is strongly influenced by T cells. Stem cell therapy after MI, using mesenchymal stem cells (MSC) or cardiomyocyte progenitor cells (CMPC), improved cardiac function, despite low cell retention and limited differentiation. As MSC secrete many factors affecting T cell proliferation and function, we hypothesized the immune response could be affected as one of the targets of stem cell therapy. Therefore, we studied the immunosuppressive properties of human BM-MSC and CMPC and their extracellular vesicles (EVs) in co-culture with activated T cells. Proliferation of T cells, measured by carboxyfluorescein succinimidyl ester dilution, was significantly reduced in the presence of BM-MSC and CMPC. The inflammatory cytokine panel of the T cells in co-culture, measured by Luminex assay, changed, with strong downregulation of IFN-gamma and TNF-alpha. The effect on proliferation was observed in both direct cell contact and transwell co-culture systems. Transfer of conditioned medium to unrelated T cells abrogated proliferation in these cells. EVs isolated from the conditioned medium of BM-MSC and CMPC prevented T cell proliferation in a dose-dependent fashion. Progenitor cells presence induces up- and downregulation of multiple previously unreported pathways in T cells. In conclusion, both BM-MSC and CMPC have a strong capacity for in vitro immunosuppression. This effect is mediated by paracrine factors, such as extracellular vesicles. Besides proliferation, many additional pathways are influenced by both BM-MSC and CMPC.

Extracellular matrix formation after transplantation of human embryonic stem cell-derived cardiomyocytes.

Transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CM) for cardiac regeneration is hampered by the formation of fibrotic tissue around the grafts, preventing electrophysiological coupling. Investigating this process, we found that: (1) beating hESC-CM in vitro are embedded in collagens, laminin and fibronectin, which they bind via appropriate integrins; (2) after transplantation into the mouse heart, hESC-CM continue to secrete collagen IV, XVIII and fibronectin; (3) integrin expression on hESC-CM largely matches the matrix type they encounter or secrete in vivo; (4) co-transplantation of hESC-derived endothelial cells and/or cardiac progenitors with hESC-CM results in the formation of functional capillaries; and (5) transplanted hESC-CM survive and mature in vivo for at least 24 weeks. These results form the basis of future developments aiming to reduce the adverse fibrotic reaction that currently complicates cell-based therapies for cardiac disease, and to provide an additional clue towards successful engraftment of cardiomyocytes by co-transplanting endothelial cells.

Usefulness and applicability of femorofemoral crossover bypass grafting.

We examined the usefulness of femorofemoral crossover bypass grafting (FFC) and factors influencing its outcome by retrospectively analyzing all FFCs performed in our hospital over a 5-year period, focusing on both patency rates and clinical efficacy. For 95 patients Kaplan-Meier patency rates were calculated (follow-up 40.4 +/- 3.0 months). Clinical outcome was defined according to Rutherford's standardized categories. The influence of cardiovascular risk factors and technical characteristics on outcome was determined. Clinical status of the limb remained improved in 89%. One- and 5-year primary, primary assisted, and secondary patency rates were 88.2% and 57.3%, 90.6% and 62.4%, and 92.6% and 68.1%, respectively. Clinical outcome of the limb was better in patients with <50% stenosis in the femoral arteries preoperatively (p = 0.033). No predictors for patency rates were identified. FFCs are effective in the medium long term for patients in all age categories independently of cardiovascular risk factors. The best predictor of clinical outcome is the preoperative degree of stenosis, with a better outcome for patients affected by <50% stenosis. Success of FFC cannot be reliably measured by graft patency alone but should be assessed by combining patency rates and clinical outcome according to standardized categories.

[Stress echocardiography in 11 patients with symptoms of ischemia and a myocardial bridge: no indication of a causal connection in 10 cases]. / Stressechocardiografie bij 11 patiënten met ischemische klachten en een myocardbrug: bij 10 geen aanwijzingen voor een causaal verband.

OBJECTIVE: To determine whether in patients with a myocardial bridge, systolic compression of the affected coronary branch may cause cardiac ischaemia and is of clinical relevance. DESIGN: Pilot inventory. METHOD: In 11 consecutive patients with an established myocardial bridge who presented with possible ischaemic symptoms angiographic dobutamine stress-echocardiography was used to visualize hypokinesia caused by ischaemia in the area ofmyocardium supplied by the bridged artery. RESULTS: Hypokinesia was observed in the area supplied by the bridged artery in one of the patients (9%). The symptoms in the other patients were not associated with the bridge. CONCLUSION: The clinical relevance of myocardial bridging appeared to be smaller than is generally assumed. In patients with known myocardial bridging and symptoms that could be caused by myocardial ischaemia, it should first be established that the bridge is actually causing the ischaemia before any therapeutic intervention aimed at the bridge is undertaken.

[Progress and clashes in stem cell therapy research]. / Vooruitgang en strubbelingen bij het onderzoek naar stamceltherapie.

The concept of stem cell therapy, the repair of damaged or diseased tissue by transplantation of healthy cells, is deceptively simple. This simplicity has led to the hype among desperate patients, their doctors and the media: it would seem that every ailment can be treated with stem cells. At this time, however, the scientific truth is mostly disappointing. The recent claim from Korea of a major breakthrough - the ability to grow stem cells from cloned embryos - turned out to be fraudulent. With the exception ofapplications in haematologic diseases, skin wounds, and bone and cartilage diseases, most of the putative therapeutic applications of stem cell therapy are still under preclinical investigation. These include the treatment of Parkinson's and Alzheimer's disease, paraplegia, cerebral infarction, amyotrophic lateral sclerosis, multiple sclerosis and muscular dystrophy. The treatment of cardiac infarction is currently being investigated in clinical trials.

Systemic dilation diathesis in patients with abdominal aortic aneurysms: a role for matrix metalloproteinase-9?

INTRODUCTION: Accumulating evidence suggests that patients with abdominal aortic aneurysm (AAA) suffer from a systemic dilating condition affecting all arteries. Matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), appear to be involved in aneurysm formation, as evidenced by increased aortic tissue MMP activity and plasma MMP levels in patients with AAA. Hypothesizing that an imbalance in plasma MMP/TIMP level might be associated with a systemic dilation diathesis, we studied mechanical vessel wall properties of non-affected arteries of patients with either AAA or aorto-iliac obstructive lesions in association with plasma MMP-9 and TIMP-1 levels. METHODS: Twenty-two patients with AAA and 12 with aorto-iliac occlusive disease (AOD) were included. Diastolic diameter (d) and distension (Deltad) were measured at the level of the common carotid artery (CCA) and suprarenal aorta (SA) using ultrasonography. Distensibility (DC) and compliance (CC) were calculated from d, Deltad and brachial pulse pressure. Plasma MMP-9 and TIMP-1 were determined with specific immunoassays. RESULTS: The average (+/-SD) age was 72.3+/-5.6 and 65.0+/-8.2 years for the AAA and AOD patients, respectively, (P=0.005). CCA diameter was 9.1+/-1.3mm in AAA patients and AOD 7.8+/-1.4mm in AOD patients, P=0.009. This difference persisted after correction for age. Plasma MMP-9 and TIMP-1 did not differ significantly between AAA and AOD patients. In the total 34 patients, the MMP-9/TIMP-1 ratio was correlated inversely with distensibility (r=-0.74, P=0.002) and to compliance (r=-0.58, P=0.024) of the suprarenal aorta. CONCLUSIONS: The CCA diameter was larger in AAA patients compared to AOD patients. MMP-9/TIMP-1 ratio was associated with decreased distensibility and compliance of the suprarenal aorta. These data support the idea that AAA patients exhibit a systemic dilation diathesis, which might be attributable to MMP/TIMP imbalances.