Statins are the cornerstone of lipid-lowering therapy and have proven efficacy in reducing atherosclerotic cardiovascular events. They have both cholesterol-lowering and pleotropic effect [1]. Although many studies demonstrate mortality benefit of statins in coronary artery disease (CAD) patients and primary prevention [2][3], some studies demonstrate statin-associated cardiomyopathy [4]. Despite their established safety profile, statin-associated myopathy remains one of the most recognized adverse effects, ranging from mild muscle pain to severe rhabdomyolysis [5]. While most research on statin-induced myotoxicity has focused on skeletal muscle, the potential influence of statins on cardiac muscle has received comparatively less attention.

In this context, evaluating the potential impact of high-intensity statin therapy on myocardial strain parameters may provide novel insights into the myocardial safety profile of statins and contribute to a better understanding of their effects beyond lipid lowering.

Cardiac myocytes, like skeletal myocytes, are striated and metabolically active cells that depend on mitochondrial function and oxidative metabolism. Given this shared physiology, it is biologically plausible that high-dose or long-term statin therapy might exert subtle effects on myocardial structure or contractile performance, even in the absence of overt clinical cardiotoxicity [6]. Traditional measures such as left ventricular ejection fraction may fail to detect these subtle changes, highlighting the need for more sensitive indices of myocardial function.

Speckle-tracking echocardiography (STE) enables the quantification of myocardial deformation through strain imaging, allowing early detection of subclinical systolic dysfunction. Recent studies have demonstrated that strain parameters are valuable markers for assessing subtle myocardial injury induced by systemic conditions or pharmacologic agents [7].

The aim of this study was to evaluate the effect of six months of high-dose statin therapy on left and right ventricular function, particularly global longitudinal strain, using conventional echocardiography, tissue Doppler imaging, and two-dimensional STE in patients without CAD receiving statin therapy for primary prevention.

This study is a single-center, prospective study. We included 38 patients with fasting low-density lipoprotein cholesterol (LDL-C) levels of 160 mg/dl or higher between the age of 18 and 65 years. All patients had intensive statin therapy for primary prevention. Intensive statin therapy is determined as 40 or 80 mg atorvastatin and 20 or 40 mg rosuvastatin. Patients with a history of CAD or heart failure, myocarditis, moderate or severe valvular disease, hypertension, diabetes mellitus, liver and kidney diseases were not included. Also patients currently on statin therapy, smokers and with ejection fraction (EF) less than 60% and with a high pretest probability of CAD were not included. The study protocol was approved by the local ethical committee (decision number: E2-21-446). We acquired informed consent from all the patients participating in our study.

All subjects underwent a standard echocardiographic examination at the initiation of intensive statin therapy and after six months of therapy. Vivid 7 ultrasound cardiovascular system (GE Healthcare) was used to obtain transthoracic echocardiographic measurements. Left ventricular ejection fraction was calculated using the biplane modified Simpson method. Diastolic function parameters such as early diastolic mitral inflow velocity (E), late diastolic mitral inflow velocity (A), and the E/A ratio were measured with pulsed wave Doppler from transmitral recordings in the apical 4-chamber view. Tissue Doppler imaging (TDI) was performed from an apical 4-chamber view. Peak velocity at the lateral and septal annulus during early diastole (e′) was measured. The ratio of peak transmitral early velocity to early diastolic mitral annular velocity (E/e′) was calculated.

Left ventricular global longitudinal strain (LV-GLS) and right ventricular global strain (RV-GS) were assessed using STE [8]. Heart rate and blood pressure were assessed immediately before echocardiographic evaluation in all participants. Only patients with values within normal limits were included in the strain analysis to avoid hemodynamic confounding. All echocardiographic examinations were performed with a GE Vivid E95 ultrasound system (GE Vingmed Ultrasound, Horten, Norway), using appropriate sector depth and frame rates between 50 and 90 frames per second. Apical views were acquired with at least three consecutive cardiac cycles. For LV-GLS, endocardial borders were manually traced in apical four-chamber, two-chamber, and three-chamber views, followed by automated tracking and manual adjustment if necessary. The average peak longitudinal strain from all 18 LV segments was calculated as the LV-GLS. For RV strain analysis, the apical four-chamber view focused on the right ventricle was used. The right ventricle (RV) was divided into six segments: the basal, mid, and apical segments of the RV free wall and septum. The region of interest was automatically generated, and the right ventricular endocardial border was manually determined at end-systole. RV free wall longitudinal strain was calculated as the average of the right ventricular lateral basal, mid, and apical segments, excluding the septal segments [9]. All analyses were performed by two independent experienced observers, and in cases of discrepancy, consensus was reached to determine the final measurements.

Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range); categorical variables were defined as percentages or counts. Left and right ventricular strain parameters at the initiation of intensive statin therapy and after 6 months of therapy were compared using the Wilcoxon Signed Rank Test for nonparametric data and the Paired Sample T-Test for parametric data. Data analyses were performed by using SPSS for Windows, version 22.0 (SPSS Inc., Chicago, IL, USA).

We analyzed 38 patients (mean age 51.5±7.6 years; 36.8% male) who started intensive statin therapy for primary prevention. After six months of intensive statin therapy, we observed that levels of creatine kinase (CK), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were significantly higher than their baseline values (115.0±73.8 U/L vs. 96.5±62.0 U/L, p=0.014; 18.5±7.0 U/L vs. 17.0±4.0 U/L, p=0.049; 20.0±17.0 U/L vs. 15.0±12.5 U/L, p=0.036, respectively). Conversely, levels of triglycerides (TG) and LDL-C decreased after the six months of statin therapy (160.0±101.8 mg/dl vs. 138.0±95.3 mg/dl, p=0.001; 200.5±39.8 mg/dl vs. 97.5±29.3 mg/dl, p<0.001, respectively) (Table 1).

All patients had preserved left ventricular systolic function, with mean LVEF values of 63.4±2.9% at baseline and 63.1±3.1% at 6 months, with no significant change during follow-up (p=0.67).

There were no significant differences in diastolic function parameters measured via TDI before and six months after intensive statin therapy. Septal and lateral e’ values were 10.0±2.3 cm/sec vs. 9.5±2.0 cm/sec (p=0.938) and 13.3±2.4 cm/sec vs. 13.5±2.3 cm/sec (p=0,886), respectively. E/e’ values were 5.4±1.3 vs. 5.0±2.0 (p=0.906).

No significant difference was observed in LVGLS and RVGLS values before and six months after intensive statin therapy (-19.2±2.3 vs. -19.4±1.7, p=0.569; -19.2±4.2 vs. -19.5±4.4, p=0.553, respectively) (Table 2, Figure 1, 2).

The present study showed that intensive statin therapy was not associated with a significant change in myocardial function measured as strain imaging in patients receiving statin for primary prevention.

Statins are widely used drug class in cardiology practice. Many studies showed that statins improved prognosis in CAD [10]. But the findings of studies that evaluate effects of statins on cardiac muscle are controversial.

In a study of 14 patients, diastolic doppler parameters were worsened after initiation of statin therapy [11]. In an other study, discontinuation of statin therapy and initiating coenzyme Q10 (CoQ10) improved diastolic dysfunction and NYHA class 4. Statin therapy was associated with an increase in brain natriuretic peptide in patients with CAD [12]. In a study of 28 patients without overt cardiovascular disease, statin therapy was associated with statisticaly significant decrease in myocardial function as evaluated with strain imaging [13]. In cancer patients treated with antracycline, primary prevention with atorvastatin did not decrease LV damage [14].

In contradictory, left ventricular systolic and diastolic strain and strain rates were improved with one year pitavastatin therapy in patients with hypercholesterolemia and preserved ejection fraction [15]. A large real world observational study with 15,000 heart failure patients (EF ≤40%) revealed that statin use was associated with a lower risk of MACE during follow up [16].

Statins may play a role in myocardial damage in a few ways. 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) is a target at immune-mediated myopathy and statin usage upregulates HMGCR [17]. In the literature, there are a few cases in which cardiac involvement was occured together with myopathy [17-19]. A similar mechanism is likely possible for cardiac myocytes. A subclinical damage may ocur due to high dose statin and antibody mediated inflammation in cardiac muscles. Considering that cardiac muscle is also striated, it is plausible that patients with statin-associated myopathy may exhibit subtle reductions in myocardial strain. However, in our cohort, no patients developed myopathy, which may explain the absence of strain alterations. Further studies including patients who develop clinically significant myopathy are needed to determine whether skeletal muscle toxicity extends to myocardial tissue, potentially leading to strain impairment. Such investigations could clarify the mechanistic interplay between lipid-lowering therapy, skeletal muscle side effects, and myocardial function.

Statins are generally well tolerated, yet skeletal muscle myopathy and, in rare cases, rhabdomyolysis, remain recognized adverse effects. The underlying mechanisms are thought to involve mitochondrial dysfunction, CoQ10 depletion, and impaired membrane integrity [20]. Statins decrease plasma CoQ10 [21][22]. Low levels of mitochondrial CoQ10 may cause a reduction in myocardial energy production and this potential mechanism may be related to impairment of myocardial diastolic and systolic functions which are highly energy dependent [4][23].

In our study, intensive lipid-lowering therapy did not result in significant changes in left or right ventricular strain parameters over a 6-month follow-up in hyperlipidemic patients. These findings suggest that intensive lipid-lowering treatment exerts no short-term detrimental effects on myocardial mechanics. An additional strength of our analysis was the inclusion of right ventricular strain. Right ventricular performance can be influenced by pulmonary loading conditions as well as systemic toxicity. The absence of significant changes in right ventricular strain further supports the short-term safety of intensive lipid-lowering therapy on global myocardial function.

Our study results can be interpreted in different ways. No change in LV strain may represent there isn’t any effect of statins on LV function in our study population. Or, it can be interpreted as statins stop worsening of hypercholesterolemia induced cardiomyopathy and preventing it from getting worse as it has been shown that hypercholesterolemia itself can impair myocardial function parameters, even in the absence of overt cardiovascular disease [24]. In our study, baseline strain values were within normal limits, suggesting preserved myocardial mechanics prior to initiation of intensive therapy. This preserved baseline function may partly explain the lack of measurable changes after treatment.

This study has some limitations. One limitation is relatively small sample size. As a strength, each patient served as its own control but if more patients were enrolled, our study would be more meaningful. Also, we followed up patients for 6 months after initiation of statin therapy and further studies are needed to evaluate long term effects of statins on ventricular functions. And finally, effects of all potential confounding factors on very sensitive modality ventricular strain cannot be controlled.

High-dose statin therapy for primary prevention does not significantly affect left or right ventricular strain parameters over a 6-month period. These findings suggest that, in individuals with preserved or subclinical cardiac function, short- to mid-term statin therapy has no measurable impact on myocardial mechanical performance.

Relationships and Activities. None.

Funding. None.