Pulmonary artery pressure monitoring in chronic heart failure: effects across clinically relevant subgroups in the MONITOR-HF trial.

BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronisation therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life, clinical, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were nonsignificant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = 0.03; adjusted Pinteraction = 0.33) and diabetics (Pinteraction = 0.01; adjusted Pinteraction = 0.06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.

Angiographic and Clinical Profile of Patients With COVID-19 Referred for Coronary Angiography During SARS-CoV-2 Outbreak: Results From a Collaborative, European, Multicenter Registry.

Data regarding angiographic characteristics, clinical profile, and inhospital outcomes of patients with coronavirus disease 2019 (COVID-19) referred for coronary angiography (CAG) are scarce. This is an observational study analyzing confirmed patients with COVID-19 referred for CAG from 10 European centers. We included 57 patients (mean age: 66 ± 15 years, 82% male) , of whom 18% had previous myocardial infarction (MI) and 29% had renal insufficiency and chronic pulmonary disease. ST-segment elevation myocardial infarction (STEMI) was the most frequent indication for CAG (58%). Coronavirus disease 2019 was confirmed after CAG in 86% and classified as mild in 49%, with 21% fully asymptomatic. A culprit lesion was identified in 79% and high thrombus burden in 42%; 7% had stent thrombosis. At 40 days follow-up, 16 (28%) patients experienced a major adverse cardiovascular event (MACE): 12 deaths (92% noncardiac), 1 MI, 2 stent thrombosis, and 1 stroke. In an European multicenter registry, patients with confirmed COVID-19 infection referred for CAG during the first wave of the severe acute respiratory syndrome coronavirus 2 pandemic presented mostly with STEMI and were predominantly males with comorbidities. Severity of COVID-19 was in general noncritical and 21% were asymptomatic at the time of CAG. Culprit coronary lesions with high thrombus burden were frequently identified, with a rate of stent thrombosis of 7%. The incidence of MACE at 40 days was high (28%), mostly due to noncardiac death.

Connected care for endocarditis and heart failure patients: a hospital-at-home programme.

BACKGROUND: Healthcare expenditure in the Netherlands is increasing at such a rate that currently 1 in 7 employees are working in healthcare/curative care. Future increases in healthcare spending will be restricted, given that 10% of the country's gross domestic product is spent on healthcare and the fact that there is a workforce shortage. Dutch healthcare consists of a curative sector (mostly hospitals) and nursing care at home. The two entities have separate national budgets (€25 bn + €20 bn respectively) AIM: In a proof of concept, we explored a new hospital-at-home model combining hospital cure and nursing home care budgets. This study tests the feasibility of (1) providing hospital care at home, (2) combining financial budgets, (3) increasing workforces by combining teams and (4) improving perspectives and increasing patient and staff satisfaction. RESULTS: We tested the feasibility of combining the budgets of a teaching hospital and home care group for cardiology. The budgets were sufficient to hire three nurse practitioners who were trained to work together with 12 home care cardiovascular nurses to provide care in a hospital-at-home setting, including intravenous treatment. Subsequently, the hospital-at-home programme for endocarditis and heart failure treatment was developed and a virtual ward was built within the e­patient record. CONCLUSION: The current model demonstrates a proof of concept for a hospital-at-home programme providing hospital-level curative care at home by merging hospital and home care nursing staff and budgets. From the clinical perspective, ambulatory intravenous antibiotic and diuretic treatment at home was effective in safely achieving a reduced length of stay of 847 days in endocarditis patients and 201 days in heart-failure-at-home patients. We call for further studies to facilitate combined home care and hospital cure budgets in cardiology to confirm this concept.

Measuring Activated Clotting Time during Cardiac Catheterization and PCI: The Effect of the Sampling Site.

RESULTS: In 100 patients (mean age 67.1, 65% male), no significant differences were observed in ACT values obtained from the guiding catheter and arterial sheath (mean difference (MD) -18.3 s; standard deviation (SD) 96 s; P=0.067). Contrarily, ACT values obtained from the intravenous line were significantly lower as compared to values obtained from the guiding catheter (MD 25.7 s; SD 75.5; P=0.003) and arterial sheath (MD 39 s; SD 102.8; P < 0.001). Furthermore, ACT measurements from the arterial sheath showed a statistically significant proportional bias when compared to the other sampling sites (sheath vs. catheter, r = 0.761, P=0.001; sheath vs. IVL, r = 1.013, P < 0.001). CONCLUSIONS: The present study shows statistical significance and possibly clinically relevant variations between ACT measurements from different sample sites. Bias in ACT measurements may be minimized by using uniform protocols for ACT measurement during cardiac catheterization.

Sex-specific temporal evolution of circulating biomarkers in patients with chronic heart failure with reduced ejection fraction.

BACKGROUND: We aimed to assess differences in clinical characteristics, prognosis, and the temporal evolution of circulating biomarkers in male and female patients with HFrEF. METHODS: We included 250 patients (66 women) with chronic heart failure (CHF) between 2011 and 2013 and performed trimonthly blood sampling during a median follow-up of 2.2 years [median (IQR) of 8 (5-10) urine and 9 (5-10) plasma samples per patient]. After completion of follow-up we measured 8 biomarkers. The primary endpoint (PE) was the composite of cardiac death, cardiac transplantation, left ventricular assist device implantation, and hospitalization due to acute or worsened CHF. Joint models were used to determine whether there were differences in the temporal patterns of the biomarkers between men and women as the PE approached. RESULTS: A total of 66 patients reached the PE of which 52 (78.8%) were male and 14 (21.2%) were female. The temporal patterns of all studied biomarkers were associated with the PE, and overall showed disadvantageous changes as the PE approached. For NT-proBNP, HsTnT, and CRP, women showed higher levels over the entire follow-up duration and concomitant numerically higher hazard ratios [NT-proBNP: women: HR(95%CI) 7.57 (3.17-21.93), men: HR(95%CI) 3.14 (2.09-4.79), p for interaction = 0.104, HsTnT: women: HR(95%CI) 6.38 (2.18-22.46), men: HR(95%CI) 4.91 (2.58-9.39), p for interaction = 0.704, CRP: women: HR(95%CI) 7.48 (3.43-19.53), men: HR(95%CI) 3.29 [2.27-5.44], p for interaction = 0.106). In contrast, temporal patterns of glomerular and tubular renal markers showed similar associations with the PE in men and women. CONCLUSION: Although interaction terms are not statistically significant, the associations of temporal patterns of NT-proBNP, HsTnT, and CRP appear more outspoken in women than in men with HFrEF, whereas associations seem similar for temporal patterns of creatinine, eGFR, Cystatin C, KIM-1 and NAG. Larger studies are needed to confirm these potential sex differences.

A randomised comparison of the effect of haemodynamic monitoring with CardioMEMS in addition to standard care on quality of life and hospitalisations in patients with chronic heart failure : Design and rationale of the MONITOR HF multicentre randomised clinical trial.

BACKGROUND: Assessing haemodynamic congestion based on filling pressures instead of clinical congestion can be a way to further improve quality of life (QoL) and clinical outcome by intervening before symptoms or weight gain occur in heart failure (HF) patients. The clinical efficacy of remote monitoring of pulmonary artery (PA) pressures (CardioMEMS; Abbott Inc., Atlanta, GA, USA) has been demonstrated in the USA. Currently, the PA sensor is not reimbursed in the European Union as its benefit when applied in addition to standard HF care is unknown in Western European countries, including the Netherlands. AIMS: To demonstrate the efficacy and cost-effectiveness of haemodynamic PA monitoring in addition to contemporary standard HF care in a high-quality Western European health care system. METHODS: The current study is a prospective, multi-centre, randomised clinical trial in 340 patients with chronic HF (New York Heart Association functional class III) randomised to HF care including remote monitoring with the CardioMEMS PA sensor or standard HF care alone. Eligible patients have at least one hospitalisation for HF in 12 months before enrolment and will be randomised in a 1:1 ratio. Minimum follow-up will be 1 year. The primary endpoint is the change in QoL as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Secondary endpoints are the number of HF hospital admissions and changes in health status assessed by EQ-5D-5L questionnaire including health care utilisation and formal cost-effectiveness analysis. CONCLUSION: The MONITOR HF trial will evaluate the efficacy and cost-effectiveness of haemodynamic monitoring by CardioMEMS in addition to standard HF care in patients with chronic HF. Clinical Trial Registration number NTR7672.

Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

BACKGROUND: It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia. METHODS AND RESULTS: This multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P = 0.47 and P = 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P = 0.54 at 3­month and P = 0.15 at 12-month follow-up). CONCLUSION: Intramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia. CLINICAL TRIAL REGISTRATION: NTR2516.

Appropriate use criteria for optical coherence tomography guidance in percutaneous coronary interventions : Recommendations of the working group of interventional cardiology of the Netherlands Society of Cardiology.

INTRODUCTION: Optical coherence tomography (OCT) enables detailed imaging of the coronary wall, lumen and intracoronary implanted devices. Responding to the lack of specific appropriate use criteria (AUC) for this technique, we conducted a literature review and a procedure for appropriate use criteria. METHODS: Twenty-one of all 184 members of the Dutch Working Group on Interventional Cardiology agreed to evaluate 49 pre-specified cases. During a meeting, factual indications were established whereupon members individually rated indications on a 9-point scale, with the opportunity to substantiate their scoring. RESULTS: Twenty-six indications were rated 'Appropriate', eighteen indications 'May be appropriate', and five 'Rarely appropriate'. Use of OCT was unanimously considered 'Appropriate' in stent thrombosis, and 'Appropriate' for guidance in PCI, especially in distal left main coronary artery and proximal left anterior descending coronary artery, unexplained angiographic abnormalities, and use of bioresorbable vascular scaffold (BVS). OCT was considered 'Rarely Appropriate' on top of fractional flow reserve (FFR) for treatment indication, assessment of strut coverage, bypass anastomoses or assessment of proximal left main coronary artery. CONCLUSIONS: The use of OCT in stent thrombosis is unanimously considered 'Appropriate' by these experts. Varying degrees of consensus exists on the appropriate use of OCT in other settings.

Effect of intramyocardial bone marrow cell injection on left ventricular dyssynchrony and global strain.

OBJECTIVE: To evaluate the effect of bone marrow cell injection on global strain and left ventricular (LV) dyssynchrony. METHODS: In 14 patients with severe postinfarction heart failure, 93 (14) x 10(6) autologous bone marrow cells were percutaneously injected in the infarction border zone. LV ejection fraction (LVEF), LV dyssynchrony and echocardiographic global strain were assessed at baseline and 3 months in patients and in a non-randomised control group of 10 patients with a history of infarction who developed heart failure and were treated medically. RESULTS: No periprocedural complications occurred during bone marrow cell injection. At 3 months mean (SD) LVEF increased from 23 (8)% to 27 (9)% (p = 0.02) and global strain improved from -7.7 (4.7)% to -8.5 (4.9)% (p = 0.04). In patients with > or =5% improvement in LVEF after bone marrow cell injection, global strain improved from -8.7 (4.6)% to -10.6 (4.5)% (p<0.01). Global strain remained unchanged in patients with <5% improvement in LVEF (-6.6 (4.9)% vs -6.4 (4.5)%, p = NS). The relation between the increase in LVEF and improvement in global strain was significant (r = 0.84, p<0.01). In patients with > or =5% improvement in LVEF, LV dyssynchrony decreased from 173 (64) ms to 116 (64) ms (p = 0.01). In patients with <5% improvement in LVEF, LV dyssynchrony remained unchanged (155 (67) ms vs 177 (81) ms, p = NS). The correlation between improvement in LVEF and reduction in LV dyssynchrony was good (r = -0.77, p<0.01). In the control group, LVEF, global strain and LV dyssynchrony did not improve. CONCLUSIONS: Bone marrow cell injection improves LVEF in patients with severe postinfarction heart failure. The improvement in LVEF was related to reduced LV dyssynchrony and increased global strain.

Alterations in plasma lipoproteins and heparin-releasable lipase activities in mice bearing the GRSL ascites tumor.

The lipoproteins in GR mice bearing the transplanted GRSL ascites tumor were characterized by density gradient ultracentrifugation and SDS-polyacrylamide gel electrophoresis. In control mice the major proportion of the lipoproteins was found in the HDL density range, but on days 4 and 5 following tumor transplantation a gradual shift into the LDL density range was observed. At the same time the apolipoprotein E content increased at the expense of apolipoprotein A-I. VLDL became moderately elevated. On days 6 and 7 all lipoproteins except VLDL reached extremely low values. The C-apolipoproteins showed a remarkable shift in their relative proportions. Plasma lecithin:cholesterol acyltransferase activity showed no significant alteration in the course of tumor growth, but the triacylglycerol lipases in postheparin plasma were strongly decreased. Lipoprotein lipase had already started to decline on day 2 following tumor transplantation. However, when assayed in the presence of heat-inactivated control plasma, a decrease was not observed before day 5. This is suggestive of a depletion of a plasma cofactor preceding the final disappearance of the enzyme itself, and is compatible with the changing apolipoprotein C pattern. Hepatic lipase showed a 50% reduction between days 3 and 4. The lipoprotein alterations in tumor-bearing mice are explained as a direct consequence of the decreased lipase activities.

Potency measurement of pertussis vaccines and consistency in production.

If one accepts the minimum requirement of 4 i.u. shd-1 for the potency of pertussis vaccine--and there is no convincing evidence to reject this--the usual MPT with 20 mice per dilution offers a sufficient guarantee that no vaccines with too low potency will be accepted, provided that the consistency in production has been sufficiently proven. As higher concentrations than necessary should be avoided in view of the undesirable side-effects, the establishment of requirements for the lower level of the 95% confidence limits might, however, entail exactly this risk.

The limulus amebocyte lysate test micromethod and application in the control of sera and vaccines.

To estimate the amount of endotoxin in sera and vaccines relatively high quantities of limulus lysate are necessary. Because this makes the control rather expensive, a micromethod was developed in which the amount of limulus lysate was reduced fivefold. This method was used to estimate endotoxin in typhoid vaccines. The relation between the reactions in man and the amount of endotoxin in the vaccines was examined. In these experiments it appeared that the limulus amebocyte lysate (LAL) test demonstrates predominantly the endotoxin in solution. The test was also used as a control test for calf sera. The culture quality of these calf sera as estimated by the lymphocyte stimulation test appeared to be influenced by previous bacterial contamination as could be demonstrated with the LAL test.

Collaborative assay of a proposed international standard for tetanus toxoid (adsorbed).

An international collaborative assay was performed with the aim of establishing an international standard for tetanus toxoid (adsorbed). Six laboratories participated. A suitable preparation in the lyophilized state was made available by the Paul Ehrlich Institut, Frankfurt am Main, Federal Republic of Germany. Preliminary experiments showed that there were no significant differences between individual ampoules and that the preparation was highly thermostable.The proposed preparation (A) was compared in guinea-pigs and mice with the existing international standard for tetanus toxoid (B), which is a plain toxoid, with another arbitrarily chosen adsorbed toxoid (C), and with a number of locally prepared preparations (D). In the mouse tests preparation B was omitted. It was found in the guinea-pig tests that 1 mg of the proposed standard contained an activity equivalent to 1.5 IU if compared with the non-adsorbed international standard but since the slopes of the log dose-response lines for the adsorbed and plain types of preparation were not parallel, this is a rough approximation only. When the different adsorbed preparations were compared, there was close correlation between the guinea-pig tests and the mouse tests. In the guinea-pig test 1 ml of preparation C corresponded to 126.5 mg of preparation A and in the mouse test to 129.9 mg of preparation A. In one laboratory comparative tests were made by titrating blood antitoxins after immunization of guinea-pigs with graded doses of the toxoids. The results corresponded very well with the data from challenge tests (1 mg of preparation A contained 1.5 IU of the plain toxoid in challenge tests and|1.4 IU in the titration test).Preparation A was established by the WHO Expert Committee on Biological Standardization as the international standard for tetanus toxoid (adsorbed) and the international unit was defined as the activity contained in 0.6667 mg of the international standard.

International collaborative studies on potency assays of diphtheria and tetanus toxoids.

Collaborative studies showed that relative potency assays for a particular type of diphtheria toxoid (adsorbed) and for tetanus toxoid (plain and adsorbed) gave very similar results, whether the assays were carried out by toxin challenge or by antitoxin titration after immunization of experimental animals with graded doses of toxoid. The same numerical results were obtained with a scoring system as with a system based on survivals only. Although skin tests were used on a very limited scale in these studies, it seems likely that they could replace lethal tests for the diphtheria challenge assays.For both tetanus and diphtheria, the adsorbed toxoid gave a higher relative potency when combined with other antigens than as a single toxoid. Both mice and guinea-pigs were used for the lethal challenge test of adsorbed tetanus toxoid. For the single tetanus toxoid the results were the same, but for the combined toxoid (DPT vaccine) the mouse assay results were about twice those of guinea-pig assays.

Titration of diphtheria and tetanus antitoxins in sera of low titre.

Available methods for titrating diphtheria and tetanus antitoxin at low concentrations in human or animal blood are surveyed, with special attention to the amount of serum required for the test.In vivo methods, especially the rabbit or guinea-pig intradermal test for diphtheria and the mouse test for tetanus, are precise and reliable. If, however, serum levels as low as about 0.001 IU/ml have to be determined, rather large amounts of serum are required: moreover, the tests are rather time-consuming and expensive.Tissue culture methods are available only for diphtheria antitoxin titration. The titres found coincide very well with those from animal tests. The titrations are less time-consuming and more economical. These methods seem to be very promising for the replacement of animal tests. Of the real in vitro methods, the haemagglutination procedure has been investigated most thoroughly and used most frequently. Low titres can be measured using small amounts of serum, but the titres thus obtained may differ considerably from those obtained in animal tests, at least for individual sera. For mass screening, the method is very suitable.A number of other methods are briefly discussed, but they are either less suitable or have not yet been sufficiently investigated.