After looking at 8 plasma sphingolipid species—including 4 ceramides and 4 sphingomyelins—with saturated fatty acids of 16, 20, 22, and 24 carbons, researchers found that higher plasma levels of Cer-16 and SM-16 were associated with increased risk of sudden cardiac death (SCD).
These findings were published in JAMA Network Open, and are based on a large, population-based cohort study including 4612 participants from the Cardiovascular Health Study. The median (SD) age was 77 (5) years and median (IQR) follow-up was 10.2 (5.5-11.6) years, with baseline data collected between January 1992 and December 1995 during annual examinations, and data analysis conducted between February 2020 and September 2023.
These new findings come at a time where the potential influence of sphingolipids, including ceramides and sphingomyelins, on the pathophysiology and risk of SCD through multiple biological activities is recognized, but the association between the fatty acid acylated to plasma sphingolipid species' length and SCD risk is unclear.
Lipids | Image credit: Vitalii Vodolazskyi – stock.adobe.com
The researchers recorded 215 cases of SCD and found that plasma ceramides and sphingomyelins with palmitic acid—Cer-16 and SM-16—were linked to an increased risk of SCD per higher SD of log sphingolipid levels. Specifically, individuals with Cer-16 had a 34% increased risk (95% CI, 1.12-1.59) and individuals with SM-16 had a similar 37% increased risk of SCD (95% CI, 1.12-1.67). According to the study, these associations did not vary based on baseline age, sex, race, or body mass index.
Additionally, after correction for multiple testing, there were no significant associations between SCD and sphingolipids that contained very long chain saturated fatty acids. These included:
- Ceramide with arachidic acid (HR, 1.06; 95% CI, 0.90-1.24)
- Ceramide with behenic acid (HR, 0.92; 95% CI, 0.77-1.10)
- Ceramide with lignoceric acid (HR, 0.92; 95% CI, 0.77-1.09)
- Sphingomyelin with arachidic acid (HR, 0.83; 95% CI, 0.71-0.98)
- Sphingomyelin with behenic acid (HR, 0.84; 95% CI, 0.70-1.00)
- Sphingomyelin with lignoceric acid (HR, 0.86; 95% CI, 0.72-1.03)
Looking deeper into the mechanism behind the connection between sphingolipids and SCD, the researchers conducted sensitivity analyses that incorporated additional adjustments for prevalent clinical diseases—including chronic obstructive pulmonary disease, heart failure, atrial fibrillation, and chronic kidney disease by estimated glomerular filtration rate (eGFR)—or electrocardiographic risk factors for SCD—heart rate, QT interval, and QRS interval. These adjustments only marginally weakened the associations observed with Cer-16 and SM-16 in relation to SCD. However, a model that included adjustments for C-reactive protein (CRP), troponin T, and N-terminal pro–brain-type natriuretic peptide (NT-proBNP) levels demonstrated a diminished association.
The researchers proceeded to investigate the correlation with nonfatal myocardial infarction (MI) to discern whether the observed associations with SCD were exclusive to SCD. In a subgroup of 4092 patients without a history of MI, each SD log difference of Cer-16 demonstrated a 21% increased risk of incident MI, affecting, 412 participants (95% CI, 1.07-1.38), and a 46% elevated risk of SCD, affecting 160 participants (HR, 1.46; 95% CI, 1.19-1.80). The SD log difference of SM-16 did not exhibit an association with nonfatal MI, but was linked to a 32% higher risk of SCD (HR, 1.32; 95% CI, 1.03-1.68).
The researchers proposed a hypothesis suggesting ceramide and sphingomyelin species with acylated palmitic acid may contribute to the increase in SCD risk through 2 linked mechanisms: direct impact on cardiac electrophysiology and an indirect effect involving ceramide release and an enhanced inflammatory response. Disruptions in efficient electrical signaling, a hallmark of cardiac arrhythmias leading to SCD, may arise from altered electrophysiological cellular communication facilitated by lipid rafts enriched in sphingomyelins.
“In the case of left ventricular tachyarrhythmias that are the cause of SCD, these are generally propagated via cell-to-cell electrical signaling through gap junctions, highly regulated areas of electrical signaling,” the authors explained. “Lipid rafts, which are enriched in sphingomyelins, play an important role in this process, both by their influence on ion channels and by proper assembly of these microdomains. Aberrant electrical signaling, possibly due to altered electrophysiological cellular communication, can predispose to SCD.”
They also noted that the parallel associations between Cer-16 and SM-16 may be due to membrane-bound sphingomyelins releasing ceramide through neutral sphingomyelinase, a stress response mechanism in ischemia and reperfusion injury. While Cer-16 is linked to both nonfatal MI and SCD, SM-16 was specifically associated with SCD, suggesting a potential impact on aberrant electrical signaling. The associations of Cer-16 with both MI and SCD persist independently of various factors, but the links to SCD are attenuated after adjusting for inflammatory and myocardial wall stress-related markers like CRP, NT-proBNP, and troponin T levels.
Based on this study, a key approach to prevent SCD involves implanting cardioverter defibrillators in individuals who are at high risk. It has been proposed to incorporate sphingolipids into the risk assessment for coronary artery disease and cardiovascular events, as indicated by previous research, and this study underscores the need for additional investigation. Subsequent research in diverse populations should assess whether including sphingolipid risk species enhances the accuracy of risk prediction.
“If the associations prove to be causal, reducing the levels of ceramide and sphingomyelin species with acylated palmitic acid may be a useful therapeutic target for the prevention of SCD,” the authors concluded. “Additional studies will be needed to establish determinants of plasma levels of ceramide and sphingomyelin species and to evaluate whether ceramide and sphingomyelin levels may have clinical utility as potential components of SCD risk scores.”
Bockus LB, Jensen PN, Fretts AM, et al. Plasma ceramides and sphingomyelins and sudden cardiac death in the cardiovascular health study. JAMA Netw Open. Published online November 17, 2023. doi:10.1001/jamanetworkopen.2023.43854