Serial cardiac biomarkers, pulmonary artery pressures and traditional parameters of fluid status in relation to prognosis in patients with chronic heart failure: Design and rationale of the BioMEMS study.

AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.

Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients: First data from the TITRATE-HF study.

AIMS: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. METHODS AND RESULTS: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. CONCLUSION: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.

Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome.

BACKGROUND: Colchicine reduces risk of cardiovascular events in patients post-myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS). OBJECTIVES: This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status. METHODS: The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed. RESULTS: In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59). CONCLUSIONS: The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684).

Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF).

AIMS: Inhibition of sodium-glucose co-transporter 2 (SGLT2) reduces the risk of death and heart failure (HF) admissions in patients with chronic HF. However, safety and clinical efficacy of SGLT2 inhibitors in patients with acute decompensated HF are unknown. METHODS AND RESULTS: In this randomized, placebo-controlled, double-blind, parallel group, multicentre pilot study, we randomized 80 acute HF patients with and without diabetes to either empagliflozin 10 mg/day or placebo for 30 days. The primary outcomes were change in visual analogue scale (VAS) dyspnoea score, diuretic response (weight change per 40 mg furosemide), change in N-terminal pro brain natriuretic peptide (NT-proBNP), and length of stay. Secondary outcomes included safety and clinical endpoints. Mean age was 76 years, 33% were female, 47% had de novo HF and median NT-proBNP was 5236 pg/mL. No difference was observed in VAS dyspnoea score, diuretic response, length of stay, or change in NT-proBNP between empagliflozin and placebo. Empagliflozin reduced a combined endpoint of in-hospital worsening HF, rehospitalization for HF or death at 60 days compared with placebo [4 (10%) vs. 13 (33%); P = 0.014]. Urinary output up until day 4 was significantly greater with empagliflozin vs. placebo [difference 3449 (95% confidence interval 578-6321) mL; P < 0.01]. Empagliflozin was safe, well tolerated, and had no adverse effects on blood pressure or renal function. CONCLUSIONS: In patients with acute HF, treatment with empagliflozin had no effect on change in VAS dyspnoea, diuretic response, NT-proBNP, and length of hospital stay, but was safe, increased urinary output and reduced a combined endpoint of worsening HF, rehospitalization for HF or death at 60 days.

Predictors of improved quality of life 1 year after pacemaker implantation.

BACKGROUND: Patient's health-related quality of life (HRQoL) of pacemaker (PM) patients has increasingly become an important issue of health care evaluation. Currently, knowledge of pacing performance and technology is more or less outlined. However, determinants of poor or good HRQoL of paced patients require further elucidation. OBJECTIVES: The purpose of this study is to determine the HRQoL 1 year after PM implantation and predictors of differences in HRQoL between pre- and post-PM implantation. METHODS: We quantified the mean differences between HRQoL before implantation (baseline) and 1 year later, assessed with the generic Medical Outcomes Survey 36-Item Short-Form Survey and EuroQol (EQ5D), and the PM patient-specific AQUAREL (Assessment of QUality of life And RElated events) questionnaires, in 501 consecutively included patients in the Dutch multicenter longitudinal FOLLOWPACE cohort study. Multivariable linear regression modeling was then performed to determine predictive factors of the HRQoL 1 year after implantation. RESULTS: The HRQoL of the patients increased markedly in the first year after implantation. Seventy percent of the patients considered their health improved, whereas 11% experienced a complete recovery in HRQoL. The most important predictors for improved HRQoL after 1 year were HRQoL at baseline, age, presence of cardiac comorbidities, and atrial fibrillation with slow ventricular response as indication for chronic pacing. CONCLUSION: In most patients receiving a PM, HRQoL increased in the first year after PM implantation. Knowledge of the predictors of this increase may aid physicians to timely differentiate between patients who most likely will benefit most from PM implantation in terms of HRQoL.

Poor health-related quality of life of patients with indication for chronic cardiac pacemaker therapy.

BACKGROUND: Studies on health-related quality of life (HRQoL) of patients awaiting pacemaker (PM) implantation are scarce, or executed in specific patient subgroups (regarding age or specific cardiac rhythm disorders). The purpose of this study was to systematically assess the HRQoL in a large unselected cohort of patients with a conventional indication for PM therapy. METHODS: Pre-PM implantation HRQoL (measured with the SF-36 questionnaire, completed at hospital admission) of 818 consecutive Dutch patients included in the FOLLOWPACE study was compared with the HRQoL in a sample of the general Dutch population, and with several cohorts of patients with other conditions. Linear regression analysis was performed to analyze determinants of this HRQoL. RESULTS: Almost all SF-36 subscale scores were substantially and significantly lower in the PM patients compared to the general population, with P-values < 0.001 in all SF-36 subscales except for "pain" and "general health perception." In the PM patients, presence of comorbidities, gender, and age were significantly associated with the overall physical component summary score (mean 38.8 +/- 27 standard deviation) whereas the overall mental component summary score (46.8 +/- 27.0) was associated with gender and age. CONCLUSION: The HRQoL of patients before first PM implantation is significantly lower than that of a general population and also various other patient populations. Physicians should be aware of this unfavorable condition and keep the time interval between the diagnosis of a cardiac rhythm disorder requiring PM implantation and the implantation procedure as short as possible.

Incidence and predictors of in-hospital events after first implantation of pacemakers.

AIMS: Despite an annual rise in the numbers of patients receiving their first pacemaker (PM), the risks of the implantation procedure remains unclear. The purpose of this prospective study is to estimate the incidence of in-hospital events after first PM implantation and to determine the predictors of these events. METHODS AND RESULTS: Patients with conventional pacing diagnosis were included in the Dutch multicentre FOLLOWPACE PM registry that prospectively documented patients' prognosis and quality of life, and PM events after first implantation. From these registry characteristics, implantation data and in-hospital findings were analysed as potential predictors for events in a sample of 1198 patients. In 111 patients studied, at least one serious in-hospital event occurred (incidence 10.1%, 95%CI: 8.9-12.3). Six variables, i.e. a lower body mass index, presence of heart failure in medical history, main indication for implantation, vena subclavia use for venous access, active atrial lead fixation, and the implantation of a dual chamber system, were found to be independent predictors of events after first PM implantation. The overall multivariable model yielded an ROC area of 0.65 (95%CI: 0.60-0.70). CONCLUSION: This large prospective multicentre study identified six variables as independent predictors for serious in-hospital events after first implantation. This may assist the implanting cardiologist and surgeon to identify patients at higher risk, during and immediately after PM implantation.

FOLLOWPACE study: a prospective study on the cost-effectiveness of routine follow-up visits in patients with a pacemaker.

AIMS: This communication describes the design of the FOLLOWPACE study. The overall aim of FOLLOWPACE is to quantify the cost-effectiveness of routine follow-up visits in patients with a pacemaker (PM). Specific aims are (i) to quantify the incidence of complications and the quality of life 1 year after PM implantation; (ii) to quantify which baseline characteristics measured during implantation are predictors of the occurrence of complications and quality of life after 1 year; (iii) to determine the added predictive value of follow-up measurements to improve the efficiency of follow-up and to demonstrate which follow-up measurements are redundant. METHODS AND RESULTS: FOLLOWPACE is a prospective, observational, prognostic cohort study. About 40 PM centres in the Netherlands will participate to include about 2,500 patients. Each patient aged >or=18 receiving a PM for the first time is eligible. At baseline, i.e. time of implantation, all potential predictors of complications and quality of life after 1 year are documented. After implantation, follow-up visits will be carried out conforming with routine care, usually three in the first year. At these visits, other potential prognostic predictors will be documented. Primary outcome is the incidence of PM- or cardiac complications at 1 year. Secondary outcome parameters are quality of life and costs after 1 year. CONCLUSION: This study will lead to definition of a more efficient routine follow-up schedule for patients with a PM, aiming to reduce time and energy while preserving the safety of pacing therapy and the prognosis of the patient. The study will ultimately provide evidence-based guidelines for PM follow-up including knowledge of the responsibilities of cardiologists, technicians, and representatives of PM manufacturers.

The FOLLOWPACE study: a prospective study on the (cost-)effectiveness of routine follow-up visits in patients with a pacemaker.

In the Netherlands, following implantation of a pacemaker (PM) commonly two or three out-patient follow-up visits are scheduled in the first year to check the patient's health and the PM programme, in order to guarantee optimal patient outcome. Anually, about 200,000 follow-up visits of 20 minutes are performed, in total about 80,000 working hours. The question arises whether and to what extent these regular follow-up checks are truly necessary for the prognosis of the patient and whether they are cost-effective. Yet no information is available on how frequently and extensively a routine PM follow-up visit should be performed. This is probably because it is largely unknown which factors - either documented at PM implantation or at the follow-up visits - predict the occurrence of complications. The FOLLOWPACE study is designed to address these issues. Below we briefly discuss the rationale, objectives and expected results of FOLLOWPACE.

Effects of postural changes on cardiac function in healthy subjects.

AIMS: To analyse the response of Doppler measurements to increased venous return in middle-aged healthy subjects. METHODS AND RESULTS: Left ventricular pulsed Doppler parameters, colour M-mode of early left ventricular filling and septal mitral annulus velocities were measured at baseline and after leg lifting (n=24). Leg lifting resulted in increased stroke volume (69 +/- 14 to 74 +/- 14 ml, P<0.01) and peak systolic annulus velocity (6.8 +/- 1.3 to 7.3 +/- 1.1 cm/s, P<0.01). Leg lifting enhanced peak early (E) mitral flow (74 +/- 13 to 80 +/- 14 cm/s, P<0.01), flow propagation (53 +/- 10 to 59 +/- 13 cm/s, P<0.01) and E' diastolic mitral annulus velocity (10.8 +/- 2.2 to 11.7 +/- 2.0 cm/s, P<0.01). There was a shortening of E wave deceleration time (178 +/- 27 to 163 +/- 27 ms, P<0.01) and isovolumic relaxation time (76 +/- 11 to 68 +/- 10 ms, P<0.01). However, individual changes in Doppler parameters differed among subjects. CONCLUSIONS: Leg lifting improved myocardial function as manifested by increase in stroke volume, systolic annulus motion and acceleration of relaxation. Flow propagation velocity and diastolic mitral annulus velocities were influenced by the induced change in cardiac preload as well.

Interspecific transfer of isolated plant mitochondria by microinjection.

Data on isolation, purification and transfer of mitochondria from a cytoplasmic male sterile line of the "Ogura" type of Raphanus sativus to a male fertile line of Brassica napus are reported. Microinjection has been used for the transfer of the donor mitochondria to the recipient protoplasts. The injected protoplasts were identified and followed individually throughout their development using a computerized microscope stage which greatly enhanced the number of injections (five-fold). The transferred donor mitochondria were stably maintained during several successive cell divisions, revealing that they were viable and functional. Several calluses were obtained from injected protoplasts without using any selection pressure. Restriction fragment length analysis of seventeen calluses, using mitochondrial DNA probes, indicated that three contained the donor "Ogura" type mitochondria. No recombinant types of mitochondria have been observed. Flow cytometric and karyotype analyses of the calluses revealed the presence of similar amount of DNA and chromosome number as those of the recipient plants of B.napus. The application of microinjection for the manipulation of cytoplasmic composition is discussed.

Vital DNA staining of agarose-embedded protoplasts and cell suspensions of Nicotiana plumbaginifolia.

The DNA of agarose-embedded protoplasts of Nicotiana plumbaginifolia was stained with Hoechst 33342 by immersing microscope slides, coated with immobilized protoplasts, into Erlenmeyer flasks containing consecutively dye solution, pH-correcting washing solutions and culture medium. After staining, protoplasts regenerated cell walls, started to divide and proliferated to calli. The culture system with immobilized protoplasts permits rapid change of culture media and accurate control of experimental conditions. The staining technique offers the opportunity for continuous observation of chromosomal behaviour and cell dynamics in individual plant cells.The same staining procedure was successfully applied to DNA of plant cells in suspension. Flow cytometric analysis revealed a retarding effect of the dye on the cell cycle, but within hours the cells recovered and showed their normal growth characteristics as compared to the controls.