Sage Journals: Discover world-class research

Abstract

Background:

Although there is strong evidence supporting the use of statin therapy after myocardial infarction (MI), some mechanistic gaps exist regarding the benefits of this therapy at the very onset of MI. Among the potential beneficial mechanisms, statins may improve myocardial electrical stability and reduce life-threatening ventricular arrhythmia, as reported in stable clinical conditions. This study was designed to evaluate whether this mechanism could also occur during the acute phase of MI.

Methods:

Consecutive patients with ST-segment elevation MI were treated without statin (n = 57) or with a simvastatin dose of 20 to 80 mg (n = 87) within the first 24 hours after MI symptom onset. Patients underwent digital electrocardiography within the first 24 hours and at the third and fifth days after MI. The QTC dispersion (QTcD) was measured both with and without the U waves.

Results:

Although QTcD values were equivalent between the groups at the first day (80.6 ± 36.0 vs 80.0 ± 32.1; P = 0.36), they were shorter among individuals using simvastatin than in those receiving no statins on the third (90.4 ± 38.6 vs 86.5 ± 36.9; P = .036) and fifth days (73.1 ± 31 vs 69.2 ± 32.6; P = .049). We obtained similar results when analyzing the QTcD duration including the U wave. All values were adjusted by an ANCOVA model after propensity-score matching.

Conclusions:

Statins administered within 24 hours of ST-segment elevation MI reduced QTc dispersion, which may potentially attenuate the substrate for life-threatening ventricular arrhythmias.

Keywords

STEMI statins QTc

Background

Early statin administration during acute coronary syndromes (ACS) is highly recommended according to the current European Society of Cardiology and American Heart Association/American College of Cardiology ACS guidelines.^1,2 A large spectrum of mechanisms may underlie this potential benefit, including the direct cellular effects of statins on the coronary arterial wall or cardiomyocytes. Indeed, among patients who underwent an early reperfusion, the mass of myocardial infarction (MI) and the peri-infarct zone were smaller in those receiving statins.^3,4

Despite this body of evidence, there are still some mechanistic gaps in the current understanding of early high-dose statin use during an ST-segment elevation MI (STEMI), although it has been shown to reduce inflammatory response and improve endothelial function.⁵ Animal models^6
-8 and clinical trials^9,10 show that statins may improve myocardial electrical stability. Statins neutralize the pro-arrhythmic effect of lysophosphatidylcholine (LPC), a metabolite that accumulates in cardiomyocytes during ischemia and triggers nonselective cation currents. Thus, by antagonizing LPC-induced currents in ionic channels, statins can attenuate the pro-arrhythmic effect of this phospholipid in ischemic myocardium.^6,7 Accordingly, high-dose statin therapy reduced the incidence of sudden cardiac death in patients with chronic coronary artery disease (CAD) by 10%,¹¹ and intensive lipid-lowering treatment after ACS consistently reduces the incidence of non-sustained ventricular tachycardia and ventricular premature beats.⁹

QTC dispersion (QTcD) is an established predictor of sudden death and arrhythmia.^9,12 Compelling evidence indicates that life-threatening ventricular arrhythmias after MI are associated with increased QTcD^13
-15 and that QTcD is decreased by statins in clinically stable patients.^10,16 The present study was therefore designed to investigate whether the effect of statins on QTcD may also occur in patients with STEMI.

Methods

Patients

This was a propensity-matched observational retrospective study conducted with prospectively obtained data from the Brazilian Heart Study (BHS), an observational and longitudinal study (ClinicalTrials.gov Identifier: NCT02062554). Consecutive patients (n = 144) who were enrolled into the BHS were selected for this investigation. The inclusion criteria for the BHS were as follows: (1) less than 24 hours after the onset of pain; (2) ST-segment elevation of at least 1 mm on the frontal leads and 2 mm on the horizontal leads; and (3) myocardial necrosis, as evidenced by an increase in at least 1 value above the 99th percentile of the reference limit of CK-MB (25 U/L) and troponin I (0.04 ng/mL) followed by a decline in both. To address the central question, patients were divided into 2 groups: those who had statins prescribed in the acute phase and those who did not.

A complete medical evaluation was performed upon hospital admission (D1) followed by an initial blood sample collection with a mean fasting time of 533 ± 201 minutes. The second sample was collected after a 12-hour overnight fast at the fifth day of hospitalization (D5). The attending physicians defined the medical treatment, including the type of reperfusion therapy and simvastatin use and dose, without the influence of the investigators. Patients were included between 2006 and 2009, and statin administration at hospital admission was not consolidated in 2004 guidelines but rather its prescription before discharge.¹⁷ Simvastatin was the only statin available in the hospital, and the study was conducted with it. Our study was approved by the local ethics committee, and all patients provided informed consent.

Definitions

Diabetes mellitus (DM) was defined as prior use of antidiabetic drugs or hemoglobin A1c (HbA1c) ≥ 6.5% at admission. Hypertension history was defined by current or prior use of antihypertensive medications or previous diagnosis of hypertension on available medical reports. Dyslipidemia and sedentarism were self-reported. Family history of CAD was defined as the occurrence of cardiovascular events in first-degree male relatives aged 55 years or less or female relatives aged 65 years or less.

Biochemical Analyses

The following blood or plasma measurements were obtained: glucose (Glucose GOD-PAP; Roche Diagnostics, Mannheim, Germany), total cholesterol (CHOD-PAP; Roche Diagnostics, Mannheim, Germany), triglycerides (GPO-PAP; Roche Diagnostics), high-density cholesterol (without sample pretreatment; Roche Diagnostics), and HbA1c (Variant II, Bio-Rad Laboratories, Hercules, California). The LDL cholesterol level was calculated using the Friedewald formula.

Electrocardiograms

Digital electrocardiogram recordings (Micromed Surface Digital Electrocardiogram) were obtained at admission and on the third (D3) and fifth (D5) days based on previous studies that demonstrated a greater QTc on day 3 post-MI with progressive normalization at discharge.^15,18 The QT interval was measured using the space between the first deflection of the QRS complex and the end of the T-wave as reference points. The end of the T-wave was considered the nadir between the T- and U-waves in case the U-wave started before the T-wave ended. A priori, if the T-wave was isoelectric or had a peak <2 mm, QT analysis would be excluded. However, no exclusions occurred on the basis of this criterion. U-waves, when identified, were included within the T wavelength, and these patients were analyzed separately as an alternate measurement of the dispersion of repolarization. QTc was calculated using Bazzet formula. QTc was measured in lead D2. QTc dispersion was calculated as the difference between the maximal and the minimal QTc intervals after calculating QTc in each of the 12 leads examined. The primary end point was the Δ QTcD between D1 and D5.

Statistical Methods

Data are presented as mean ± standard deviation for normally distributed data and as median (interquartile range) for non-normally distributed data. Patients were divided into 2 groups depending on whether they received simvastatin (S; 20-80 mg/day) or did not receive simvastatin (NS). Due to the significant imbalance in baseline covariates between the S and the NS groups (Table 1), we used propensity score matching to assemble a balanced cohort of patients. We estimated propensity scores (covariates: age, gender, diabetes, use of antihypertensive drugs, heart failure, dyslipidemia, prior MI, prior stroke, systolic blood pressure, diastolic blood pressure, smoking, reperfusion therapy, time to reperfusion therapy, Killip class, peak CKMB level) for statin use for each of the 144 patients by using a nonparsimonious multivariable logistic regression model (c statistic = 0.87; Supplementary Figure 1) and used that to match 54 pairs of patients in the S and NS groups. We assessed the effectiveness of matching and bias reduction by estimating standardized differences, expressed as a percentage of the pooled standard deviations (Supplementary Figures 2 and 3). The χ² test was used to compare categorical data, and Student t test or Wilcoxon rank sum test were used to compare baseline parametric and nonparametric data, respectively. Additionally, ANCOVA models adjusted to the propensity scores were created to compare the QTcD across S and NS groups, after adjusting for age, sex, DM, and baseline QTcD. A 2-sided P value of .05 was considered statistically significant. Statistical analyses were performed using SPSS for Mac version 20.0 and R for Mac version 3.5.1.

Table 1.

Characteristics of the Enrolled Participants.

	Simvastatin Treatment During Hospitalization		P
	NS	S
Participants, n	57	87
Gender male, %	80	80	.97
Age, years	59 ± 10	60 ± 9	.59
Diabetes, %	22.8	48	.02
Dyslipidemia, %	33	38	.26
Prior MI, %	8.7	12.9	.44
Prior stroke, %	1.7	5.9	.22
Previous CABG	3.5	1.2	.35
Sedentarism, %	57.8	66	.28
Smoking habit, %	35	34.5	.94
Hypertension, %	60	73	.07
GRACE (points)	130 (115-140)	127 (117-144)	.50
Ejection fraction (Simpson), %	58 (47.3-60)	53 (45-59)	.37
Admission SBP, mm Hg	145 ± 28	145 ± 43	.30
Admission DBP, mm Hg	89 ± 17	90 ± 24	.75
Admission heart rate, bpm	74 ± 20	78 ± 19	.73
BMI, kg/m²	27.7 ± 11	27.5 ± 5	.88
Waist circumference, cm	94 ± 12	98.1 ± 11	.055
Peak CK-MB	175.7 (70-290)	188.2 (140-318)	.94
Infarction mass by CMRi, g	10.9 (6.7-18.8)	14.3 (9.9-22.3)	.42
Mean statin dose, mg/d	0	63.56 ± 19.81	<.001
Any reperfusion therapy, %	84	73	.13
Thrombolytic therapy, %	74	67	.22
Primary angioplasty, %	4	7	.33
Time to reperfusion, minute	356 ± 468	343 ± 444	.90
BB use, %	60	67	.12
ACEI/ARB use, %	50	50	.42
Glomerular filtration rate, mL/min	62 ± 20	66 ± 21	.71
HbA1c, %	6.4 ± 1.7	6.6 ± 1.7	.30
Killip I, %	86	88	.23
Admission HDL-C, mg/dL	38.5 (33.3-43.3)	36 (29-42)	.078
Admission LDL-C, mg/dL	123 (96.5-161)	141 (108-163)	.91
Fifth day LDL-C, mg/dL	85 (72.3-94.6)	76 (61.5-94.4)	.25
Delta LDL-C, mg/dL	-24.8	-27	.67
Admission triglycerides, mg/dL	118.5 (88-170.7)	146 (96-244)	.69
Admission glycaemia, mg/dL	128 (110.5-166.3)	127 (112-159)	.19
Admission CRP, mg/dL	0.47 (0.15 -1.18)	1 (0.39 -1.94)	.18
Fifth day CRP, mg/dL	2.49 (0.9-6.6)	3.66 (1.8-8.2)	.98

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BB, β-blocker; BMI, body mass index; CABG, coronary artery bypass graft; CMRi, cardiac magnetic resonance; CRP, C-reactive protein; DBP, diastolic blood pressure; HbA1c, hemoglobin A1c; HDL-C, High-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; SBP, systolic blood pressure.

Results

Table 1 depicts the characteristics of the study participants categorized on the basis of statin usage (S and NS groups). Based on the BHS selection criteria, the enrolled patients exclusively manifested STEMI, met the criteria for high risk, had extensive MI, and were mostly treated with reperfusion. Despite the observational nature, there was great similarity between the NS and the S groups. As shown in the table, patients had a similar extent of MI without a difference in MI mass on magnetic resonance assessments (10.9 [6.7-18.8] in the NS group vs 14.3 [9.9-22.3] in the S group; P = .42). Other characteristics confirmed the lack of difference between the groups, such as peak CK-MB level (175.7 [70-290] vs 188.2 [140-318]; P = .94), Killip class I prevalence (86 vs 88; P = .23), and even GRACE points (130 [115-140] vs 127 [117-144]; P = .50) The baseline characteristics were not different between the groups as demonstrated in Table 1. As an exception, there were more patients with DM in the S group (28.8% vs 48%; P = .02). Nevertheless, the mean HbA1c level was similar in both the groups (6.4 ± 1.7 vs 6.6 ± 1.7; P = .30), which probably reflects an increased frequency of prediabetes and good HbA1c control among patients with DM.

As for treatment, both groups underwent similar management. Only 78% of all patients had undergone any reperfusion therapy, which included primary PCI, thrombolysis, and any angioplasty done in the first 24 hours of the event (including late primary PCI and rescue PCI). There were no intergroup differences for any of the types of reperfusion as shown in Table 1. The same was true for β-blocker use (60% vs 67%; P = .12). Of the 144 patients, 58 did not receive any statin, 14 received simvastatin at a dose of 20 mg, 30 at a dose of 40 mg, and 43 at a dose of 80 mg.

In general, QTc increased from admission to D3 (481.6 ± 45.2 to 491.2 ± 50.7) and decreased from D3 to D5 (461.7 ± 40.1). Patients in the S group had an average QTcD on D1 similar to that in the NS group (80.6 ± 36.8 milliseconds vs 80.0 ± 32.2 milliseconds, P = .36; Figure 1). As expected, QTcD increased between admission and D3 and subsequently decreased by D5. From D1 to D3, the S group showed an increase of 8% ± 15% in QTcD, while the NS group showed an increase of 12% ± 6% (P < .001). From D1 to D5, the S group showed a decrease of 14% ± 1% in QTcD, while the NS group showed a decrease of 9% ± 9% (P < .001). Similar results were obtained when analyzing the QTcD duration including the U-wave.

Figure 1.

Graphical representation of the sequential evolution of QTC dispersion (QTcD) in the study population.

A comparison of QTcD changes during the first 5 days between the groups indicated that individuals in the NS group showed a greater amplitude of QTcD changes than their counterparts: (ΔQTcD D1-D3: 9.7 ± 51.9 milliseconds vs 7.8 ± 39.8 milliseconds; P < .001) and (ΔQTcD D1-D5: −7.2 ± 44.7 milliseconds vs −10.8 ± −39.6 milliseconds; P < .001]). After adjusting for the propensity score, the change in QTcD between D1 and D5 (ΔQTcD D1-D5) was statistically significant (P = .025), whereas ΔQTcD between D1 and D3 lost significance (P = .34). The main results are shown in Table 2.

Table 2.

Sequential Evolution of QTc Following MI Categorized According to Statin Use.

	Statin Use		P ^a
	NS	S	P ^a
	57	87
QTc (D1), milliseconds	475.6 ± 43	484.1 ± 48.6	.88
QTc (D3), milliseconds	485.8 ± 47.2	492.63 ± 49.8	.70
QTc (D5), milliseconds	457.1 ± 41.6	463 ± 37.5	.82
QTcD (D1), milliseconds	80.6 ± 36	80 ± 32	.36
QTcD (D3), milliseconds	90.4 ± 38.6	86.5 ± 36.9	.036
QTcD (D5), milliseconds	73.1 ± 31	69.2 ± 32.6	.049
Delta QTcD (D1-D3), milliseconds^b	9.7 ± 51.9 (12 ± 6%)	7.8 ± 39.8 (8 ± 15%)	<.001
Delta QTcD (D1-D5), milliseconds^c	−7.2 ± 44.7 (−9 ± 9%)	−10.8 ± −39.6 (−14 ± 1%)	<.001

Abbreviations: ANCOVA, analysis of covariance; DM, diabetes mellitus; MI, myocardial infarction; QTc, corrected QT interval; QTcD, QTC dispersion.

^a P values adjusted in the ANCOVA model for first day QTcD, age, DM, and sex.

^b β = 0.99.

^c β = 0.53.

Adding the U-wave into the repolarization dispersion analysis produced equivalent results, with more QTcD in D3 in the NS group (192.7 ± 80.6 milliseconds vs 162.8 ± 83.4 milliseconds; P = .003) and a less significant decrease by D5 (163.2 ± 89.1 ms vs 149.5 ± 89.1 milliseconds; P = .002). Results of these analysis are detailed in Table 3.

Table 3.

Sequential Evolution of QTc Dispersion Considering the U Wave Following MI Categorized According to Statin Use.

	Statin Use		P ^a
	NS	S	P ^a
N	57	87
QTcD w/U (D1), milliseconds	172.9 ± 91	144.3 ± 83	.24
QTcD w/U (D3), milliseconds	192.7 ± 80.6	162.8 ± 83.4	.003
QTcD w/U (D5), milliseconds	163.2 ± 89.1	149.5 ± 89.1	.002
Delta QTcD w/U (D1-D3), milliseconds	19.8 ± 101.5	19.8 ± 100.3	.18
Delta QTcD w/U (D1-D5), milliseconds	−9.6 ± 99.1	5.5 ± 100.4	.55

Abbreviations: ANCOVA, analysis of covariance; DM, diabetes mellitus; MI, myocardial infarction; QTc, corrected QT interval; QTcD, QTC dispersion.

^a P values adjusted for first day QTcD, age, DM, and sex.

Discussion

Dispersion of the QTc has been shown to predict the adverse events after MI, peaking after 48 to 72 hours and returning to baseline values during the next 5 to 10 days.¹⁸ Hence, the amplitude of the change and the residual QTcD at the end of the acute phase have been considered to be useful markers for short- and long-term outcomes. In the present study, statin use was associated with both a lower acute-phase generation of QTcD and a lower residual QTcD before discharge. Thus, a shortening QTcD may potentially represent a way of decreasing the substrate for life-threatening ventricular arrhythmias, which would be considered among the potential mechanisms of benefit for statin use during the acute phase of STEMI. We believe this STEMI treatment profile reflects those treated in the public system of Brazil.

Although novel, this finding is consistent with previous studies in patients with stable heart failure or hypercholesterolemia who also showed a decrease in QTcD and the QT interval after statin treatment.^10,16 Myocardial tissue heterogeneity has been considered to be the substrate for both QTcD and ventricular arrhythmias after MI.^19,20 We previously reported that the size of MI tissue heterogeneity, as estimated by cardiac magnetic resonance imaging, is strongly associated with inflammatory activity³ and that statin therapy reduces the inflammatory response after MI.⁵ In addition, statin use in patients with STEMI and in animal models attenuated the collagen breakdown.^21,22 By inference, our hypothesis was that a reduction in inflammatory activity with statin therapy could help reduce QTcD. Thus, although the present study cannot confirm or even scale the association between the anti-inflammatory effect of statins and the reduction in QTcD, the present findings are in agreement with such an assumption. Interestingly, this finding maintained its consistency even when the entire repolarization, including the U-wave, was considered.

Another possible mechanism is the direct effect of statins on myocyte membrane calcium currents. l-α-LPC is a metabolite of cellular membrane phosphatidylcholine, which increases intracellular calcium mobilization in myocytes. LPC is accumulated in ischemic hearts, which contributes to the cardiac arrhythmias during ischemia and post-ischemia reperfusion. There are multiple models in which statins have been proven not only to reduce LPC in ischemia but also to counteract its deleterious consequences such as ventricular arrhythmias—the Langendorff rat heart model, Guinea pig myocyte voltage clamp method, and even human aorta endothelial cells. This could reduce ischemia, thus contributing to reduced post-MI myocardial tissue heterogeneity, making the heart less prone to reentry—the main mechanism of post-MI arrhythmia.^6
-8

Some limitations must be considered when interpreting these findings. With the present sample size and duration of the study, it is not possible to estimate the impact of QTcD mitigation on the incidence of ventricular arrhythmias. Some of the patients were receiving simvastatin 80 mg/d, a dose that is no longer recommended, although statin intolerance was not found during the study. Unfortunately, this group of patients did not have access to state-of-the-art reperfusion, and primary angioplasty was used in a minority of patients. Therefore, this therapy, which can be a major driver of myocardial heterogeneity after MI, is a limitation of this study since this population cannot be readily extrapolated to a population treated with current guidelines. Fortunately, the mean time to reperfusion was quite reasonable, within 5 to 6 hours. Similarly, other mainstay drugs in the treatment of STEMI, such as ACEi, ARBs, and β-blockers, had a low rate of use in this study. However, this can be a strength since there is evidence that these drugs can actually influence QTcD.²³ Finally, the present findings should not be extrapolated to other forms of ACS manifestations since only cases of STEMI were enrolled.

Another important limitation is that inflammation is a complex process. There is limited evidence showing that statins might influence myocardial electrical stability.^6,7 However, the detailed mechanism by which statins could modulate inflammation to influence myocardial electrical stability is not fully understood. Additional experimental data are needed to support this hypothesis.

In conclusion, clinical and experimental data indicate that statins have a wide array of favorable actions in the context of ACS. In this study, we add to this understanding the notion that the attenuation of QTcD may also occur in patients with STEMI who receive early treatment with statins.

Supplemental Material

Supplemental Material, Supplementary_Figure_1_-_ROC_for_PSI - Statin Use in the Early Phase of ST-Segment Elevation Myocardial Infarction Is Associated With Decreased QTc Dispersion

Supplemental Material, Supplementary_Figure_1_-_ROC_for_PSI for Statin Use in the Early Phase of ST-Segment Elevation Myocardial Infarction Is Associated With Decreased QTc Dispersion by Daniel B. Munhoz, Luiz Sergio F. Carvalho, Frank N. C. Venancio, Osorio Luis Rangel de Almeida, Jose C. Quinaglia e Silva, Otavio R. Coelho-Filho, Wilson Nadruz, Andrei C. Sposito and on behalf of the Brasilia Heart Study Group in Journal of Cardiovascular Pharmacology and Therapeutics

Supplemental Material

Supplemental Material, Supplementary_Figure_2_-_Rplot_-_propensity_score_QTC - Statin Use in the Early Phase of ST-Segment Elevation Myocardial Infarction Is Associated With Decreased QTc Dispersion

Supplemental Material, Supplementary_Figure_2_-_Rplot_-_propensity_score_QTC for Statin Use in the Early Phase of ST-Segment Elevation Myocardial Infarction Is Associated With Decreased QTc Dispersion by Daniel B. Munhoz, Luiz Sergio F. Carvalho, Frank N. C. Venancio, Osorio Luis Rangel de Almeida, Jose C. Quinaglia e Silva, Otavio R. Coelho-Filho, Wilson Nadruz, Andrei C. Sposito and on behalf of the Brasilia Heart Study Group in Journal of Cardiovascular Pharmacology and Therapeutics

Supplemental Material

Supplemental Material, Supplementary_Figure_3_-_ - Statin Use in the Early Phase of ST-Segment Elevation Myocardial Infarction Is Associated With Decreased QTc Dispersion

Supplemental Material, Supplementary_Figure_3_-_ for Statin Use in the Early Phase of ST-Segment Elevation Myocardial Infarction Is Associated With Decreased QTc Dispersion by Daniel B. Munhoz, Luiz Sergio F. Carvalho, Frank N. C. Venancio, Osorio Luis Rangel de Almeida, Jose C. Quinaglia e Silva, Otavio R. Coelho-Filho, Wilson Nadruz, Andrei C. Sposito and on behalf of the Brasilia Heart Study Group in Journal of Cardiovascular Pharmacology and Therapeutics

Footnotes

Authors’ Note

The authors had full access to the data and take responsibility for its integrity. All authors have read the manuscript and agreed to submit it as written. Informed consent was obtained from all individual participants included in the study. Ethical approval: All procedures performed were in accordance and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards, and ethical approval was obtained from Comite de Ética em Pesquisa da Faculdade de Ciências Médicas da Unicamp under the number 635.911.

Author Contributions

D.B.M., F.N.V., O.L.R.A. and J.C.Q.S. collected outpatient data, performed the digital ECGs and contributed on data analyses. D.B.M. prepared the manuscript. L.S.F.C., W.N., O.R.C.-F. and A.C.S. reviewed the manuscript. A.C.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Prof. Sposito is recipient of a Research Career Awards from the Brazilian National Research Council (CNPq).

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Daniel B. Munhoz

Supplemental Material

Supplemental material for this article is available online.

References

Ibanez

James

Agewall

, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–177.

O’Gara

Kushner

Ascheim

, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology foundation/American Heart Association task force on practice guidelines. Circulation. 2013;127(4):e362–425.

Quinaglia e Silva

Coelho-Filho

Andrade

, et al. Peri-infarct zone characterized by cardiac magnetic resonance imaging is directly associated with the inflammatory activity during acute phase myocardial infarction. Inflammation. 2014;37(3):678–685.

Marenzi

Cosentino

Cortinovis

, et al. Myocardial infarct size in patients on long-term statin therapy undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction. Am J Cardiol. 2015;116(12):1791–1797.

Sposito

Santos

de Faria

, et al. Timing and dose of statin therapy define its impact on inflammatory and endothelial responses during myocardial infarction. Arterioscler Thromb Vasc Biol. 2011;31(5):1240–1246.

Matsuoka

Suzuki

, et al. Inhibitory effect of fluvastatin on lysophosphatidylcholine-induced nonselective cation current in Guinea pig ventricular myocytes. Mol Pharmacol. 2002;62(3):602–607.

Yao

Wang

, et al. Pravastatin attenuates cardiac dysfunction induced by lysophosphatidylcholine in isolated rat hearts. Eur J Pharmacol. 2010;640(1-3):139–142.

Yokoyama

Ishibashi

Ohkawara

, et al. HMG-CoA reductase inhibitors suppress intracellular calcium mobilization and membrane current induced by lysophosphatidylcholine in endothelial cells. Circulation. 2002;105(8):962–967.

Zhou

Wan

Wang

Zhong

Xue

. The effect of early and intensive statin therapy on ventricular premature beat or nonsustained ventricular tachycardia in patients with acute coronary syndrome. Clin Cardiol. 2011;34(1):59–63.

10.

Mark

Katona

. Effect of fluvastatin on QT dispersion: a new pleiotropic effect? Am J Cardiol. 2000;85(7):919–920.

11.

Rahimi

Majoni

Merhi

Emberson

. Effect of statins on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of published and unpublished evidence from randomized trials. Eur Heart J. 2012;33(13):1571–1581.

12.

Elming

Holm

Jun

, et al. The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens. Eur Heart J. 1998;19(9):1391–1400.

13.

Chen

Fetics

Berger

Trayanova

. Unstable QT interval dynamics precedes ventricular tachycardia onset in patients with acute myocardial infarction: a novel approach to detect instability in QT interval dynamics from clinical ECG. Circ Arrhythm Electrophysiol. 2011;4(6):858–866.

14.

Glancy

Garratt

Woods

de Bono

. QT dispersion and mortality after myocardial infarction. Lancet. 1995;345(8955):945–948.

15.

Mulay

Quadri

. QT dispersion and early arrhythmic risk in acute myocardial infarction. Indian Heart J. 2004;56(6):636–641.

16.

Vrtovec

Okrajsek

Golicnik

Ferjan

Starc

Radovancevic

. Atorvastatin therapy increases heart rate variability, decreases QT variability, and shortens QTc interval duration in patients with advanced chronic heart failure. J Card Fail. 2005;11(9):684–690.

17.

Antman

Anbe

Armstrong

, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110(5):588–636.

18.

Glancy

Garratt

de Bono

. Dynamics of QT dispersion during myocardial infarction and ischaemia. Int j cardiol. 1996;57(1):55–60.

19.

Schuleri

Centola

George

, et al. Characterization of peri-infarct zone heterogeneity by contrast-enhanced multidetector computed tomography: a comparison with magnetic resonance imaging. J Am Coll Cardiol. 2009;53(18):1699–1707.

20.

Schmidt

Azevedo

Cheng

, et al. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation. 2007;115(15):2006–2014.

21.

Reichert

Pereira do Carmo

Galluce Torina

, et al. Atorvastatin improves ventricular remodeling after myocardial infarction by interfering with collagen metabolism. PLoS One. 2016;11(11):e0166845.

22.

Nakaya

Uzui

Shimizu

, et al. Pravastatin suppresses the increase in matrix metalloproteinase-2 levels after acute myocardial infarction. Int J Cardiol. 2005;105(1):67–73.

23.

Kassotis

Mongwa

Reddy

. Effects of angiotensin-converting enzyme inhibitor therapy on QT dispersion post acute myocardial infarction. Pacing Clin Electrophysiol. 2003;26(4 Pt 1):843–848.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

1.35 MB

5.50 MB