Mortality prediction in ventricular septal rupture at high altitude: A novel tool for resource-limited regions

Abstract

The innovative study by Zhang et al published in the World Journal of Cardiology focused on predicting 30-day mortality in patients with acute myocardial infarction complicated by ventricular septal rupture at high altitudes. Based on a retrospective analysis of 48 patients from Yunnan Province, China, the authors identified four independent predictors of mortality: Age; Elevated uric acid levels; Interleukin-6 and decreased hemoglobin. Integrating these factors into a nomogram demonstrated high predictive accuracy (area under the curve = 0.939). This model addressed the critical challenge of risk stratification in the resource-limited settings typical of high-altitude areas. This editorial underscored the practical value of the nomogram for timely identification of candidates for intensive therapy and surgical intervention while emphasizing the need for model validation in multicenter cohorts to optimize the management of these patients.

Key Words: Ventricular septal rupture; Acute myocardial infarction; High altitude; Mortality prediction; Resource-limited settings; Uric acid; Interleukin-6; Hemoglobin

Core Tip: In resource-limited high-altitude regions, ventricular septal rupture complicating myocardial infarction is associated with high mortality rates. Zhang et al developed a nomogram predicting 30-day mortality in patients with ventricular septal rupture, incorporating the following parameters: Age; Uric acid levels; Interleukin-6 and hemoglobin. The model demonstrated high predictive accuracy (area under the curve = 0.939) and enabled timely identification of candidates for emergency surgical intervention. The primary limitation for clinical implementation is the lack of routine interleukin-6 testing availability in most healthcare facilities. Multicenter validation is required prior to adoption in clinical practice.

INTRODUCTION

Ventricular septal rupture (VSR) complicating acute myocardial infarction (AMI) remains one of the most dreaded and fatal mechanical complications in modern cardiology despite advances in reperfusion therapy. The incidence of VSR, previously 1%-3%, has significantly decreased: First to 0.6%[1] due to the introduction of percutaneous coronary interventions and subsequently to 0.2%-0.4%[2,3] with their widespread use. However, no further reduction in the incidence of this complication was observed[2], and mortality associated with this condition remains high[4], reaching ≥ 70% in some studies and cohorts[5-8].

Early diagnosis and risk stratification are crucial for improving outcomes[9], and proper selection of patients for surgical treatment is needed to improve prognosis[4,10]. However, the rarity of VSR results in a limited evidence base[11-13] and inconsistent findings across studies. For example, in the study by Ning et al[10], female sex and low platelet count were independent risk factors for in-hospital death in patients with VSR[10]. In the study by Luo et al[8], logistic regression analysis revealed that white blood cell, cardiogenic shock, and left ventricular ejection fraction were independent risk factors for early in-hospital mortality. The authors developed a nomogram for predicting short-term mortality risk, which showed robust discrimination with an area under the receiver operating characteristic curve of 0.956[8].

The study by Zu et al[13] analyzed numerous prognostic factors for mortality in AMI with VSR, synthesizing data from various studies[13]. However, none of the previously published works address the possibility of predicting the development of VSR and fatal outcomes in patients residing in high-altitude conditions. Predictive models for patients with AMI and VSR are extremely important for high-altitude areas, but they are currently absent. Chronic hypoxia creates a unique pathological background of increased myocardial oxygen demand, erythrocytosis, elevated pulmonary vascular resistance, and an imbalance in coagulation-inflammatory cascades[3,14]. The clinical dilemma of choosing the optimal timing for risky surgical correction is compounded by resource limitations in such regions.

RISK FACTORS AND PREDICTIVE MODEL FOR MORTALITY IN AMI WITH VSR AT HIGH ALTITUDES

It is precisely within this context that the study by Zhang et al[3] in the World Journal of Cardiology represented a significant step forward, offering a tool for risk stratification and personalizing the management approach for patients with VSR in high-altitude settings.

The study, conducted at Fuwai Yunnan Hospital (Kunming, Yunnan Province, China, altitude 1874 m), was a retrospective analysis of 48 patients with AMI complicated by VSR hospitalized between 2017 and 2024. Patients were divided into 30-day survival (n = 30) and mortality (n = 18) groups. The authors performed a thorough analysis of clinical and anamnestic data, laboratory markers, echocardiographic parameters, and treatment data.

Using univariate and multivariate logistic regression analyses, the authors identified the independent predictors of 30-day mortality as age, uric acid level, interleukin-6 (IL-6), and hemoglobin (Hb) level (odds ratio = 1.147, 1.006, 1.034, and 0.941, respectively). While the roles of age, uric acid, and IL-6 were expected, the association of Hb with prognosis requires explanation. Although the difference in Hb level between the survivor and non-survivor groups did not reach statistical significance (115.3 ± 28.5 g/L vs 128.1 ± 18.9 g/L, P = 0.067), the authors noted that a clinically significant trend towards lower Hb in non-survivors included this parameter in the multivariate analysis, confirming its independent prognostic significance for 30-day mortality in VSR and demonstrating an inverse relationship with risk.

This is particularly interesting in high-altitude conditions where compensatory erythrocytosis is typical. Even though compensatory erythrocytosis (Hb > 170 g/L) is the result of an adaptation to hypoxia, it carries deleterious effects including a significant increase in blood viscosity, worsening of microcirculation, an increased risk of thromboses, and an increase in cardiac afterload[3]. These factors also increase the risk of adverse outcomes in AMI. However, low Hb levels also adversely affect prognosis in AMI. Anemia (low Hb levels) critically impairs oxygen delivery to ischemic tissues. Thus, the relationship between mortality in patients with AMI complicated by VSR and Hb levels follows a U-shaped curve.

The authors suggest that the low Hb in non-survivors might reflect acute blood loss, chronic anemia, or nutritional deficiency, acting as additional factors for adverse outcomes. Furthermore, a low Hb level may also decrease due to hemodilution resulting from heart failure, complicating either the AMI itself or the VSR. The identified impact of Hb level on mortality underscored the value of the model specifically developed for high-altitude conditions.

Unlike Hb level, the IL-6 Level significantly differed between the group of survivors and the deceased. Among survivors it was 49.3 ± 33.5 pg/mL vs 110.7 ± 94.5 pg/mL in the deceased group (P = 0.015). In the course of further univariate analysis, IL-6 as the sole predictor had the highest prognostic value, emphasizing the leading role of this proinflammatory marker released during myocardial ischemia in predicting outcomes. Elevated IL-6 Levels can lead to myocardial cell apoptosis, ventricular remodeling, and deteriorated heart function[3].

Based on the identified predictors, a prognostic nomogram was developed using R software, and its accuracy was assessed using receiver operating characteristic analysis (area under the curve = 0.939) and calibration curves. The predicted values closely matched the actual values, combined with the Hosmer-Lemeshow goodness-of-fit test (χ² = 2.268, P = 0.971), indicating excellent agreement between predicted and observed outcomes.

High accuracy of the model enables the recommendation of its use in the practical activity of doctors in remote high-altitude regions with limited resources for diagnostics and treatment of VSR in patients with AMI. Early identification of patients with a very high risk of death predicted by this nomogram will allow the most effective distribution of deficient resources. Clinicians can also consider emergency transportation to more equipped centers and earlier surgical treatment and can obtain the greatest benefit from emergency intervention.

INTERPRETIVE CONSIDERATIONS

Undoubtedly, the study had limitations inherent to pilot works, including a retrospective design, small sample size (n = 48), single-center nature, and short-term follow-up. However, the most important limiting factor in implementation of the developed nomogram is the inability to rapidly and accurately measure IL-6 in routine hospital settings, especially in resource-limited regions (although the authors themselves did not face any problems in determining IL levels in their study). Consequently, this nomogram can only be used in clinics where this measurement is feasible. Subsequent research requires the search for simpler algorithms and/or surrogate markers. The authors themselves emphasize this necessity[3].

Potential markers may include C-reactive protein level, leukocyte count, and various leukocyte indices such as the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio[15,16] among others. Given the limited availability of IL-6 testing in routine practice, subsequent studies should consider developing predictive models that do not incorporate this parameter.

The study did not include some potentially important markers such as other cytokines (tumor necrosis factor alpha, IL-1 beta), markers of oxidative stress, detailed shunt parameters on echocardiography, and tissue perfusion indicators. However, this is understandable as most of these cannot be used routinely. The authors emphasized that this model also requires validation in future multicenter prospective studies.

CONCLUSION

Nevertheless, at this stage, the developed model is important as it offers a concrete pathway to improving outcomes in this vulnerable patient group through early prediction and consequently targeted interventions. Early identification of patients with a high predicted risk of death will allow directing such patients to specialized centers, disregarding the risks of transportation, to optimize preoperative preparation and to determine the sequence and urgency of surgical intervention. The high surgical risks will be outweighed by the increased chance of survival. Further validation and refinement of the model through multicenter prospective studies will pave the way for implementing a truly personalized approach to managing VSR in the most extreme environments on our planet. Implementing this nomogram into the routine practice of cardiology and cardiac surgery departments serving high-altitude populations has the real potential of saving lives of patients with VSR.