Cardiology

Prognostic value of admission serum magnesium in acute myocardial infarction complicated by malignant ventricular arrhythmias

a b s t r a c t

Objectives: Although electrolyte abnormalities are related to worse clinical outcomes in patients with acute myo- cardial infarction (AMI), little is known about the association between admission serum magnesium level and ad- verse events in AMI patients complicated by out-of-hospital cardiac arrest presenting with malignant ventricular arrhythmias (OHCA-MVA). We investigated the prognostic value of serum magnesium level on admission in these patients.

Methods: We retrospectively analyzed the data of 165 consecutive reperfused AMI patients complicated with OHCA-MVA between April 2007 and February 2020 in our university hospital. Serum magnesium concentration was measured on admission. The primary outcome was in-hospital death.

Results: Fifty-four patients (33%) died during hospitalization. Higher serum magnesium level was significantly re- lated to in-hospital death (Fine & Gray’s test; p < 0.001). In multivariable logistic regression analyses, serum mag- nesium level on admission was independently associated with in-hospital death (hazard ratio 2.68, 95% confidence interval 1.24-5.80) even after adjustment for covariates. Furthermore, the incidences of cardiogenic shock necessitating an intra-aortic balloon pump (p = 0.005) or extracorporeal membrane oxygenation (p < 0.001), tracheal intubation (p < 0.001) and Persistent vegetative state (p = 0.002) were significantly higher in patients with higher serum magnesium level than in those with lower serum magnesium level.

Conclusions: In reperfused AMI patients complicated by OHCA-MVA, admission serum magnesium level might be a potential surrogate marker for predicting in-hospital death.

(C) 2021

  1. Introduction

Acute myocardial infarction (MI) is one of the most critical forms of atherosclerotic disease, accompanied by various complications such as congestive heart failure and fatal ventricular arrhythmias [1]. Several risk scores have been developed to stratify acute MI (AMI) patients ac- cording to the risk of mortality or adverse cardiac events after reperfu- sion therapy [2-4]. However, these models were derived from datasets that excluded patients presenting with cardiogenic shock or cardiac ar- rest, especially those complicated by malignant ventricular arrhythmias such as ventricular fibrillation (VF) or pulseless ventricular

* Corresponding author at: Department of cardiovascular medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita- ku, Sapporo, Hokkaido 060-8638, Japan.

E-mail address: [email protected] (T. Nagai).

1 Yoshifumi Mizuguchi and Takao Konishi contributed equally to this work.

tachycardia (VT). Hence, it is still difficult to determine the prognosis in reperfused AMI patients who have out-of-hospital cardiac arrest pre- senting with malignant ventricular arrhythmias (OHCA-MVA), based on these prognostic models. Generally, MVAs are among the most power- ful determinants of subsequent worse clinical outcomes in reperfused AMI patients [5-7]. Masuda, et al. reported that the rate of in-hospital death was significantly higher in patients who developed acute-phase MVA than in those without MVA (14.6% vs. 4.3%) [8]. Therefore, early risk stratification is important for predicting clinical outcomes in pa- tients presenting with AMI, especially in those who are resuscitated from OHCA-MVA.

Previous studies have demonstrated a relationship between abnor- malities of electrolytes (e.g. serum sodium and potassium) and worse clinical outcomes in patients with reperfused AMI [9-12]. Magnesium is one of the essential minerals, and an activator of a number of enzymes involved in many catalytic reactions in the human body [13]. Notably, elevated serum magnesium level is associated with higher magnesium

https://doi.org/10.1016/j.ajem.2021.02.005

0735-6757/(C) 2021

leakage from infarcted myocardium, which may lead to MVA and in- hospital death in patients with acute coronary syndrome [14-16]. How- ever, in these studies, the timing of serum magnesium measurement was not consistent, and little is known about the prognostic value of serum magnesium level on admission, especially in critically ill patients with AMI complicated by OHCA-MVA who undergo primary percutane- ous coronary intervention (PCI).

Accordingly, the aim of the present study was to investigate whether serum magnesium level on admission is associated with subsequent in- hospital clinical outcomes in reperfused AMI patients complicated by OHCA-MVA.

  1. Methods
    1. Study design

Data from AMI patients complicated by OHCA-MVA who underwent Primary PCI at Hokkaido University Hospital between April 2007 and February 2020 were retrospectively analyzed. The study protocol was approved by the ethics committee of Hokkaido University Hospital (No. 019-0235). In this study, because patient information was anonymized and de-identified prior to analyses, written informed con- sent was not obtained from each patient, but patients were informed of entry into the study and allowed to opt out.

    1. Study population

From the 167 consecutive AMI patients complicated by OHCA-MVA, those without measurement of serum magnesium level on admission (n = 2) were excluded. Ultimately, 165 patients were examined. We defined the cut-off value of serum magnesium level as >2.3 mg/dL (me- dian), which was consistent with a previous report [17].

    1. Blood sampling and PCI procedures

Venous or arterial blood samples were obtained on admission for measuring routine laboratory parameters. Primary PCI was performed using standard techniques. The use of a thrombectomy device, intravas- cular imaging device, pre-dilatation, stent choice, post-dilatation, and the initiation of an intra-arterial balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO) were at the operators’ discretion.

    1. Clinical outcomes

The primary study outcome of interest was All-cause death during the indexed hospitalization. The secondary study outcomes were in- hospital adverse events including cardiogenic shock necessitating IABP and/or ECMO, invasive ventilator support, sustained VT or VF, mechan- ical complications (left ventricular free wall rupture, interventricular septal rupture or Papillary muscle rupture), emergent coronary artery bypass grafting (CABG) and persistent vegetative state.

    1. Statistical analyses

Results are presented as mean +- standard deviation when normally distributed, and as median and interquartile range (IQR) when non- normally distributed. Between-group differences were analyzed using Pearson’s chi-squared test or Fisher’s exact test for categorical variables and Student’s t-test or Mann-Whitney U test for continuous variables as appropriate. Multivariable linear regression analysis was performed based on the variables achieving p < 0.10 on univariable linear regres- sion analysis, to explore the factors associated with admission serum magnesium level. The association between categories of serum magne- sium and the risk of in-hospital mortality was evaluated by a competing-risks regression model according to the method of Fine and Gray [18]. Estimates are presented as a subhazard ratio (sHR) and

adjusted by the competing effect of in-hospital death and discharge in the 30-day follow-up. The association between parameters and in- hospital death was assessed by multivariable logistic regression analy- sis. We constructed a logistic regression model to estimate propensity scores in the association between the category of serum magnesium levels and clinically relevant prognostic factors related to in-hospital death (age, sex, Killip classes, estimated glomerular filtration rate, left main coronary artery as infarct related artery and final TIMI flow grade), then entered these scores in the multivariable model. The logistic regression model for estimating propensity scores showed good discrimination (c-index 0.73) and calibration (p = 0.28 in the Hosmer-Lemeshow goodness-of-Fit test). Moreover, stepwise selection with a p-value of 0.10 for backward elimination was used to select the best predictive model for confirming robustness. All tests were two tailed, and a value of p < 0.05 was considered statistically significant. All analyses were performed with SPSS(R) 26.0 (IBM Corp, Armonk, NY, USA) and Stata(R) MP64 version 16 (StataCorp, College Station, TX, USA).

  1. Results
    1. Baseline characteristics

The median admission serum magnesium level was 2.3 mg/dL (in- terquartile range [IQR] 2.1-2.7) (Fig. 1). Baseline characteristics of the total 165 studied patients are presented in Table 1. Patients with higher serum magnesium level had higher prevalence of Killip class III or IV and chronic kidney disease, lower prescription rate of ?-blockers, angiotensin-converting enzyme inhibitors or Angiotensin II receptor blockers, calcium channel blockers and statins initiated after admission, higher serum sodium and peak creatine kinase (CK) levels, and lower hemoglobin level, estimated glomerular filtration rate and left ventricu- lar ejection fraction (LVEF) than those with lower serum magnesium level. There were no significant differences in terms of age, sex and pre-intervention TIMI flow grade between the groups.

    1. Relationships between serum magnesium level and clinical variables

Multivariable linear regression analyses demonstrated that Killip class III or IV and peak CK were independently associated with admis- sion serum magnesium level (Table 2).

    1. Serum magnesium level and primary outcome

During the median follow-up period of 20 (IQR 10-41) days, in- hospital death occurred in 54 (33%) study patients. A competing-risks regression model revealed that a higher serum magnesium level on ad- mission was significantly associated with higher in-hospital mortality (Fig. 2). In multivariable logistic regression analyses, serum magnesium on admission was independently associated with in-hospital death even after adjustment for covariates (Table 3).

    1. Serum magnesium level and secondary outcomes

The incidences of cardiogenic shock necessitating IABP or ECMO, tra- cheal intubation, and persistent vegetative state or tracheostomy were significantly higher in patients with higher serum magnesium level than in those with lower serum magnesium level (Table 4). However, the incidences of sustained VT or VF after PCI, thrombotic events, Cardiac rupture, Implantable cardioverter defibrillator and CABG were compa- rable between the groups.

  1. Discussion

In the present study, we found that higher serum magnesium level on admission was independently associated with higher in-hospital mortality, and several parameters reflecting the severity of AMI,

Image of Fig. 1

Fig. 1. Distribution of admission serum magnesium level.

including Killip class and peak CK, were related to the admission serum magnesium level. Furthermore, the incidences of In-hospital adverse events including cardiogenic shock necessitating IABP or ECMO, tra- cheal intubation, and persistent vegetative state or tracheostomy were significantly higher in patients with higher serum magnesium level than in those with lower serum magnesium level. Our findings indicate the importance of assessing admission serum magnesium level for fur- ther risk stratification in reperfused patients with AMI complicated by OHCA-MVA.

Several mechanisms might explain the increased serum magnesium in patients presenting with AMI complicated by OHCA-MVA. First, be- cause magnesium leakage from infarcted myocardium occurs after AMI, its concentration could be transiently increased in the peripheral circulation. Although most magnesium in the cell is bound to intracellu- lar proteins such as Sarcoplasmic reticulum or sequestered by mito- chondria, the intracellular free magnesium concentration is estimated to be about 1.2-2 times higher than plasma free magnesium [19,20]. In fact, an increasing trend in serum magnesium with time was ob- served during the first 3-4 days in patients with AMI [16,21,22]. The second potential mechanism is magnesium leakage from injured myo- cardium due to defibrillation or MVA itself [23,24]. Stendig-Lindberg, et al. reported that defibrillation against VF caused magnesium efflux, and that the mean serum magnesium level was significantly higher after defibrillation than before defibrillation in a feline model (0.991 +- 0.182 vs. 0.824 +- 0.182 mmol/L, p < 0.05) [23]. Salerno,

et al. also revealed that serum magnesium was significantly increased in VF subjects 7 min after resuscitation, using a Canine model [24].

Interestingly, peak CK and Killip class were significantly associated with serum magnesium level on admission in the present study. Peak CK and CK myocardial band are well-known enzymatic markers of an infarcted area and important predictors of mortality in patients with AMI [25,26]. Also, higher Killip class is associated with high mortality rate after AMI [27]. Therefore, the higher serum magnesium level on ad- mission might have reflected larger infarct size and severity of AMI, which led to higher in-hospital mortality and higher incidence of car- diogenic shock. A prolonged shock state followed by extensive Cerebral hypoxia might cause a poor neurological outcome such as a persistent vegetative state or the need for tracheostomy.

The effects of hypermagnesemia on the cardiovascular system in- clude hypotension, bradycardia, atrioventricular block, interventricular

conduction delay and cardiac arrest [28]. Turlapaty, et al. reported that magnesium causes vascular relaxation as well as antagonising the effect of vasopressor agents [29]. The effect is mediated via prostaglandin I2 and calcium flux, as cyclo-oxygenase inhibitors and calcium channel blockers prevent the hypotensive effect of magnesium [28]. Although this negative inotropic effect of hypermagnesemia might contribute to prolonged hypotension, leading to a higher prevalence of cardiogenic shock necessitating IABP or ECMO in patients with higher serum mag- nesium level (Table 4), the adverse effects of magnesium toxicity do not generally manifest until serum magnesium concentration exceeds

4.8 mg/dL (= 2 mmol/L) [30]. Because few patients in this study had serum magnesium that exceeded this level, hypermagnesemia might be useful as a surrogate marker of adverse outcomes in patients with MVA after AMI, rather than a primary factor that worsens the patho- physiological condition of AMI.

Our observations are well concordant with those reported previ- ously. Indeed, an increased serum magnesium level could be an inde- pendent determinant of worse clinical outcomes among patients admitted to the coronary care unit or emergency department, including the settings of heart failure, AMI and cardiogenic shock [14,15,17,31,32]. Importantly, hypomagnesemia could also increase the risk of in- hospital mortality in patients with AMI. Shafiq A, et al. demonstrated a U-shape relationship between serum magnesium level and in-hospital mortality in AMI patients (< 1.8, 1.8-1.9, 1.9-2.0, > 2.0 mg/dL vs. 7.4,

4.1, 4.7, 9.7%, respectively) [14]. In our study population, there was only one patient with hypomagnesemia (serum magnesium level <= 1.4 mg/dL); therefore, we could not confirm a U-shape relationship.

    1. Limitations

Our study has certain limitations. First, the present retrospective, ob- servational study, conducted at a university hospital, had a small sample size, thereby limiting the ability to generalize the findings and the statis- tical power for detecting differences in negative data. Therefore, further multicenter prospective studies with a larger sample size are warranted to confirm our present findings. Second, some important prognostic variables (e.g. B-type natriuretic peptide) might not have been fully es- timated. Third, the actual interval between the timing of blood tests and the administration of magnesium was unclear; therefore, magnesium

Table 1

Baseline characteristics.

Variables

Overall

Serum magnesium

p Value

<= 2.3 mg/dL

> 2.3 mg/dL

Number

165

86

79

Age, years

63.4 +- 12.4

63.3 +- 12.1

63.6 +- 12.7

0.83

Male, n (%)

146 (88)

75 (87)

71 (90)

0.59

Presenting characteristics, n (%)

Killip class III or IV

146 (88)

68 (79)

78 (99)

<0.001

STEMI

156 (95)

81 (94)

75 (95)

1.0

By-stander CPR

80 (48)

39 (45)

41 (52)

0.44

Cardiovascular risk factors, n (%) Diabetes mellitus

58 (35)

36 (42)

22 (28)

0.060

Hypertension

83 (50)

47 (55)

36 (46)

0.24

Dyslipidemia

68 (41)

46 (53)

22 (28)

0.001

Chronic kidney disease

102 (62)

45 (52)

57 (72)

0.009

Current smoking

50 (30)

29 (34)

21 (27)

0.32

Family history of CAD

8 (5)

4 (5)

4 (5)

1.0

Prior PCI or CABG

22 (13)

12 (14)

10 (13)

0.81

Prior cerebral infarction

17 (10)

12 (14)

5 (6)

0.108

peripheral artery disease

7 (4)

4 (5)

3 (4)

1.0

Medications prior to admission, n (%) Aspirin

13 (8)

6 (7)

7 (9)

0.65

Clopidogrel

7 (4)

4 (5)

3 (4)

1.0

?-blockers

6 (4)

2 (2)

4 (5)

0.43

ACEIs or ARBs

18 (11)

10 (12)

8 (10)

0.76

Statins

14 (8)

8 (9)

6 (8)

0.69

Laboratory tests Hemoglobin, g/dL

12.9 +- 2.2

13.4 +- 2.2

12.3 +- 2.1

0.002

CRP, mg/dL

0.09 (0.04-0.33)

0.08 (0.03-0.32)

0.10 (0.04-0.43)

0.54

Serum sodium, mEq/L

140 (138-142)

139 (138-142)

141 (138-143)

0.008

Serum potassium, mEq/L

3.8 (3.4-4.4)

3.8 (3.4-4.2)

3.9 (3.4-4.7)

0.28

Serum magnesium, mg/dL

2.3 (2.1-2.7)

2.1 (2.0-2.2)

2.7 (2.5-2.9)

<0.001

eGFR, mL/min

54.5 +- 19.6

58.3 +- 19.8

50.4 +- 18.7

0.009

CK, IU/L

149 (93-262)

124 (81-210)

179 (102-320)

0.002

Peak CK, IU/L

4521 (1416-10,530)

2671 (887-7407)

7294 (3634-13,716)

<0.001

LVEF, %

43 (26-52)

48 (39-56)

28 (10-45)

<0.001

Infarct related artery, n (%)

0.181

LMCA

14 (8)

4 (5)

10 (13)

LAD

86 (52)

43 (50)

43 (54)

LCX

25 (15)

15 (17)

10 (13)

RCA

40 (24)

24 (28)

16 (20)

TIMI flow grade pre-intervention, n (%)

0.197

0

69 (42)

32 (37)

37 (47)

1

27 (16)

12 (14)

15 (19)

2

41 (25)

27 (31)

14 (18)

3

28 (17)

15 (17)

13 (16)

Time from symptom onset and reperfusion (min)

154 (123-199)

151 (119-191)

162 (126-204)

0.31

Procedures, n (%)

0.52

Plain old Balloon angioplasty alone

8 (5)

6 (7)

2 (3)

Bare metal stent

78 (47)

42 (49)

36 (46)

Drug eluting stent

74 (45)

36 (42)

38 (48)

Drug coated balloon

1 (1)

0

1 (1)

Final TIMI grade of flow, n (%)

0.137

0

1 (1)

0

1 (1)

1

4 (2)

1 (1)

3 (4)

2

31 (19)

12 (14)

19 (24)

3

129 (78)

73 (85)

56 (71)

Medications initiated after admission, n (%) Aspirin

163 (99)

86 (100)

77 (97)

0.23

Clopidogrel

81 (49)

44 (51)

37 (47)

0.58

Prasugrel

70 (42)

35 (41)

35 (44)

0.64

Cilostazol

28 (17)

14 (16)

14 (18)

0.81

Ticlopidine

20 (12)

10 (12)

10 (13)

0.84

?-blockers

80 (48)

59 (69)

21 (27)

<0.001

ACEIs or ARBs

85 (52)

61 (71)

24 (30)

<0.001

Calcium channel blockers

32 (19)

22 (26)

10 (13)

0.036

Statins

135 (82)

78 (91)

57 (72)

0.002

Diuretics

73 (44)

38 (44)

35 (44)

0.99

Values are mean +- standard deviation, median (interquartile range) or percentages. STEMI: ST-segment elevation myocardial infarction; CAD: coronary artery disease; PCI: percutaneous coronary intervention; CABG: Coronary artery bypass grafting; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; CPR: cardiopulmonary resuscitation; CRP: C-reactive protein; eGFR: estimated glomerular filtration rate; CK: creatine kinase; LVEF: left ventricular ejection fraction; LMCA: left main coronary artery; LAD: left anterior de- scending artery; LCX: left circumflex artery; RCA: right coronary artery; TIMI: Thrombolysis In Myocardial Infarction.

Table 2

Linear regression analyses for admission serum magnesium level.

Variables Univariable Multivariable

? coefficient p Value ? coefficient p Value

Killip class III or IV 0.28 <0.001 0.25 0.001

Hemoglobin -0.15 0.051 -0.02 0.80

Serum sodium 0.20 0.010 0.16 0.040

Serum potassium 0.16 0.042 0.21 0.006

eGFR -0.17 0.025 -0.11 0.138

Log peak CK 0.23 0.003 0.19 0.011

LMCA as the infarct related artery 0.11 0.173 Not selected –

Final TIMI grade of flow <3 0.10 0.186 Not selected –

Abbreviations as in Table 1.

Table 3

Logistic regression analyses for in-hospital death.

Models Serum magnesium, mg/dL

OR (95% CI) p Value

Model 1: Crude 1.41 (1.03-1.92) 0.032

Model 2: Adjusted by propensity scores 2.68 (1.24-5.80) 0.012

Model 3: Adjusted by stepwise backward selection 3.54 (1.61-7.77) 0.002 OR: odds ratio; CI: confidence interval.

Table 4

In-hospital secondary outcomes according to serum magnesium level.

Variables, n (%) Overall Serum magnesium p

administration would affect the levels of magnesium in some patients. Finally, important pieces of information such as past history of hyper-

<= 2.3 mg/dL > 2.3 mg/dL

Number 165 86 79

Value

tension, diabetes mellitus and dyslipidemia, and doses of medications were not completely available in the present study because some pa- tients were in a vegetative state during hospitalization and did not

Cardiogenic shock/need for

IABP, n (%)

Cardiogenic shock/need for ECMO, n (%)

90 (55) 38 (44) 52 (66) 0.005

88 (53) 26 (30) 62 (78) <0.001

have family or relatives.

  1. Conclusions

Our analyses revealed that higher serum magnesium level on admis- sion was associated with worse in-hospital clinical outcomes in patients with reperfused AMI complicated by OHCA-MVA, along with higher Killip class and larger infarct size. Our findings indicate the potential value of assessing serum magnesium level for further risk stratification in these patients.

Declaration of competing interest

Authors have reported that they have no relationships relevant to the content of this paper to disclose.

Tracheal intubation, n (%) 144 (87) 66 (77) 78 (99) <0.001

Sustained VT, VF after PCI, n 7 (4) 3 (3) 4 (5) 0.71

(%)

Thrombotic events, n (%) 6 (4) 4 (5) 2 (3) 0.68

AST/SAT

2 (1)

1 (1)

1 (1)

1.0

Left ventricular thrombus

2 (1)

2 (2)

0

0.50

Cerebral infarction

2 (1)

1 (1)

1 (1)

1.0

mechanical complications, n

1 (1)

1 (1)

0

1.0

(%)

Left ventricular free wall

1 (1)

1 (1)

0

1.0

rupture

Ventricular septal rupture

0

0

0

Papillary muscle rupture

0

0

0

ICD, n (%)

8 (5)

7 (8)

1 (1)

0.066

CABG, n (%)

2 (1)

2 (2)

0

0.50

Persistent vegetative state or tracheostomy, n (%)

37 (22)

11 (13)

26 (33)

0.002

IABP: intra-aortic balloon pump; ECMO: extracorporeal membrane oxygenation; VT: ven- tricular tachycardia; VF: ventricular fibrillation; PCI: percutaneous coronary intervention; AST: acute Stent thrombosis; SAT: subacute stent thrombosis; ICD: implantable cardioverter defibrillator; CABG: coronary artery bypass grafting.

Image of Fig. 2

Fig. 2. Cumulative incidence of in-hospital death according to serum magnesium level. Mg: serum magnesium, sHR: subhazard ratio.

Acknowledgements

The authors are grateful for the contributions of all the investigators, clinical research coordinators, and laboratory technicians involved in this study.

Funding sources

This study was supported by a Grant-in-Aid for Research Activity Start-up (Japan Society for the Promotion of Science KAKENHI, 19K23931, Dr Konishi). The funding sources had no involvement in any research process.

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