Functional classification of extrasystoles based on hemodynamic features and risk of arterial vascular complications

INTRODUCTION

Extrasystoles (ES) is the most common form of arrhythmia, reported in up to 95% of individuals according to various studies^[1-3]. The causes of this rhythm disturbance are diverse, encompassing both physiological and organic origins. The clinical significance of ES depends on its 24-h frequency, specific characteristics, clinical manifestations, and the presence of underlying structural heart disease^[4-7].

Subsequent studies have explored the etiology, pathogenesis, and clinical manifestations of this arrhythmia. Sh. Kinoshita is particularly associated with describing the re-entry mechanism - a theory that remains highly relevant today. Several classifications (e.g., Lown, Ryan) were developed in the last century^[8]. Current widely accepted classifications of ES primarily focus on electrocardiographic (ECG) patterns, determining the ectopic focus and the frequency of occurrences per hour^[9-11]. However, these classifications do not account for the timing of ES in relation to the biomechanical phases of the cardiac cycle.

In clinical practice, cardiologists must not only establish the presence of ES but also determine its type, identify the underlying cause, and assess the necessity of intervention. Consequently, even rare or isolated ES events typically receive therapeutic attention, regardless of their timing within the cardiac cycle. Nevertheless, when evaluating the need for antiarrhythmic therapy and the risk of complications, the timing of extrasystolic ventricular contractions is often overlooked. Importantly, the term “early” ES currently refers specifically to the “R-on-T” phenomenon as detected on ECG, rather than to its placement within the heart’s biomechanical cycle.

Furthermore, assessments of cardiac biomechanics and arterial kinetics are not routinely performed in patients with ES. Non-invasive methods such as digital apexcardiography (ACG) and sphygmography (SG) are not included in the standard diagnostic workup for arrhythmias. Yet, clinical observations indicate that major kinetic parameters of the arteries undergo marked changes during rhythm disturbances, contributing to pathogenic mechanisms in patients with cardiovascular disease. Therefore, arterial and cardiac biomechanics should be considered when evaluating patients with arrhythmia.

Given that existing classifications of ES do not consider the timing of contractions within the cardiac cycle or their impact on arterial biomechanics, there is a need for a new functional framework. Therefore, the objective of this study is to develop a classification of ES based on cardiac biomechanics, arterial hemodynamics and kinetics, and the associated risk of vascular events.

MATERIALS AND METHODS

We conducted a monocentric, prospective study involving 634 patients with ≥700 ES per 24 h, without atrial fibrillation (AF). The control group consisted of 106 patients without AF who had < 700 ES per 24 h. The study was conducted at the Clinics of the Samara State Medical University. All participants (740 patients in total) were admitted for elective procedures to confirm the diagnosis of coronary heart disease, evaluate stable angina pectoris, and determine the necessity of surgical intervention for coronary atherosclerotic lesions, including percutaneous coronary intervention, stenting, or coronary artery bypass grafting. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Samara State Medical University (Protocol No. 248, dated April 27, 2022; Chairperson: Prof. L.T. Volova). Written informed consent was obtained from all patients.

Inclusion criteria for the main group: male or female; ≥ 18 years; ≥ 700 ES per 24 h on 24 h ECG monitoring; absence of AF; signed informed consent.

Inclusion criteria for the control group: male or female; ≥ 18 years; < 700 ES per 24 h; absence of AF.

Exclusion criteria (for both groups): arterial hypertension with blood pressure > 160/100 mmHg; familial hypercholesterolemia; chronic kidney disease with estimated glomerular filtration rate (eGFR) < 60 mL/min; chronic heart failure New York Heart Association (NYHA) class III or higher; chronic infections; intracardiac thrombosis; chronic obstructive pulmonary disease (COPD) of more than mild severity; hematological disorders with a hypercoagulable state; myocardial infarction, stroke, or transient ischemic attack within the past year; aortic or left ventricular aneurysm; prosthetic heart valves; obstructive atherosclerosis of the lower limb arteries; hemodynamically significant carotid bifurcation stenosis; cardiomyopathies.

Patients in the main group were further divided into two subgroups, A and B, based on the timing of ventricular systole in relation to transmitral blood flow, regardless of the ectopic focus location. Subgroup A (early variant) included 192 patients in whom ventricular systole occurred before the peak of transmitral blood flow (before peak E on Doppler echocardiography). Subgroup B (late variant) consisted of 442 patients in whom ventricular systole occurred after the transmitral peak E. The smaller size of subgroup A reflects the lower prevalence of the early ES variant. The transmitral E peak is the first peak of transmitral flow measured by pulsed-wave Doppler echocardiography in the apical 4-chamber view, corresponding to the rapid filling phase of the left ventricle.

Figure 1 illustrates the rationale for selecting 700 ES/24 h as the cutoff for dividing patients into groups. Receiver operating characteristic (ROC) curve analysis identified 700 ES/24 h as the optimal cutoff, with an area under the curve (AUC) of 0.83, providing the best balance between sensitivity and specificity.

Figure 1. Sensitivity and specificity analysis for determining the threshold of 700 ES/24 h. ES: Extrasystoles.

The overall study design is presented in Figure 2.

Figure 2. Study design scheme. ES: Extrasystoles.

All patients underwent mandatory laboratory tests, including complete blood count with leukocyte differential and platelet count, urinalysis, and biochemical blood tests (urea, creatinine and clearance, glucose, alanine transaminase (ALT), aspartate transaminase (AST), bilirubin, fibrinogen, prothrombin time, antithrombin III, activated partial thromboplastin time (APTT), creatine kinase-MB (MB-CK), international normalised ratio (INR), troponin T, myoglobin, and lipid profile: total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), atherogenic index, and triglycerides). Instrumental examinations included transthoracic or transesophageal echocardiography, coronary angiography, exercise stress echocardiography, 24 h Holter ECG monitoring, Doppler ultrasound of the brachiocephalic arteries, lower extremity arteries, renal arteries, and abdominal aorta, as well as digital ACG and SG of the arteries (common carotid artery and posterior tibial artery). Additional investigations, when indicated, included renal ultrasound, computed tomography (CT) of the adrenal glands and brain, pan-cerebral angiography, and thyroid ultrasound.

In the main group, both supraventricular and ventricular ES were detected in subgroups A and B. Most patients in both the main and control groups received β-blockers (bisoprolol 2.5-10 mg/day), mainly as part of complex therapy for coronary artery disease (98 patients in subgroup 1A, 228 in subgroup 1B, and 76 in the control group). Since β-blockers are the first-line treatment for ES (Lebedev DS, Mikhailov EN, 2021), antiarrhythmic drugs from other classes were prescribed less frequently, and only in cases of symptomatic ES (propafenone in 4 patients in subgroup A and 8 patients in subgroup B). No patients in this study underwent catheter ablation. To correct lipid profiles, all patients received statins (atorvastatin, rosuvastatin, or pitavastatin) or therapeutic doses of ethyl esters of omega-3 fatty acids starting at the outpatient stage. Under this therapy, lipidogram parameters were comparable between subgroups. Treatment was continued both during hospitalization and after discharge. Some patients in the main and control groups also received antiplatelet therapy (acetylsalicylic acid 70-100 mg/day) at the outpatient stage (101 patients in subgroup A, 269 in subgroup B, and 68 in the control group). Coronary angiography was performed in all patients; Percutaneous coronary intervention (PCI) with coronary stenting was performed in 36, 92, and 24 patients in subgroups A, B, and the control group, respectively.

By days 2-7 after myocardial revascularization, some patients with symptomatic ES reported improvement or resolution of subjective arrhythmia symptoms. In all cases, drug-eluting stents were used. After PCI and stenting, patients received dual or triple antithrombotic therapy in accordance with clinical guidelines. Bleeding risk was assessed using the PRECISE-DAPT score. For patients with low risk (score < 25), dual therapy (clopidogrel 75 mg/day plus acetylsalicylic acid 70-100 mg/day) was prescribed for 6 months post-PCI, followed by acetylsalicylic acid alone. For high-risk patients, dual therapy was limited to 1-3 months, after which monotherapy with acetylsalicylic acid was continued.

The prospective clinical phase involved one year of follow-up, with visits scheduled at 6 and 12 months. The composite endpoints included ischemic vascular complications within one year: cerebral ischemic events, myocardial infarction, and thrombosis or embolism in other vascular territories.

Data were analyzed using evidence-based medicine principles. Sample size was determined with free online power calculators (https://www.sealedenvelope.com/power/binary-superiority/), assuming a significance level (α) of 5%. Statistical methods were selected considering that with large sample sizes, the law of averages applies even when data distributions deviate from normality. Each parameter was tested for normality. If normally distributed, parametric methods were employed: quantitative variables were expressed as mean ± standard deviation, and intergroup comparisons were conducted using one-way analysis of variance (ANOVA; reporting F-value, degrees of freedom, and P-value). If normality was not met, quantitative variables were summarized as medians with interquartile ranges (Q1 and Q3), and intergroup comparisons were performed with the Kruskal-Wallis test (reporting H statistic and P-value), followed by Steel-Dwass-Critchlow-Fligner pairwise tests as needed. Categorical variables were summarized as frequencies and percentages. For pairwise comparisons, multiple-testing correction was applied using the Dunn method. Results were presented as bar charts with mean values and 95% confidence intervals, or medians with interquartile ranges, along with p-values for significant intergroup differences. Categorical distributions were analyzed with χ2 tests when expected cell frequencies exceeded 5, or Fisher’s exact test otherwise. Odds ratios (ORs) for ischemic vascular events (cerebral ischemia, myocardial infarction, and embolic events in other vascular territories) within 1 year were calculated according to ES types, categorized by the timing of ventricular systole within the cardiac cycle.

For all statistical tests, significance was defined as P ≤ 0.05. Analyses were performed using MedCalc® Statistical Software version 20.118 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2022), GraphPad Prism version 10.1.0 (GraphPad Software, San Diego, California, USA; www.graphpad.com), and the R open-source environment (https://cran.rstudio.com/).

Potential sources of bias were considered, and preventive measures were applied. Measurement errors were minimized by using standardized, authorized equipment and quantitative data evaluation. Selection bias was avoided through strict inclusion and exclusion criteria. Observation and recall biases were minimized by relying on quantitative measurements. Confirmation bias was prevented by using objective data and prospective analysis.

The minimum required sample size was calculated as 512 participants using the above-mentioned online power calculators.

RESULTS

At baseline, the clinical and instrumental data showed no significant differences between the main subgroups and the control group. The primary distinction between subgroups A and B was related to the characteristics of the diagnosed ES - specifically, the timing of the onset of ventricular systole in relation to the cardiac cycle (i.e., whether it occurred before or after the peak of transmitral blood flow) [Table 1].

However, a follow-up analysis of control endpoints after one year showed a statistically significant increase in arterial vascular events - including ischemic stroke (IS), transient ischemic attack (TIA), and thrombosis or embolism of peripheral arteries - among patients experiencing 700 or more ES per 24 h. This effect was particularly pronounced in subgroup A, in which ES occurred before the peak of transmitral blood flow [Table 2].

In patients with ES occurring before the transmitral blood flow peak at rates of 700 or more per 24 h, the OR for arterial vascular complications was 7.923 (95%CI: 2.377, 26.406), z = 3.370, P < 0.001. Conversely, for ES occurring after the peak, the OR was 2.500 (95%CI: 0.748, 8.353), z = 1.489, P = 0.137. Overall, individuals with ES ≥ 700 per 24 h had an OR of 3.989 (95%CI: 1.231, 12.930), z = 2.306, P = 0.021 for developing any arterial vascular complication within one year. These findings indicate that the risk of arterial vascular complications is influenced not only by the quantity of ES exceeding 700 per 24 h but also by their timing within the cardiac cycle.

To better understand these results, we analyzed hemodynamic parameters for each ES type across subgroups and the control group. Primary parameters included linear blood flow velocity and volumetric blood flow in the common carotid and posterior tibial arteries, measured by Doppler ultrasound. For subgroups A and B, these parameters were calculated for regular, ES, and first postextrasystolic (1PES) cardiac cycles. Key hemodynamic parameters for each group are presented in Table 3.

In addition to the analyzed hemodynamic parameters, we calculated key data on cardiac biomechanics and arterial kinetics (common carotid artery and posterior tibial artery) using digital ACG and SG in patients with ES from subgroups A and B, as well as during regular heart contractions in the control group [Figure 3].

Figure 3. Apexcardiography (1) and sphygmography of the common carotid artery (2) and posterior tibial artery (3) in patients with ES. R - regular pulse wave; ES - extrasystole; 1PES - first postextrasystolic wave. 1PES: First postextrasystolic; ES: extrasystole.

For subgroups A and B, we calculated key biomechanical and kinetic parameters (velocity, acceleration, power, and work) for ES, regular, and 1PES pulse waves. Comparing the 1PES parameters in patients of subgroups A and B with those recorded during regular pulse waves in the control group revealed a clear trend: all kinetic parameters measured by ACG and SG - velocity, acceleration, power, and work - increased during 1PES. This effect was most pronounced in subgroup A, representing patients with “early” ES, where the ventricular systole of the ES occurs before the peak of transmitral blood flow. The most comprehensive parameter, work, is presented in Figure 4. Work was calculated automatically based on the physical formula A = P*t (where A = work, P = power, t = time). All analyzed parameters and detailed group data are provided in Supplementary Table 1

Figure 4. Work parameter based on digital ACG and SG data from the common carotid and posterior tibial arteries (P < 0.001) in subgroups A, B, and the control group. Data are presented as medians (horizontal line), means (cross), 1st and 3rd quartile boundaries (box edges), and minima and maxima (whisker ends). ACG: Apexcardiography; SG: sphygmography.

During 1PES, hemodynamic parameters notably increase, particularly during early type of the ES, prior to the peak of transmitral blood flow E observed on EchoCG within the cardiac cycle. This indicates that the timing of ventricular systole during ES is critical in modulating hemodynamic parameters associated with the subsequent 1PES.

The timing of ventricular systole in ES plays a decisive role in determining changes in cardiac hemodynamics, heart biomechanics, and arterial kinetics (velocity, acceleration, power, and work). Specifically, it affects the 1PES’s ability to restore adequate blood flow, thereby determining cardiac output, the characteristics of the 1PES contraction, and the magnitude of its hemodynamic effect.

CONCLUSIONS

Given the impact on hemodynamics and the differences in the occurrence of ischemic arterial events (such as cerebral ischemic events, myocardial infarction, and thrombotic or embolic events in other vascular territories), it is reasonable to further classify ES based on the timing of ventricular contractions within the cardiac cycle.

This classification includes:

(1) Early ES: ventricular systole occurs before the peak of transmitral blood flow in the cardiac cycle.

(2) Late ES: ventricular systole occurs after the peak of transmitral blood flow in the cardiac cycle.

The highest risk of ischemic vascular events in various arterial regions is associated with early ES, in which ventricular contractions occur before the peak of transmitral blood flow (the E wave on echocardiography). This risk becomes clinically significant when ES frequency reaches 700 or more episodes per 24 h, regardless of the ectopic origin.