The effect of increased plasma potassium on myocardial function; a randomized POTCAST substudy

The current substudy was prespecified in the protocol for the Targeted potassium level to decrease arrhythmia burden in high-risk patients with cardiovascular diseases (POTCAST) trial (www.​clinicaltrials.​gov [NCT03833089]). The design of the POTCAST trial has been described previously [20]. In brief, the POTCAST trial is an ongoing randomized clinical trial aiming at enrolling 1,000 patients at a high risk of malignant arrythmia, defined as patients with an implantable cardioverter defibrillator (ICD) implanted as part of routine clinical management for primary or secondary prevention due to inherited or acquired heart diseases. Patients are randomized (1:1) through a concealed computer-generated sequence (project-RedCap.org) [21, 22] to either usual standard of care or usual standard of care with the addition of dietary guidance on increased potassium intake, oral potassium supplements, and mineralocorticoid receptor antagonists (MRA) to increase and maintain p-K between 4.5 mmol/l and 5.0 mmol/l. Inclusion criteria for POTCAST are screening p-K ≤ 4.3 mmol/l and treatment with an ICD. Exclusion criteria are an eGFR < 30 ml/min/1.73 m², pregnancy, seeking pregnancy, or lack of ability to provide informed consent.

For the present study, 50 consecutive patients from the POTCAST trial with LVEF between 35 and 55% were included between June 1, 2020 and May 31, 2021. Patients were excluded from the final analysis if any of the following criteria were present: echocardiographic image quality too poor for 2D-speckle tracking criteria, acute coronary events during follow-up, any changes in heart failure medication during follow-up unrelated to the study, and difference in rhythm at baseline and follow-up echocardiographies.

The study was performed according to the declaration of Helsinki. All patients provided informed consent. The study was approved by regional Danish committee of health research ethics (Regional Videnskabsetisk komité) — Protocol approval no. H-18,044,908 and by the Danish Data Protection Agency — approval no. VD-2018-453.

Patients in the control group continued standard medical treatment. In addition to the standard treatment patients in the intervention group were educated in intake of a potassium rich diet and commenced oral potassium supplement and/or MRA (spironolactone or eplerenone) according to the POTCAST protocol [20]. Because myocardial deformation imaging is sensitive to loading conditions, potassium supplements were chosen as first line intervention to reduce variance in preload and afterload caused by a blood pressure reduction of MRAs. If target p-K levels could not be reached with potassium supplements alone, MRA was used as second line treatment. With close monitoring of renal function and blood pressure, patients were given incremental doses of study medication until target p-K (4.5-5.0 mmol/l) or maximum dosages of potassium supplement (4500 mg ~ 60 mmol) and MRA (50 mg eplerenone or 100 mg spironolactone) were reached.

Transthoracic echocardiography was performed at enrollment after measurements of p-K⁺, p-Na⁺, p-Mg²⁺, p-Ca²⁺, and p-creatinine and of the blood pressure. Repeated echocardiography was scheduled as soon as possible after either target p-K was met, or maximum dose of study medication was reached. Patients allocated to the control group were scheduled to repeated echocardiography six weeks after baseline due to preliminary results from the POTCAST trial showing that it takes six weeks on average to reach target p-K of 4.5-5.0 mmol/l. P-K and blood pressure were measured immediately after the follow-up echocardiography in both groups. The follow-up echocardiography was scheduled approximately at the same time of day as the baseline echocardiography in order to reduce variance caused by circadian changes in volume status, blood pressure and p-K as well as variation caused by the pharmacokinetics of the patients’ other daily medication.

All echocardiographies were performed by a single investigator using the same ultrasound system (Vivid E9, GE healthcare), the same probe (M5S-D, GE) and the same analyzing software (EchoPac, version 203.66). Cine loops from 3 standard apical views (2-chamber, 4-chamber, and apical long-axis) were recorded using gray-scale harmonic imaging and saved in raw data format. Images were obtained at an acquisition rate of 50 to 90 frames per second. Left ventricular end-diastolic and end-systolic volumes and left ventricular ejection fraction (LVEF) were obtained using Simpson’s biplane method. For 2D-speckle tracking analysis, the inner endocardial borders were traced in the end-systolic frame in images from the three standard apical views. Speckles were tracked frame by-frame throughout the left ventricular wall during the cardiac cycle and basal-, mid-, and apical regions of interest were drawn (Fig. 1). Segments that failed to track were manually adjusted by the operator. Any segments that subsequently failed to track were excluded. GLS was calculated as the mean peak negative longitudinal strain before aortic valve closure of all successfully tracked segments according to an 18-segment model, and mechanical dispersion (MD) was calculated as the standard deviation of time-to-peak negative longitudinal strain in the 12 basal and midventricular segments [23]. Measurements of diastolic function included early diastolic mitral inflow velocity (E), late diastolic mitral inflow velocity (A), E/A ratio, and the average of the septal and lateral early diastolic mitral annular velocity (e’) [24]. Right ventricular function was evaluated by Tricuspid Annular Plane Systolic Excursion (TAPSE) and right ventricular free wall strain (RV FWS). For RV FWS, end-systole was defined at the time of pulmonic valve closure.

Off-line image analyses were independently performed by two investigators blinded to randomization allocation, clinical data and blood test results to reduce the risk of bias.

The predefined outcomes were differences in changes from baseline to follow-up between the two groups in 2D-speckle tracking derived indices of systolic function: GLS, MD and for assessment of diastolic function: E/A, e´ and E/e´.

A subgroup analysis was performed on patients in the intervention group that only received dietary guidance and potassium as a supplement to reach target p-K levels to test if the effects of increasing potassium levels on myocardial function was independent of the effects of MRA on loading conditions.

Values are summarized as mean (standard deviation) or median (interquartile range). Continues data of normal distribution were compared using students t-test. Within-individual comparisons between baseline and follow-up echocardiographies were performed using the paired t-test. Fisher’s Exact test was used to compare categorical variables. Mean difference in changes was calculated as the between group difference in paired estimates to control for random differences in baseline measurements. Thus, the presented results represent absolute changes between study groups. Estimated differences are presented with 95% confidence intervals (95%CI). General linear models were used to assess the correlation between p-K and echocardiographic measurements and presented with R² values obtained from the final models. Interobserver variations was estimated as Single Score Intraclass Correlation. Analyses were done using a standard statistical software program (R version 4.1.0).

To detect a clinically meaningful difference in changes in GLS of 1% with a standard deviation of 1.5 and with a two-tailed α = 0.05 and 1-β = 0.8 in a 1:1 randomization design, 21 patients in each group were needed. A total of 50 patients were included to account for potential dropouts.