Prevalence and Significance of Elevated Cardiac Enzymes among Sickle Cell Disease Patients at King Abdulaziz University Hospital

1. Introduction

Sickle cell disease (SCD) is an autosomal recessive abnormality of the beta-globin chain of hemoglobin (Hgb), resulting in decreased deformability and increased adhesion of the sickle cells causing microvascular occlusion and hemolytic anemia (1). Patients with sickle cell disease are prone to progressive organ damage throughout the body. One of the vital organs that the sickling process can harm is the heart. Cardiovascular complications are becoming more common and are the most common cause of mortality in patients with SCD (2). Pulmonary hypertension left and right ventricular dysfunction, cardiac iron overload, dysrhythmia, myocardial ischemia, and sudden death are all consequences that can be induced by SCD (3).

The prevalence and significance of elevated cardiac markers still need to be well known. We attempted to answer this question by evaluating SCD patients admitted to King Abdulaziz University Hospital (KAUH) within the last five years.

2. Materials and Methods

A retrospective study was conducted in June 2022 to March 2023 at King Abdulaziz University Hospital (KAUH), a tertiary center in Jeddah, Saudi Arabia. All patients with SCD patients who were 18 years and above and follow-up in the hematology department were screened. The data collection sheet was used to fill in the information obtained from medical records. It included demographic data, comorbid conditions, hospital admissions, ER visits, cardiac markers; troponin, lactate dehydrogenase (LDH), creatine kinase (CK-MB), ECG changes, blood transfusion, and medication.

• Statistical Analysis

Microsoft Excel 2021 was used for data entry. All statistical analyses were performed by SPSS version-18.0 software. Frequencies and percentages were generated for nominal and ordinal variables. Spearman's rank correlation was used to detect the association between cardiac markers levels with each of the following (ER visits, age). Furthermore, the rank biserial correlation coefficient linked cardiac markers with ECG, anticoagulant & antiplatelet, hydroxyurea, patient state, and blood transfusion. Statistical significance was set at P values of <0.05 with a 95% confidence interval.

• Research ethics

The research ethics committee of KAUH approved this study with reference number (IRB 360-22). The study adhered to appropriate ethics guidelines. Without revealing patient identities, all included patients' medical records were analyzed.

3. Results

A total of 537 patient records were reviewed during the study period, of which 270 patients met the inclusion criteria. Among these, 144 (53.3%) were female. 108 (40%) were aged 21 to 30, and 101 (37.4%) were aged 31 to 40. The most prevalent blood group type was O+ (accounting for 144, or 53.3%). Furthermore, Thalassemia, hypertension, and hepatitis C were the commonest comorbidities in our patients, represented by 78 (29%), 13 (4.8%), and 11 (4%), respectively (Table 1).

We have shown (Figure A1) the percentages of patients according to the levels of different cardiac markers (N/A, low, normal, high) and their ER visits. The remaining patients had their tests done during their inpatient or routine outpatient visits.

The relationship between cardiac markers and ER visits was significant (p=0.01). However, the percentages mentioned only demonstrate the different rates of patients depending on their different enzyme levels and whether they visited the ER (Table 2).

The relationship between CK-MB and LDH enzyme levels, and the patient state showed no significant relationship. However, a highly significant association was found between troponin and the patient state, suggesting that high troponin levels affect patient mortality (Figure A2).

A descriptive analysis of patients’ findings including ER visits, patient status, the need for blood transfusion, the use of hydroxyurea, ECG findings, the use of anticoagulation, and age groups can be found in (Supplementary Table 1). There was no significant association found between cardiac markers and the need for blood transfusion, the use of hydroxyurea, ECG findings and the use of anticoagulation (Table 2).

The need for blood transfusion was either in the form of simple or exchange blood transfusion. In an attempt to analyze each variable on its own, the correlation continued to be insignificant (Supplementary Table 2)

4. Discussion

Few published papers studied the relationship between elevated cardiac markers and myocardial infarction in patients with SCD in Saudi Arabia. Thus, this retrospective study examines the significance of cardiac markers levels in patients with SCD and their implications for patient outcomes between June 2022 to March 2023

In our study, female patients (53.3%) are slightly more than males (46.7%), similar to regional research in Saudi Arabia, which found that females represent 52.2% (4). Also, another study in New York found that females (54.3%) are more than half of the patients (5). Additionally, we found that 29% of the patients have co-existent Thalassemia disorder in contrast to another study which was only 5% (6) (Table 1).

We’ve also found that out of the 270 patients, only 11 (4.1%) patients are deceased; this result is similar to a randomized clinical trial; they enrolled 274 patients, approximately equal to our sample size, out of those, only 6 (2%) patients had died all of which were judged as unrelated to treatment (7) (Table 4, Figure A6).

The results revealed that compared to other cardiac markers, patients with high LDH visited the ER most frequently (Table 3, Figure A3,A4,A5). Various mechanisms elevate LDH in SCD patients, including intravascular hemolysis, ischemia-reperfusion damage, and tissue necrosis (8). There are five isoenzymes for LDH: LDH-1 to LDH-5. LDH-1 specifically marks myocardial damage, and LDH-2 indicates more red blood cell breakdown but can still be elevated in myocardial damage (9). Testing for LDH at our institution does not discriminate between isoenzymes, and the elevated LDH doesn't necessarily imply myocardial infarction. Moreover, prior studies proved that LDH is strongly correlated with the markers of hemolysis (10, 11); this explains why most patients who visited the ER had high LDH in this study(Table 3, Figure A5).It also showed that 3.7% with elevated LDH have died; even though ten out of 11 cases with high LDH have passed away, there is an increased number of alive patients with high LDH (74.8%)(Figure A5,A8).. Another study showed a clear trend toward an association between LDH and all-cause mortality. However, it did not reach statistical significance (12).

Our study showed elevated levels of troponin (9.3%) and a significant relationship between high troponin levels and mortality. We found that 5.9% of those with elevated troponin have died (Table 3, Figure A7,A8,A9). Also, another study found that troponin elevation significantly increases the likelihood of death with a hazard ratio of 2.6 (13). Another paper showed high troponin levels during the vaso-occlusive crisis but without the mortality association (14). Furthermore, a study showed a marked elevation of troponin in patients with SCD. Still, it was not related to the traditional cardiovascular risk factors but somewhat related to the hemolytic burden and pulmonary hypertension, which they thought was why SCD affects the heart and ultimately increases the mortality rate (15) .

While multiple medication options are available for SCD, hydroxyurea is the most effective in reducing the frequency of painful crises, spleen dysfunction, pulmonary hypertension, and other complications (16). Studies have confirmed that hydroxyurea reduces the frequency and severity of painful crises, decreases the reliance on blood transfusions, and enhances overall survival rates in patients with SCD. Hydroxyurea is also relatively safe and well-tolerated, with minimal adverse effects reported by patients (16, 17). In our cohort, we found no relevant connection between the use of hydroxyurea and elevated cardiac markers (Table 3, Table 4 Figure A10, Figure A11, Figure A12, Figure A13). During vaso-occlusive crisis (VOC) , elevated troponin and galectin protein levels were observed, indicating myocardial damage (18). However, multiple studies suggest that hydroxyurea may reduce VOC and help prevent the occurrence of acute coronary syndrome (19, 20). Based on the findings of those studies and previous research, hydroxyurea has become the standard of care for many SCD patients due to its success rate and safety profile.

Table 4. Descriptive analysis.

Variable		Group	N	%
Patient state		Died	11	(4.1%)
		Alive	259	(95.9%)
Using Hydroxyurea		No	57	(21.1%)
		Yes	213	(78.9%)
Need for blood transfusion		No	46	(17%)
		Yes	224	(83%)
Age		Minimum	0	3.7%
		Maximum	2740	0.4%
		Mean	40
		Median	7
		Standard deviation	228
Number of blood transfusion	Simple transfusion	Minimum	0
		Maximum	180
		Mean	12
		Standard deviation	22
	Exchange transfusion	Minimum	0
		Maximum	94
		Mean	7
		Standard deviation	17
	Total transfusion	Minimum	0
		Maximum	215
		Mean	20
		Standard deviation	36
ECG		N/A	221	(81.9%)
		Abnormal	33	(12.2%)
		Normal	16	(5.9%)
Age		Minimum	19
		Maximum	82
		Mean	32.2
		Median	32
		Standard deviation	8.78
Antiplatelets/ Anticoagulant medication		No	28	(10.4%)
		Yes	242	(89.6%)

Table 4. Descriptive analysis.

Variable		Group	N	%
Patient state		Died	11	(4.1%)
		Alive	259	(95.9%)
Using Hydroxyurea		No	57	(21.1%)
		Yes	213	(78.9%)
Need for blood transfusion		No	46	(17%)
		Yes	224	(83%)
Age		Minimum	0	3.7%
		Maximum	2740	0.4%
		Mean	40
		Median	7
		Standard deviation	228
Number of blood transfusion	Simple transfusion	Minimum	0
		Maximum	180
		Mean	12
		Standard deviation	22
	Exchange transfusion	Minimum	0
		Maximum	94
		Mean	7
		Standard deviation	17
	Total transfusion	Minimum	0
		Maximum	215
		Mean	20
		Standard deviation	36
ECG		N/A	221	(81.9%)
		Abnormal	33	(12.2%)
		Normal	16	(5.9%)
Age		Minimum	19
		Maximum	82
		Mean	32.2
		Median	32
		Standard deviation	8.78
Antiplatelets/ Anticoagulant medication		No	28	(10.4%)
		Yes	242	(89.6%)

Patients with SCD often require blood transfusions to manage their symptoms, including replacing unhealthy sickled cells with healthy red blood cells. According to a systematic review by Akaba et al., transfusion therapy is crucial in managing SCD and reducing potential complications associated with the disease (21). In our study, 83% of participants required blood transfusions, while 17% did not (Table 3, Figure A14).. While blood transfusions are a widely used treatment option for SCD, there is no established connection between blood transfusion and cardiac markers levels. Previous studies have not tested the relationship between blood transfusion and cardiac enzyme levels. However, a 2008 study found that six patients with myocardial infarction (MI) survived after receiving a simple blood transfusion (22). This suggests that blood transfusions may reduce cardiovascular complications in patients with SCD. Although there was no significant association between blood transfusion and cardiac markers, individuals who required blood transfusions had normal troponin and CK levels (41.9%), (60.4%) respectively, while LDH levels were high (76.3%) (Table 3, Figure A15, A16, A17). LDH is known to be closely correlated with intravascular hemolysis, as mentioned above, which is a medical emergency and an indication for blood transfusion in patients with SCD (23). Further investigations are needed to fully define the relationship between blood transfusions and cardiac markers in individuals with SCD.

This study's finding suggests no evidence of a statistically significant correlation between electrocardiogram (ECG) changes and cardiac markers (Table 3, Figure A18,A19, A20). Furthermore, a review of 19 cases of documented MI in SCD by Ishak et al. demonstrates that ECG findings and cardiac markers are frequently unhelpful in diagnosing myocardial infarction in SCD patients (24). Also, a review by Voskaridou et al. reported that ECG is often unhelpful, as nonspecific ST-T wave changes commonly exist in SCD (25). Nonetheless, Dosunmo et al. stipulated that patient with SCD in a steady state tend to have ECG abnormalities before age 20 (26). However, the findings in this study could be inconclusive due to the nature of the data, as a large amount of data is unknown (82%).

Our study showed a significant relationship between age and cardiac markers level CK-MB and Troponin (p=0.001) . The majority from age group ( 21 - 30), (31 to 40), and (more than 50 years old) have normal levels (23.7%, 23.7%, and 1.1% respectively), while less than 21 years old the CPK level most of them are N/A (3.7).Moreover , Age and cardiac enzyme (troponin) level demonstrated a moderate correlation. The majority of the age groups (21-30),(31-40), and (41-50), had a normal troponin level (15.6%, 17% and 7.8% respectively) and mainly high in the (31-40) and (41-50) groups (3.3%, 3.3%.) while being low in (21-30) and (31-40) age groups (7.4% ,7%). (Table 3, Figure A21, A22, A23). Although No previous studies have assessed the relationship between age and cardiac markers levels in adult patients with SCD specifically . A study by Ali et al. consisting of 289 patients with SCD, with an age range from 6 months to 18 years, showed that cardiac abnormalities in patients with SCD correlate with the age of the patients and the severity of the disease (27).

Patients with SCD commonly exhibit altered platelet function, activation, inflammation, and endothelial dysfunction. Hence, it places them in a high-risk category for thrombotic complications (28). Although some studies have attempted to establish a connection between the use of antiplatelet medications and a decrease in VOC, there is no conclusive evidence regarding using antiplatelet agents to prevent VOCs in SCD patients (29). The studies investigating the association between anticoagulants and cardiac markers have been limited in number. Furthermore, while this research demonstrated no relationship between antiplatelet use and variations in cardiac markers (Table 3,4 Figure A24, A25) , additional research is required to monitor the extended use of antiplatelet agents and assess their impact on cardiac markers levels.

Notably, limitations of this study include the possibility of inaccuracies in the documentation of patients' data given the retrospective nature of the study. Additionally, since the study was conducted in a specific region in Saudi Arabia, its findings may not accurately reflect other areas. Thus, further research is necessary to confirm the significance of cardiac markers in SCD, particularly in other regions.

5. Conclusions

The study identifies a significant correlation between elevated cardiac markers levels and patient age, frequency of ER visits, and mortality rates. Specifically, most patients visiting the ER had high LDH levels, while elevated troponin levels were associated with increased mortality rates, potentially indicating damage to cardiomyocytes. We also found that many factors can affect the sensitivity of cardiac markers in patients with SCD in diagnosing MI, thus rendering the diagnosis of MI in SCD imprecise.