Murphy, Sabina A.

Importance Although the Martin-Hopkins equation is widely validated and used to estimate low-density lipoprotein cholesterol (LDL-C) for clinical care, a simplified equation could streamline implementation and enable broader adoption. Objective To develop a simplified machine learning–based alternative to the Martin-Hopkins equation using multivariate adaptive regression splines (LDL-C–MH-MARS) and compare its performance with the Friedewald (LDL-C–F), Sampson–National Institutes of Health (LDL-C–S), Modified Sampson (LDL-C–MS), and Martin-Hopkins (LDL-C–MH) equations. Design, Setting, and Participants The Very Large Database of Lipids is a cross-sectional database of clinical lipid measurements from a population-representative convenience sample of adult and pediatric patients. Lipid measurements were performed by Vertical Auto Profile ultracentrifugation between October 1, 2015, and June 30, 2019. The study included patients with complete lipid panel data who were randomly assigned to a training set and a test set. External validation against preparative ultracentrifugation-based LDL-C measurements was performed in reference laboratory datasets from the Mayo Clinic (broad LDL-C concentrations) and the Further Cardiovascular Outcomes Research With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition in Subjects with Elevated Risk (FOURIER) trial (observations from patients with low LDL-C concentrations while taking evolocumab). Study data were analyzed from January to October 2025. Exposures LDL-C–F, LDL-C–S, LDL-C–MS, LDL-C–MH, and LDL-C–MH-MARS equations. Main Outcomes and Measures Accuracy of estimated vs ultracentrifugation-measured LDL-C concentration based on bias, root mean square error (RMSE), and concordance by guideline-based categories. Results The study included 4 939 528 patients (mean [SD] age, 56 [16] years; 2 635 486 female [53%]) with complete lipid panel data who were randomly assigned to a training set (n = 3 292 889) and a test set (n = 1 646 639). LDL-C–MH-MARS equation demonstrated a very low median (IQR) bias of −0.1 (−2.1 to 1.8) mg/dL (to convert to millimoles per liter, multiply by 0.0259), comparable with LDL-C–MH. The median (IQR) difference between the MARS and original Martin-Hopkins equations (ie, LDL-C–MH-MARS – LDL-C–MH) was −0.5 (−1.2 to 0) mg/dL, further suggesting comparability between the 2 methods. The RMSE was smallest for LDL-C–MH-MARS (4.7 mg/dL) and LDL-C–MH (4.9 mg/dL), followed by LDL-C–S (5.8 mg/dL), LDL-C-MS (6.0 mg/dL), and LDL-C–F (7.2 mg/dL). The proportion of patients correctly classified according to clinical categories was nearly identical for LDL-C–MH-MARS (89.7%) and LDL-C–MH (89.6%) but lower for LDL-C–S (86.3%), LDL-C–MS (84.7%), and LDL-C–F (83.1%). The LDL-C–MH-MARS, LDL-C–MH, LDL-C–MS, LDL-C–S, and LDL-C–F equations underestimated LDL-C concentration in 16%, 17%, 28%, 39%, and 60%, respectively, when classifying LDL-C less than 70 mg/dL in patients with triglyceride concentrations of 200 to 399 mg/dL (to convert to millimoles per liter, multiply by 0.0113). The patterns of results were similar in external validation datasets, with the LDL-C–MH-MARS and LDL-C–MH equations demonstrating the highest accuracy. Conclusions and Relevance Study results suggest that the new machine learning–based LDL-C equation provided results comparable with those of the original Martin-Hopkins method while simplifying implementation to a single equation.

Background— Ranolazine, a piperazine derivative, reduces ischemia via inhibition of the late phase of the inward sodium current (late I Na ) during cardiac repolarization, with a consequent reduction in intracellular sodium and calcium overload. Increased intracellular calcium leads to both mechanical dysfunction and electric instability. Ranolazine reduces proarrhythmic substrate and triggers such as early afterdepolarization in experimental models. However, the potential antiarrhythmic actions of ranolazine have yet to be demonstrated in humans. Methods and Results— The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis in Myocardial Infarction (TIMI) 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non–ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG (Holter) recording was performed for the first 7 days after randomization. A prespecified set of arrhythmias were evaluated by a core laboratory blinded to treatment and outcomes. Of the 6560 patients in MERLIN-TIMI 36, 6351 (97%) had continuous ECG recordings that could be evaluated for arrhythmia analysis. Treatment with ranolazine resulted in significantly lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular tachycardia lasting ≥8 beats (166 [5.3%] versus 265 [8.3%]; P <0.001), supraventricular tachycardia (1413 [44.7%] versus 1752 [55.0%]; P <0.001), or new-onset atrial fibrillation (55 [1.7%] versus 75 [2.4%]; P =0.08). In addition, pauses ≥3 seconds were less frequent with ranolazine (97 [3.1%] versus 136 [4.3%]; P =0.01). Conclusions— Ranolazine, an inhibitor of late I Na , appears to have antiarrhythmic effects as assessed by continuous ECG monitoring of patients in the first week after admission for acute coronary syndrome. Studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.

Background — The TIMI myocardial perfusion grade (TMPG) and ST-segment resolution both reflect perfusion and are associated with mortality after thrombolysis for acute myocardial infarction. We hypothesized that these measures would also be associated with infarct size by single photon emission computed tomography (SPECT). Methods and Results — In the LIMIT AMI trial (Limitation of Myocardial Injury following Thrombolysis in Acute Myocardial Infarction) of lytic monotherapy versus lytic plus rhuMAb CD18, early 90-minute TMPG (n=221) and ST segment resolution (n=242) were compared with subsequent SPECT Technetium-99 m Sestamibi, measuring the percentage of the left ventricle with no Sestamibi uptake. Infarct sizes were larger with TMPG 0 or 1 (a closed or stained myocardium) than with TMPG 2 or 3 (open myocardium, median 13% versus 7%, P =0.004). Infarcts were also larger in patients with no ST segment resolution (median 15%) or incomplete resolution (11%) than in those with complete resolution (6%, overall P =0.0001). The difference in infarct size by TMPG persisted when stratified by category of ST resolution. Conclusions — There may be a pathophysiological link between early restoration of tissue-level perfusion and reduced subsequent infarct size that may partially explain why these early angiographic and electrocardiographic measures are associated with long-term survival.