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Article
Peer-Review Record

Age Variation in Patients with Troponin Level Elevation Without Obstructive Culprit Lesion or Suspected Myocardial Infarction with Non-Obstructive Coronary Arteries—Long-Term Data Covering over Decade

J. Clin. Med. 2024, 13(24), 7685; https://doi.org/10.3390/jcm13247685
by Mohammad Abumayyaleh 1,2,*,†, Clara Schlettert 3,†, Daniel Materzok 3, Andreas Mügge 3,4, Nazha Hamdani 5, Ibrahim Akin 1, Assem Aweimer 3 and Ibrahim El-Battrawy 4,5
Reviewer 1: Anonymous
Reviewer 2: Anonymous
Reviewer 3: Anonymous
Reviewer 4: Anonymous
J. Clin. Med. 2024, 13(24), 7685; https://doi.org/10.3390/jcm13247685
Submission received: 20 October 2024 / Revised: 2 December 2024 / Accepted: 9 December 2024 / Published: 17 December 2024
(This article belongs to the Section Cardiology)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors evaluated the impact of age on patients with elevated troponin without an obstructive lesion, analyzing data from 373 individuals. They found that older patients had a higher rate of major adverse cardiovascular events during hospitalization compared to younger groups. Specifically, non-sustained ventricular tachycardia was more prevalent in patients aged 51 to 60 years. Additionally, long-term follow-up indicated increased cardiovascular mortality in older patients compared to younger ones.

Congratulations to the authors on this interesting work addressing a highly relevant topic. 

Issues/Suggestions:

Methods: The inclusion criteria should be improved, particularly regarding the following points:

·       The authors screened all patients with chest pain or diagnosed acute coronary syndrome. Which guidelines were followed for this process?

·       Including the criteria for defining MINOCA according to the European Society of Cardiology guidelines would be beneficial.

·       Was cardiac magnetic resonance imaging performed? CMR is necessary to determine the ischemic nature of myocardial damage and confirm the diagnosis of MINOCA. Additionally, CMR is crucial for prognostic purposes, as it identifies three phenotypes with differing prognoses: late gadolinium enhancement positive/mapping positive, late gadolinium enhancement negative/mapping positive, and normal CMR. Expanding the bibliography and discussion on this topic would be useful.

·       How were the age cut-offs determined for the population division? I suggest also considering a division based on the median age of the population.

How do the authors explain such a low left ventricular ejection fraction upon admission? Were other categories of patients included (e.g., takotsubo)?

The population was largely under-treated. Could this have influenced the outcomes? I recommend expanding the discussion on this point, considering that patients with MINOCA are at high risk for reinfarction and that managing low-density lipoprotein levels is mandatory (cite: 10.1016/j.pcad.2023.10.006).

Finally, considering the study's limitations and design, I recommend toning down the conclusions and interpretation of the results.

Comments on the Quality of English Language

Perform a thorough proofreading to correct grammatical issues and ensure clarity and readability.

Author Response

Issues/Suggestions:

Methods: The inclusion criteria should be improved, particularly regarding the following points:

  • The authors screened all patients with chest pain or diagnosed acute coronary syndrome. Which guidelines were followed for this process?

Response:

  • Any case with a positive troponin value without significant coronary stenosis was screened. Troponin was determined in cases of suspected acute coronary syndrome (ACS). A total of 373 patients fulfilled the inclusion criteria. To meet these criteria, patients first had to meet the modified criteria for acute myocardial infarction (AMI) according to the "Fourth Universal Definition of Myocardial Infarction". First, there had to be an increase or decrease in cardiac troponin levels, with at least one value above the 99th percentile in the laboratory. Secondly, there had to be clinical evidence of MI, as evidenced by at least one of the following conditions Symptoms of myocardial ischemia, new ischemic changes on the electrocardiogram, pathological Q waves, evidence of new loss of viable myocardium or new regional wall motion abnormalities suggesting an ischemic cause, or evidence of coronary thrombus by angiography or autopsy. As a secondary criterion, coronary artery obstruction had to be excluded in patients undergoing angiography. This was the case if the stenosis in any of the major epicardial vessels was <50% and no subsequent intervention was performed. ACS Guidelines 2023 have been followed as a reference for this manuscript. We revised and improved the material and methods section as required.

 

  • Including the criteria for defining MINOCA according to the European Society of Cardiology guidelines would be beneficial.

Response:

  • Thank you for your suggestion. The criteria for defining myocardial infarction with non-obstructive coronary arteries (MINOCA) are outlined in the Methods section of the manuscript, where we referenced the 2023 ACS guidelines.
  • Was cardiac magnetic resonance imaging performed? CMR is necessary to determine the ischemic nature of myocardial damage and confirm the diagnosis of MINOCA. Additionally, CMR is crucial for prognostic purposes, as it identifies three phenotypes with differing prognoses: late gadolinium enhancement positive/mapping positive, late gadolinium enhancement negative/mapping positive, and normal CMR. Expanding the bibliography and discussion on this topic would be useful.

Response:

  • Thank you for your question. We have data on 68 cardiac magnetic resonance imaging (CMR) scans that confirmed the diagnosis of MINOCA in our cohort. However, further detailed phenotypic classification, such as late gadolinium enhancement positivity or mapping, was not specifically collected. We have data from a total of 68 patients with CMR. This is ultimately a limitation of the study, that no systematic implementation of this investigation was carried out. LGE was positive in 32 patients and negative in 36 patients.
  • How were the age cut-offs determined for the population division? I suggest also considering a division based on the median age of the population.

Response:

  • We divided the patients in four groups in quartiles as required, see new statistic below. The first division is based on the number of investigated patients to have comparable number of patients in all groups. However, the results from your suggestion are comparable as compared to the old division of age groups.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 1: Baseline characteristics of 373 patients initially presenting Troponin-positive with non-obstructive coronary artery disease according to age  

Variables  

All patients  

n=373 

<52 

n=88 

52-64 

n=95 

65-75 

n=91 

>75 

n=99 

P 

Value 

Age – years, mean+SD 

63+15.6 

41±9.4 

59±3.5 

70±2.8 

80±3.8 

 

<0.001 

Male – no, (%) 

185 (49.6) 

63 (71.6) 

52 (54.7) 

33 (36.3) 

37 (37.4) 

<0.001 

BMI – kg/m2, mean+SD  

27.6+5.6 

27.9±5.9 

27.8±6 

27.1±5.2 

27.7±5.3 

0.781 

Duration of hospitalization – days, mean+SD 

10+8.5 

8±9.3 

10.3±10.1 

10.9±9.2 

10.8±8.7 

 

0.068 

Symptoms – no, (%) 

 

 

 

 

 

 

   Angina pectoris  

226 (61.6) 

63 (71.6) 

56 (59) 

50 (55) 

57 (57.6) 

0.099 

   Dyspnea  

164 (44.4) 

21 (23.9) 

49 (51.6) 

46 (50.6) 

48 (48.5) 

<0.001 

   Palpations 

45 (12.3) 

13 (14.8) 

8 (8.4) 

15 (16.5) 

9 (9.1) 

0.246 

Clinic parameter, mean + SD 

 

 

 

 

 

 

    Systolic BP, mmHg 

146.6+64.4 

138±25.5 

141±31.2 

161.8±11.7 

144.6±27.6 

0.126 

    Diastolic BP, mmHg 

84.8+18.1 

86.8±17.1 

84±22.4 

85±15.2 

80.7±16.6 

0.137 

    Heart rate, bpm 

89.8+28.6 

84.5±23.5 

92±29.7 

92.8±31.3 

86.3±29.2 

0.298 

ECG – no, (%) 

 

 

 

 

 

 

   ST elevation  

55 (14.8) 

28 (31.8) 

7 (7.4) 

7 (7.7) 

13 (13.1) 

<0.001 

   Inversed T-Waves 

183 (49.2) 

28 (31.8) 

49 (51.6) 

50 (55) 

56 (56.6) 

0.002 

Medical history – no, (%) 

 

 

 

 

 

 

   Current Smoking 

85 (23.1) 

34 (39.1) 

27 (28.4) 

16 (17.6) 

8 (8.1) 

<0.001 

   Obesity – no, (%) 

112 (30) 

27 (30.7) 

30 (31.6) 

25 (27.5) 

30 (30.3) 

0.938 

   Arterial hypertension  

253 (68.2) 

37 (42.1) 

60 (63.2) 

73 (80.2) 

83 (83.8) 

<0.001 

   Dyslipidemia 

99 (26.6) 

18 (20.5) 

25 (26.3) 

24 (26.4) 

32 (32.3) 

0.341 

   Diabetes Mellitus  

65 (17.5) 

8 (9.1) 

16 (16.8) 

15 (16.5) 

26 (26.3) 

0.021 

   COPD 

47 (12.6) 

1 (1.1) 

13 (13.7) 

19 (20.9) 

14 (14.1) 

<0.001 

   Bronchial Asthma   

33 (8.9) 

8 (9.1) 

11 (11.6) 

6 (6.6) 

8 (8.1) 

0.663 

   Malignancy  

47 (12.7) 

2 (2.3) 

8 (8.4) 

18 (19.8) 

19 (19.2) 

<0.001 

   Kidney disease 

53 (14.3) 

5 (5.7) 

12 (12.6) 

8 (8.8) 

28 (28.3) 

<0.001 

   Neurological disease  

90 (24.3) 

12 (13.6) 

20 (21.1) 

23 (25.3) 

35 (35.4) 

0.006 

  Autoimmune disease 

17 (4.6) 

5 (5.7) 

5 (5.3) 

0 (0) 

7 (7.1) 

0.103 

   Psychiatric disease  

39 (10.5) 

8 (9.1) 

16 (16.8) 

8 (8.8) 

7 (7.1) 

0.114 

   Pacemaker  

14 (3.8) 

0 (0) 

2 (2.1) 

5 (5.5) 

7 (7.1) 

0.047 

History of Malignant cardiac arrhythmias* 

8 (2.2) 

0 (0) 

0 (0) 

4 (4.4) 

4 (4) 

0.049 

    Bradycardic arrhythmias 

6 (1.6) 

0 (0) 

0 (0) 

3 (3.3) 

3 (3) 

0.119 

     - AV block 2 Mobitz 

3 (0.8) 

0 (0) 

0 (0) 

2 (2.2) 

1 (1) 

0.291 

     - AV block 3 

3 (0.8) 

0 (0) 

0 (0) 

1 (1.1) 

2 (2) 

0.339 

     - Asystole 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 

    Ventricular arrhythmias 

1 (0.3) 

0 (0) 

0 (0) 

1 (1.1) 

0 (0) 

0.381 

      - sustained 

1 (0.3) 

0 (0) 

0 (0)  

1 (1.1) 

0 (0) 

0.381 

      - non-sustained 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 

      - ventricular fibrillation 

0 (0) 

0 (0) 

0 (0)  

0 (0) 

0 (0) 

0 

     Torsade de pointes 

1 (0.3) 

0 (0) 

0 (0) 

0 (0) 

1 (1) 

0.434 

     Atrial fibrillation  

57 (15.4) 

1 (1.4) 

9 (9.5) 

12 (13.3) 

16 (16.2) 

0.005 

Laboratory values, mean + SD 

 

 

 

 

 

 

 Troponin (µg/l) 

2.1+8.4 

2.7±5.2 

0.1±14.5 

1.6±6.7 

0.2±0.6 

0.129 

  Creatin Phosphokinase (U/l) 

288.6+548.9 

5.7±6.5 

6.6±14.3 

3.8±5.6 

463.5 ±4553.2 

0.446 

  BNP (pg/ml) 

65.1±123 

27.7±61.5 

61.2±101.6 

48.8±199 

37.5±29 

0.003 

  Creatinine (mg/dl) 

93.5±45.7 

82.6±17.9 

79.2±71.9 

90±32 

103.4±40.4 

0.017 

   TSH (mU/l) 

2+1.7 

2±1.2 

1.5±2.5 

1.5±1.2  

1.9±1.3 

0.114 

    fT3 (pmol/l) 

5.2+1 

5.5±1 

5.3±1.1 

4.9±1.1  

4.7±0.6 

0.087 

    fT4 (ng/l) 

10.6±2.8 

13.4±2.3 

11.7±2.2 

14.1±4.6 

14.5±3.5 

0.029 

Echocardiography data, n (%)  

 

 

 

 

 

 

  LVEF %, (on admission),  

  mean + SD 

36.9±25.7 

56±21.8 

 

33.2±26.3 

34.9±26.3 

 

32.7±25.4 

<0.001 

  - LVEF > 50 % 

170 (66.9) 

58 (65.9) 

36 (37.9) 

37 (41.1) 

39 (39.4) 

0.035 

  - LVEF 40-49 % 

31 (12.2) 

5 (5.7) 

9 (9.5) 

6 (6.7) 

11 (11.1) 

0.211 

   - LVEF < 40 % 

52 (20.5) 

9 (10.2) 

12 (12.6) 

18 (20) 

13 (13.1) 

0.133 

  Left ventricular hypertrophy 

103 (29.1) 

17 (19.5) 

27 (28.4) 

24 (26.7) 

35 (35.4) 

0.044 

  Tricuspid valve regurgitation 

89 (24.2) 

8 (9.1) 

25 (27.4) 

22 (24.4) 

34 (34.3) 

<0.001 

    - mild 

63 (17.1) 

6 (6.8) 

20 (21.1) 

13 (14.4) 

24 (24.2) 

0.007 

    - moderate 

23 (6.3) 

2 (2.3) 

4 (4.2) 

9 (10) 

8 (8.1) 

0.127 

    - severe  

3 (0.8) 

0 (0) 

1 (1.1) 

0 (0) 

2 (2) 

0.341 

   Mitral valve regurgitation 

106 (28.8) 

9 (10.2) 

22 (23.2) 

31 (34.4) 

44 (44.4) 

<0.001 

    - mild 

77 (20.9) 

8 (9.1) 

17 (17.9) 

20 (22.2) 

32 (32.3) 

0.001 

    - moderate 

19 (5.2) 

1 (1.1) 

3 (3.2) 

8 (8.8) 

7 (7.1) 

0.077 

    - severe  

10 (2.7) 

0 (0) 

2 (2.1) 

3 (3.3) 

5 (5) 

0.188 

   Aortic valve regurgitation 

39 (10.6) 

2 (2.3) 

7 (7.4) 

11 (12.1) 

19 (19.2) 

0.001 

    - mild 

31 (8.4) 

2 (2.3) 

5 (5.3) 

9 (9.9) 

15 (15.2) 

0.008 

    - moderate 

4 (1.1) 

0 (0) 

2 (2.1) 

1 (1.1) 

1 (1) 

0.579 

    - severe  

4 (1.1) 

0 (0) 

0 (0) 

1 (1.1) 

3 (3) 

0.137 

Drugs on admission, n (%) 

 

 

 

 

 

 

ß-Blocker 

131 (35.2) 

11 (12.5) 

33 (34.7) 

38 (41.8) 

49 (49.5) 

<0.001 

ACE inhibitor 

121 (32.6) 

16 (18.2) 

30 (31.6) 

32 (35.2) 

43 (43.4) 

0.002 

Sartans

57 (15.3) 

4 (4.6) 

15 (15.8) 

15 (16.5) 

23 (23) 

0.005 

Ca-Blocker  

74 (19.9) 

7 (8) 

15 (15.8) 

18 (19.8) 

34 (34.3) 

<0.001 

Diuretics 

101 (27.2) 

11 (12.5) 

19 (20) 

19 (20.9) 

52 (52.5) 

<0.001 

Statin 

281 (76.8) 

10 (11.5) 

16 (16.8) 

24 (26.4) 

35 (35.4) 

<0.001 

Anticoagulants** 

58 (15.6) 

1 (1.1) 

9 (9.6) 

19 (20.9) 

29 (29.3) 

<0.001 

Aspirin 

79 (21.2) 

7 (8) 

25 (26.3) 

17 (18.7) 

30 (30.3) 

<0.001 

Clopidogrel  

18 (4.8) 

2 (2.3) 

5 (5.3) 

4 (4.4) 

7 (7.1) 

0.494 

Prasugrel  

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 

Antiarrhythmics*** 

10 (2.7) 

1 (1.1) 

3 (3.2) 

4 (4.4) 

2 (2) 

0.558 

p values for the comparison between groups of ages; SD, Standard deviation; BMI, body mass index; BP, blood pressure; ECG, Electrocardiogram;  COPD, Chronic obstructive pulmonary disease; AV, atrioventricular; BNP, brain natriuretic Peptide; LVEF, left ventricular ejection fraction; ACE, Angiotensin-converting-enzyme; *, only one malignant cardiac/supraventricular arrhythmia is counted per patient (even if one patient has several arrhythmias at the same time); ** Coumarin, heparin, selective factor 10-blocker, direct thrombin inhibitors; ***, Ivabradine, Flecainide, Sotalol, Dronedarone, Digitalis.

 

 

 

 

 

 

Table 2: Medication at discharge   

 

All patients  

n=373 

<52 

n=88 

52-64 

n=95 

65-75 

n=91 

>75 

n=99 

P 

Value 

ß-Blocker 

270 (72.4) 

57 (64.8) 

74 (77.9) 

69 (75.8) 

70 (70.7) 

0.199 

ACE inhibitor  

224 (60.1) 

54 (61.4) 

59 (62.1) 

54 (59.3) 

57 (57.6) 

0.919 

Sartans

62 (16.6) 

6 (6.8) 

17 (17.9) 

18 (19.8) 

21 (21.2) 

0.039 

Ca Blocker 

100 (26.8) 

14 (15.9) 

23 (24.2) 

24 (26.4) 

39 (39.4) 

0.003 

Diuretics   

166 (44.5) 

16 (18.2) 

39 (41.1) 

45 (49.5) 

66 (66.7) 

<0.001 

Statin 

206 (55.2) 

27 (30.7) 

42 (44.2) 

42 (46.2) 

56 (56.6) 

0.005 

Anticoagulants* 

104 (27.9) 

5 (5.7) 

25 (26.3) 

34 (37.4) 

40 (40.4) 

<0.001 

Aspirin 

175 (46.9) 

30 (34.1) 

50 (52.6) 

43 (47.3) 

52 (52.5) 

0.040 

Clopidogrel  

68 (18.2) 

15 (17.1) 

19 (20) 

14 (15.4) 

20 (20.2) 

0.795 

Prasugrel  

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 

Antiarrhythmics** 

26 (7) 

2 (2.3) 

6 (6.3) 

12 (13.2) 

6 (6.1) 

0.035 

ACE, Angiotensin-converting-enzyme; * Coumarin, Heparin, selective factor 10-blocker, direct thrombin inhibitors; ** Ivabradine, Flecainide, Sotalol, Dronedarone, Digitalis.

 

 

 

 

 

 

 

 

 

 

 

 

Table 3: In-hospital complications according to age 

 

All patients  

n=373 

<52 

n=88 

52-64 

n=95 

65-75 

n=91 

>75 

n=99 

P 

Value 

Adverse event 

132 (35.5) 

14 (15.9) 

37 (39) 

36 (39.6) 

45 (45.5) 

<0.001 

  CPR 

7 (1.9) 

0 (0) 

4 (4.2) 

1 (1.1) 

2 (2) 

0.188 

  Left ventricular  

  thrombus  

3 (0.8) 

1 (1.1) 

1 (1.1) 

0 (0) 

1 (1) 

0.807 

  Thromboembolic event 

3 (0.8) 

1 (1.1) 

1 (1.1) 

0 (0) 

1 (1) 

0.807 

  Pulmonary edema  

9 (2.7) 

1 (1.1) 

4 (4.2) 

2 (2.2) 

2 (2) 

0.576 

  Cardiogenic shock  

9 (2.7) 

1 (1.1) 

4 (4.2) 

2 (2.2) 

2 (2) 

0.576 

  Invasive ventilation  

29 (7.8) 

4 (4.6) 

12 (12.6) 

7 (7.7) 

6 (6) 

0.187 

  Non-invasive  

  ventilation 

11 (3) 

1 (1.1) 

1 (1.1) 

6 (6.6) 

3 (3) 

0.093 

  Stroke 

1 (0.3) 

0 (0) 

1 (1.1) 

0 (0) 

0 (0) 

0.404 

  Malignant cardiac  

  arrhythmias*  

(On admission/in hospital) 

39 (10.5) 

8 (9.1) 

14 () 

8 (8.8) 

9 (9.1) 

0.478 

    Bradycardic     

    arrhythmias 

13 (3.5) 

3 (3.4) 

2 (2.1) 

4 (4.49 

4 (4) 

0.838 

     - AV block 2 Mobitz 

3 (0.8) 

2 (2.3) 

0 (0) 

1 (1.1) 

0 (0) 

0.258 

     - AV block 3 

1 (0.3) 

0 (0) 

0 (0) 

0 (0) 

1 (1) 

0.430 

     - Asystole 

10 (2.7) 

2 (2.3) 

2 (2.1) 

3 (3.3) 

3 (3) 

0.950 

    Ventricular arrhythmias 

14 (3.8) 

2 (2.3) 

6 (6.3) 

3 (3.3) 

3 (3) 

0.486 

      - sustained 

8 (2.2) 

2 (2.3) 

2 (2.1) 

2 (2.2) 

2 (2) 

0.999 

      - non-sustained 

6 (1.6) 

0 (0) 

4 (4.2) 

1 (1.1) 

1 (1) 

0.114 

      - ventricular fibrillation 

16 (4.3) 

3 (3.4) 

9 (9.5) 

1 (1.1) 

3 (3) 

0.029 

     Torsade de pointes 

2 (0.5) 

0 (0) 

1 (1.1) 

0 (0) 

1 (1) 

0.604 

  Supraventricular  

  arrhythmias* 

85 (22.8) 

4 (4.6) 

19 (20) 

27 (29.7) 

35 (35.4) 

<0.001 

     Atrial fibrillation 

77 (20.6) 

3 (3.4) 

14 (14.7) 

26 (28.6) 

34 (34.3) 

<0.001 

      - first appearance 

43 (11.5) 

3 (3.4) 

7 (7.4) 

11 (12.1) 

22 (12.1) 

<0.001 

      - recurrent  

34 (9.1) 

0 (0) 

7 (7.4) 

15 (16.5) 

12 () 

<0.001 

     Atrial flutter  

9 (2.4) 

1 (1.1) 

5 (5.3) 

2 (2.2) 

1 (1) 

0.194 

     - first appearance 

9 (2.4) 

1 (1.1) 

5 (5.3) 

2 (2.2) 

1 (1) 

0.194 

     - recurrent 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 

  In-hospital death 

10 (2.7) 

0 (0) 

4 (4.2) 

3 (3.3) 

3 (3) 

0.329 

     Cardiac caused death 

6 (1.6) 

0 (0) 

3 (3.2) 

2 (2.2) 

1 (1) 

0.349 

     Non-cardiac caused death 

4 (1.1) 

0 (0) 

1 (1.1) 

1 (1.1) 

2 (2) 

0.619 

Adverse event, major adverse cardiac and cerebrovascular events; CPR, cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; AV, atrioventricular; *, only one malignant cardiac/supraventricular arrhythmia is counted per patient (even if one patient has several arrhythmias at the same time).

 

 

 

 

 

 

 

 

 

Table 4: in-hospital treatment approach   

 

All patients  

n=373 

<52 

n=88 

52-64 

n=95 

65-75 

n=91 

>75 

n=99 

P 

Value 

FU EF (%) 

49+14.7 

60±12,1 

49.2±15 

42.2±15.1 

43.8±12 

<0.001 

  - LVEF >50%

100 (26.8) 

37 (42.1) 

28 (29.5) 

13 (14.3) 

22 (22.2) 

<0.001 

  - LVEF 40-49%

27 (7.2) 

5 (5.7) 

6 (6.3) 

6 (6.6) 

10 (10.1) 

0.636 

  - LVEF <40%

50 (13.4) 

6 (6.8) 

11 (11.6) 

19 (20.9) 

14 (14.1) 

0.037 

Cardioversion 

50 (13.9) 

6 (6.8) 

21 (22.1) 

20 (22) 

17 (17.2) 

0.019 

Pacemaker   

64 (17.2) 

2 (2.3) 

11 (11.6) 

5 (5.5) 

6 (6.1) 

0.076 

Life Vest   

24 (6.5) 

6 (6.8) 

4 (4.2) 

2 (2.2) 

0 (0) 

0.056 

FU EF, follow up ejection fraction; LVEF, left ventricular ejection fraction.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 5: Clinical Outcome according to age at follow-up.  

 

All patients  

n=288 

<52 

n=68 

52-64 

n=72 

65-75 

n=65 

>75 

n=83 

P 

Value 

Adverse event  

100 (34.8) 

4 (5.9) 

16 (22.2) 

25 (38.5) 

53 (63.9) 

<0.001 

  Stroke 

10 (4.2) 

2 (2.9) 

2 (2.8) 

1 (1.5) 

5 (6) 

0.398 

  Thromboembolic event  

6 (2.5) 

2 (2.9) 

0 (0) 

1 (1.5) 

3 (3.6) 

0.229 

   Recurrence of Troponin-positive with non-obstructive CAD 

3 (1.3) 

0 (0) 

1 (1.4) 

2 (3.1) 

0 (0) 

0.253 

   Cardiac arrest  

4 (1.7) 

0 (0) 

1 (1.4) 

2 (3.1) 

1 (1.2) 

0.473 

   Percutaneous coronary intervention  

17 (7.2) 

2 (2.9) 

4 (5.6) 

6 (9.2) 

5 (6) 

0.266 

   Death 

69 (24.1) 

0 (0) 

10 (13.9) 

17 (26.2) 

42 (50.6) 

<0.001 

    - cardiac caused death 

5 (2.1) 

0 (0) 

0 (0) 

3 (4.6) 

2 (2.4) 

0.062 

    - non-cardiac caused death 

12 (5.1) 

0 (0) 

5 (6.9) 

1 (1.5) 

6 (7.2) 

0.012 

Adverse event, major adverse cardiac and cerebrovascular events; CAD, coronary artery disease; NSTEMI, Non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; CPR, cardiopulmonary resuscitation 

 

 

 

 

 

 

How do the authors explain such a low left ventricular ejection fraction upon admission? Were other categories of patients included (e.g., takotsubo)?

Response:

  • Thank you for your question. Among the study population, 22 patients (5.9%) were diagnosed with takotsubo syndrome (TTS), a condition known to cause transient left ventricular dysfunction and low ejection fraction upon admission. Additionally, 48 patients (12.9%) had myocarditis, which can also contribute to reduced left ventricular ejection fraction (LVEF) during the acute phase of the disease. Importantly, in several cases, the low LVEF observed at admission improved during follow-up, likely reflecting recovery from these reversible or acute conditions.

The population was largely under-treated. Could this have influenced the outcomes? I recommend expanding the discussion on this point, considering that patients with MINOCA are at high risk for reinfarction and that managing low-density lipoprotein levels is mandatory (cite: 10.1016/j.pcad.2023.10.006).

Response:

  • We conducted a comprehensive investigation into the impact of demographics, clinical characteristics, ECG findings, medical history, laboratory values, and medications on both in-hospital and long-term outcomes. In the univariate analysis, some drugs were identified as a predictor for in-hospital outcomes (adverse events and in-hospital mortality), but this association was not confirmed in the multivariate analysis. Similarly, certain medications emerged as predictors for long-term outcomes in the univariate analysis but lost significance in the multivariate model (refer to Tables 6 and 7). We appreciate your suggestion and have expanded the discussion to address the potential influence of under-treatment on patient outcomes. Specifically, we cited the recommended reference (10.1016/j.pcad.2023.10.006) highlighting the high risk of reinfarction in patients with MINOCA, often due to the progression of atherosclerosis that necessitates revascularization. Furthermore, LDL-C management appeared to be suboptimal in these patients.

 

 

 

 

 

Table 6: univariate and multiple Logistic Regression Analysis for in-hospital outcome 

Variable 

Univariate analysis 

 

Multivariable analysis 

 

OR 

95% CI 

P value 

OR 

95% CI 

P value 

Age  

1.03 

1.018-1.050 

<0.001 

 

1.00 

0.959-1.047 

0.919 

 

Male 

1.24 

0.809-1.892 

0.327 

 

 

 

 

 

BMI 

1.01 

0.974-1.052 

0.537 

 

 

 

 

 

Symptoms 

 

 

 

 

 

 

 

 

Angina pectoris 

0.24 

0.150-0.373 

<0.001 

 

0.19 

0.054-0.627 

0.007 

 

Dyspnea 

1.56 

1.086-2.574 

0.020 

 

2.20 

0.524-8-955 

0.270 

 

Palpations 

3.33 

1.753-6.324 

<0.001 

 

7.68 

1.377-42.839 

0.020 

 

Clinic parameter 

 

 

 

 

 

 

 

 

Systolic BP 

1.00 

0.987-1.004 

0.280 

 

 

 

 

 

Diastolic BP 

0.10 

1.012-1.026 

0.097 

 

 

 

 

 

Heart rate  

1.03 

1.021-1.040 

<0.001 

 

1.04 

1.016-1.072 

0.002 

 

ECG Data  

 

 

 

 

 

 

 

 

ST-segment elevation 

0.64 

0.341-1.216 

0.175 

 

 

 

 

 

Inversed T-Waves 

0.74 

0.481-1.131 

0.162 

 

 

 

 

 

Medical history  

 

 

 

 

 

 

 

 

Current Smoker  

0.67 

0.392-1.133 

0.134 

 

 

 

 

 

Diabetes mellitus  

1.39 

0.803-2.397 

0.241 

 

 

 

 

 

Obesity (BMI > 30 kg/m2) 

1.20 

0.761-1.906 

0.427 

 

 

 

 

 

Arterial Hypertension 

2.31 

1.407-3.806 

<0.001 

 

2.22 

0.453-10.942 

0.325 

 

Pulmonary disease  

1.492 

0.895-2.490 

0.125 

 

 

 

 

 

Dyslipidemia  

0.89 

0.549-1.451 

0.647 

 

 

 

 

 

Malignancy 

1.31 

0.702-2.458 

0.393 

 

 

 

 

 

Neurological disease  

1.33 

0.813-2.163 

0.258 

 

 

 

 

 

Kidney disease  

1.50 

0.830-2.704 

0.180 

 

 

 

 

 

Autoimmune disease 

2.17 

0.815-5.757 

0.121 

 

 

 

 

 

Psychiatric disease  

0.80 

0.391-1.635 

0.540 

 

 

 

 

 

Malignant cardiac arrhythmias 

1.11 

0.261-4.721 

0.887 

 

 

 

 

 

Supraventricular arrhythmias 

5.86 

3.157-10.864 

<0.001 

 

3.70 

0.721-19-023 

0.117 

 

Laboratory values 

 

 

 

 

 

 

 

 

Troponin

1.00 

0.999-1.000 

0.164 

 

 

 

 

 

Creatine phosphokinase 

1.00 

1.000-1.002 

0.657 

 

 

 

 

 

BNP 

1.00 

1.000-1.003 

0.037 

 

1.00 

0.999-1.017 

0.095 

 

Creatinine 

1.02 

1.009-1.023 

<0.001 

 

1.03 

1.001-1.050 

0.042 

 

TSH  

1.12 

0.891-1.287 

0.094 

 

 

 

 

 

fT3 

0.83 

0.534-1.284 

0.399 

 

 

 

 

 

fT4 

1.04 

0.896-1.214 

0.587 

 

 

 

 

 

Echocardiography data, n (%)

 

 

 

 

 

 

 

 

LVEF ≥50% 

0.29 

0.169-0.505 

<0.001 

 

3.38 

0.624-18.301 

0.158 

 

LVEF 40-49% 

2.35 

1.099-5.020 

0.028 

 

6.48 

0.862-48.796 

0.069 

 

LVEF ≤ 40 % 

2.72 

1.459-5.066 

0.002 

 

0.42 

0.058-2.966 

0.381 

 

Tricuspid valve regurgitation 

2.86 

1.752-4.673 

<0.001 

 

2.35 

0.451-12.271 

0.310 

 

Mitral valve regurgitation 

2.74 

1.719-4.368 

<0.001 

 

0.29 

0.046-1.762 

0.177 

 

Aortic valve regurgitation 

1.68 

0.862-3.289 

0.127 

 

 

 

 

 

Drugs on admission 

 

 

 

 

 

 

 

 

ß-Blocker 

1.92 

1.237-2.990 

0.004 

 

1.61 

0.435-5.963 

0.476 

 

ACE inhibitor 

1.28 

0.814-2.005 

0.286 

 

 

 

 

 

Sartane 

2.16 

1.223-3.826 

0.008 

 

0.27 

0.053-1.374 

0.115 

 

Ca-Blocker 

1.43 

0.848-2.403 

0.180 

 

 

 

 

 

Diuretics 

2.44 

1.523-3.894 

<0.001 

 

1.56 

0.407-5.970 

0.518 

 

Statin 

0.92 

0.548-1.535 

0.742 

 

 

 

 

 

Anticoagulants 

3.17 

1.784-5.631 

<0.001 

 

2.42 

0.416-14.051 

0.326 

 

Aspirin 

0.65 

0.377-1.125 

0.124 

 

 

 

 

 

Antiarrhythmics  

1.23 

0.342-4.452 

0.749 

 

 

 

 

 

OR, Odds ratio; CI, confidence interval; BP, blood pressure; ECG, Electrocardiogram; BMI, body mass index; BNP, brain natriuretic Peptide; LVEF, left ventricular ejection fraction; ACE, Angiotensin-converting-enzyme 

 

 

Table 7: univariate and multiple Logistic Regression Analysis for long-term outcome 

Variable 

Univariate analysis 

 

Multivariable analysis 

 

OR 

95% CI 

P value 

OR 

95% CI 

P value 

Age  

1.09 

1.060-1.112 

<0.001 

 

1.07 

1.013-1.137 

0.017 

 

Male 

0.55 

0.333-0.898 

0.017 

 

0.28 

0.064-1.252 

0.096 

 

BMI 

0.99 

0.727-1.351 

0.954 

 

 

 

 

 

Symptoms 

 

 

 

 

 

 

 

 

Angina pectoris 

0.85 

0.511-1.421 

0.540 

 

 

 

 

 

Dyspnea 

2-39 

1.448-3.954 

<0.001 

 

3.09 

0.753-12.694 

0.117 

 

Palpations 

0.52 

0.216-1.248 

0.143 

 

 

 

 

 

Clinic parameter 

 

 

 

 

 

 

 

 

Systolic BP 

1.00 

0.991-1.004 

0.505 

 

 

 

 

 

Diastolic BP 

0.99 

0.976-1.007 

0.296 

 

 

 

 

 

Heart rate  

1.00 

0.991-1.008 

0.922 

 

 

 

 

 

ECG Data  

 

 

 

 

 

 

 

 

ST-segment elevation 

0.92 

0.453-1.881 

0.825 

 

 

 

 

 

Inversed T-Waves 

1.86 

1.131-3.062 

0.015 

 

1.33 

0.391-4.511 

0.649 

 

Medical history  

 

 

 

 

 

 

 

 

Current Smoker  

0.44 

0.230-0.845 

0.014 

 

1.24 

0.241-6.383 

0.798 

 

Diabetes mellitus  

2.51 

1.362-4.624 

0.003 

 

14.00 

2.181-89.933 

0.005 

 

Obesity (BMI > 30 kg/m2) 

1.33 

0.792-2.231 

0.281 

 

 

 

 

 

Arterial Hypertension 

1.78 

1.021-3.091 

0.042 

 

0.50 

0.079-3.113 

0.454 

 

Pulmonary disease  

2.13 

1.187-3.836 

0.011 

 

0.43 

0.077-2.378 

0.331 

 

Dyslipidemia 

1.18 

0.685-2.045 

0.546 

 

 

 

 

 

Malignancy 

1.34 

0.705-2.527 

0.375 

 

 

 

 

 

Neurological disease  

3.15 

1.811-5.461 

<0.001 

 

0.80 

0.207-3.072 

0.743 

 

Kidney disease  

2.21 

1.154-4.235 

0.017 

 

    

 

 

Autoimmune disease 

0.88 

0.298-2.622 

0.825 

 

 

 

 

 

Malignant cardiac arrhythmias 

2.64 

0.579-12.031 

0.210 

 

 

 

 

 

Supraventricular arrhythmias 

2.78 

1.387-5.553 

0.004 

 

 

 

 

 

Laboratory values 

 

 

 

 

 

 

 

 

Troponin 

0.99 

0.939-1.053 

0.848 

 

 

 

 

 

Creatine phosphokinase 

1.00 

1.000-1.001 

0.724 

 

 

 

 

 

BNP 

1.00 

1.000-1.001 

0.015 

 

0.83 

0.124-5.511 

0.843 

 

Creatinine 

2.00 

1.014-3.938 

0.045 

 

3.64 

0.346-38.301 

0.282 

 

TSH  

0.86 

0.693-1.068 

0.172 

 

 

 

 

 

fT3 

0.59 

0.237-1.474 

0.260 

 

 

 

 

 

fT4 

1.16 

0.935-1.445 

0.176 

 

 

 

 

 

Echocardiography data, n (%)

 

 

 

 

 

 

 

 

LVEF ≥50%  

0.78 

0.418-1.439 

0.420 

 

 

 

 

 

LVEF 40-49% 

0.54 

0.193-1.510 

0.240 

 

 

 

 

 

LVEF ≤ 40 % 

1.90 

0.959-3.760 

0.066 

 

 

 

 

 

Tricuspid valve regurgitation 

0.90 

0.512-1.583 

0.715 

 

 

 

 

 

Mitral valve regurgitation 

1.04 

0.612-1.777 

0.878 

 

 

 

 

 

Aortic valve regurgitation 

1.03 

0.488-2.189 

0.931 

 

 

 

 

 

Drugs on admission 

 

 

 

 

 

 

 

 

ß-Blocker 

1.74 

1.054-2.880 

0.030 

 

0.38 

0.092-1.558 

0.179 

 

ACE inhibitor 

1.78 

1.056-2.991 

0.030 

 

1.78 

0.450-7.069 

0.410 

 

Sartans 

1.31 

0.684-2.511 

0.416 

 

 

 

 

 

Ca-Blocker 

1.61 

0.988-3.330 

0.055 

 

 

 

 

 

Diuretics 

2.28 

1.344-3.877 

0.002 

 

0.65 

0.152-2.743 

0.552 

 

Statins 

1.03 

0.566-1.869 

0.925 

 

 

 

 

 

Anticoagulants 

1.81 

0.955-3.440 

0.069 

 

 

 

 

 

Aspirin 

1.89 

1.055-3.395 

0.032 

 

3.33 

0.593-18.698 

0.172 

 

Antiarrhythmics  

2.05 

0.784-5.334 

0.143 

 

 

 

 

 

OR, Odds ratio; CI, confidence interval; BP, blood pressure; ECG, Electrocardiogram; BMI, body mass index; BNP, brain natriuretic Peptide; LVEF, left ventricular ejection fraction; ACE, Angiotensin-converting-enzyme 

 

 

 Finally, considering the study's limitations and design, I recommend toning down the conclusions and interpretation of the results.

Response:

  • We have carefully revised the discussion to address this concern. The conclusions and interpretations have been rephrased to reflect a more cautious and balanced tone, taking into account the study's limitations and design.

 

Comments on the Quality of English Language

Perform a thorough proofreading to correct grammatical issues and ensure clarity and readability.

Response:

  • We have thoroughly proofread the manuscript to correct grammatical issues and enhance clarity and readability. Necessary revisions have been implemented to ensure the language meets a high standard of quality.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors conducted a cohort study on 373 patients with elevated troponin but no obstructive coronary lesion, screened from 24,775 patients, grouped by age (<51, 51-60, 61-70, >70). Older patients had higher rates of major adverse cardiovascular events during hospitalization (47.2% in >70 vs. 15.4% in <51; p<0.001). Non-sustained ventricular tachycardia was most common in the 51-60 group (5.6%; p=0.027). At 11 years, cardiovascular mortality remained highest in older patients (4.2% in >70 group; p=0.042), suggesting age correlates with increased adverse outcomes in these cases. Primary limitations include the study's retrospective nature and small sample size.

Below are several suggestions to improve the manuscript.

 

1.     Introduction: In the sentence, “However, the prognosis of this condition is not benign… compared to patients with CAD at one-year follow-up,” I suggest adding that patients with MINOCA have an incidence of heart failure similar to those with obstructive CAD but typically have preserved ejection fraction, as recently demonstrated (cite PMID: 37596114).

2.     In the “study population” section, please provide a precise definition of coronary artery disease (CAD) as used in the study. If the definition is CAD > 50%, I recommend specifying "obstructive CAD" consistently throughout the manuscript.

3.     Since the authors excluded only non-cardiac causes of myocardial injury, it is essential to also report the cardiac etiologies of the included patients, such as myocarditis, Takotsubo syndrome, true MINOCA, and cardiomyopathies. If patients with non-ischemic myocardial injury were excluded, this should be explicitly stated in the methods, along with the diagnostic modalities used to determine the final diagnosis (e.g., CMR).

4.     Figure 1: It appears that 30 patients did not consent to participate in the study, yet the results section includes data from a total of 373 patients, seemingly counting these 30 individuals. If these patients did not consent to data usage, they should not be included in any analysis. Please clarify this aspect.

5.     The primary endpoint should be clearly stated in the abstract as well.

6.     Table 1: If supraventricular arrhythmias only refer to atrial fibrillation episodes, it would be clearer to report atrial fibrillation directly as the event.

7.     Table 2: Please include data on statin therapy.

8.     Discussion: The sentence “the occurrence of troponin elevation without an obstructive culprit lesion is more common in patients >70 years old” may be misleading. This study did not assess the incidence of the event across age groups within the general population. We do not have information on how many patients >70 years experienced troponin elevation without obstructive CAD.

9.     Discussion: In the sentence “On the other side, in a systemic review, patients suffering from troponin elevation without an obstructive culprit lesion tended to be younger and female,” I would also specify that women with MINOCA aged ≤70 have a worse prognosis (higher MACE) compared to men and women with MIOCA, likely due to distinct pathophysiology affecting long-term prognosis (PMID: 37261384).

10.  Please specify what cMRT stands for in the text.

Author Response

The authors conducted a cohort study on 373 patients with elevated troponin but no obstructive coronary lesion, screened from 24,775 patients, grouped by age (<51, 51-60, 61-70, >70). Older patients had higher rates of major adverse cardiovascular events during hospitalization (47.2% in >70 vs. 15.4% in <51; p<0.001). Non-sustained ventricular tachycardia was most common in the 51-60 group (5.6%; p=0.027). At 11 years, cardiovascular mortality remained highest in older patients (4.2% in >70 group; p=0.042), suggesting age correlates with increased adverse outcomes in these cases. Primary limitations include the study's retrospective nature and small sample size.

Below are several suggestions to improve the manuscript.

 

  1. Introduction: In the sentence, “However, the prognosis of this condition is not benign… compared to patients with CAD at one-year follow-up,” I suggest adding that patients with MINOCA have an incidence of heart failure similar to those with obstructive CAD but typically have preserved ejection fraction, as recently demonstrated (cite PMID: 37596114).

Answer:

  • Thank you for your suggestion. We have incorporated this important finding into the introduction as follows: However, the prognosis of this condition is not benign. Patients with troponin elevation without obstructive coronary artery disease (CAD), as observed in the ACUITY trial, exhibited an increased risk of all cause-mortality compared to those with CAD at one-year follow-up [6]. Furthermore, these patients experienced a high incidence of heart failure (HF), comparable to individuals with obstructive CAD. Notably, HF in this population was predominantly characterized by preserved ejection fraction (HFpEF).

 

 

 

  1. In the “study population” section, please provide a precise definition of coronary artery disease (CAD) as used in the study. If the definition is CAD > 50%, I recommend specifying "obstructive CAD" consistently throughout the manuscript.

Answer:

  • Thank you for your feedback. We have clarified the definition of coronary artery disease (CAD) in the “Study Population” section, specifying that obstructive CAD was defined as coronary artery stenosis >50%. Additionally, we have ensured consistent use of the term "obstructive CAD" throughout the manuscript to align with this definition and avoid ambiguity.

 

  1. Since the authors excluded only non-cardiac causes of myocardial injury, it is essential to also report the cardiac etiologies of the included patients, such as myocarditis, Takotsubo syndrome, true MINOCA, and cardiomyopathies. If patients with non-ischemic myocardial injury were excluded, this should be explicitly stated in the methods, along with the diagnostic modalities used to determine the final diagnosis (e.g., CMR).

Answer:

  • Thank you for your question. Troponin was determined in cases of suspected acute coronary syndrome (ACS). A total of 373 patients fulfilled the inclusion criteria. To meet these criteria, patients first had to meet the modified criteria for acute myocardial infarction (AMI) according to the "Fourth Universal Definition of Myocardial Infarction". First, there had to be an increase or decrease in cardiac troponin levels, with at least one value above the 99th percentile in the laboratory. Secondly, there had to be clinical evidence of MI, as evidenced by at least one of the following conditions Symptoms of myocardial ischemia, new ischemic changes on the electrocardiogram, pathological Q waves, evidence of new loss of viable myocardium or new regional wall motion abnormalities suggesting an ischemic cause, or evidence of coronary thrombus by angiography or autopsy. As a secondary criterion, coronary artery obstruction had to be excluded in patients undergoing angiography. This was the case if the stenosis in any of the major epicardial vessels was <50% and no subsequent intervention was performed. Among the study population, 22 patients (5.9%) were diagnosed with Takotsubo syndrome (TTS), 48 patients (12.9%) had myocarditis, 219 patients (58.7%) presented with troponin elevation without obstructive CAD (suspected true MINOCA), and 12 patients (3.2%) had concomitant valve disease. We stated that in the methods.
  1. Figure 1: It appears that 30 patients did not consent to participate in the study, yet the results section includes data from a total of 373 patients, seemingly counting these 30 individuals. If these patients did not consent to data usage, they should not be included in any analysis. Please clarify this aspect.

Answer:

  • Thank you for your observation. The 30 patients in question did not consent to participate in the follow-up portion of the study but explicitly agreed to the use of their data collected during hospitalization and from source records for research purposes. As such, their data were included in the baseline characteristics and outcomes analysis where applicable, but they were excluded from the follow-up-specific analyses. This approach aligns with ethical standards and the consent provided by the patients.

 

  1. The primary endpoint should be clearly stated in the abstract as well.

Answer:

  • We stated primary endpoints (cardiovascular and non-cardiovascular mortality at long-term) in the abstract.

 

  1. Table 1: If supraventricular arrhythmias only refer to atrial fibrillation episodes, it would be clearer to report atrial fibrillation directly as the event.

Answer:

  • We deleted the row for supraventricular arrhythmias and directly reported the rate of AF.

 

  1. Table 2: Please include data on statin therapy.

Answer:

  • We have included data on statin therapy in Table 2. The rate of statin therapy was higher in older patients compared to younger patients.

 

  1. Discussion: The sentence “the occurrence of troponin elevation without an obstructive culprit lesion is more common in patients >70 years old” may be misleading. This study did not assess the incidence of the event across age groups within the general population. We do not have information on how many patients >70 years experienced troponin elevation without obstructive CAD.

Answer:

  • Thank you for your feedback. We have revised the sentence to clarify that, within our study cohort, the occurrence of troponin elevation without an obstructive culprit lesion was observed more frequently in patients >70 years old compared to other age groups. However, we acknowledge that our study does not provide data on the incidence of this condition in the general population.
  1. Discussion: In the sentence “On the other side, in a systemic review, patients suffering from troponin elevation without an obstructive culprit lesion tended to be younger and female,” I would also specify that women with MINOCA aged ≤70 have a worse prognosis (higher MACE) compared to men and women with MIOCA, likely due to distinct pathophysiology affecting long-term prognosis (PMID: 37261384).

Answer:

  • Thank you for your suggestion. We have incorporated the reference into our discussion: Another study highlighted that women aged ≤70 years with MINOCA had worse prognoses, with significantly higher rates of major adverse cardiovascular events (MACE) compared to men and women with MI and obstructive CAD. This difference was attributed to distinct pathophysiological mechanisms affecting long-term outcomes.

 

  1. Please specify what cMRT stands for in the text.
  • We apologize for the oversight. "CMR" stands for cardiac magnetic resonance imaging. We have corrected this term throughout the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

Authors of this original study analyzed in-hospital complications and the occurrence of adverse events in patients with elevated troponin level and non-obstructive CAD. All parts of this manuscript are technically good: abstract is good; Introduction section gives all necessary information about planned research. Methodology is generally well explained and statistical methods are adequate. Results are generally good presented; discussion is well conducted. References are adequate. 

My comments are:

  1. methodology inclusion/exclusion criteria: authors excluded some conditions that can cause troponin elevation, but they did not mention stress induced cardiomyopathy, myocarditis… Did authors perform some other diagnostic procedures other than coronary angiography to be sure that diagnosis in all patients is MINOCA? 

  2. Results:  I will only suggest modifying Kaplan Meier curves  (for better curve visibility) (Figure 3).

  3. What about other predictors for in-hospital and long-term adverse events? As I can see, authors performed only basic analysis, not univariate and multivariate analysis that will include troponin level with other baseline, clinical, echocardiographic variables…..

Thank you

Author Response

Authors of this original study analyzed in-hospital complications and the occurrence of adverse events in patients with elevated troponin level and non-obstructive CAD. All parts of this manuscript are technically good: abstract is good; Introduction section gives all necessary information about planned research. Methodology is generally well explained and statistical methods are adequate. Results are generally good presented; discussion is well conducted. References are adequate. 

My comments are:

 

  1. methodology inclusion/exclusion criteria: authors excluded some conditions that can cause troponin elevation, but they did not mention stress induced cardiomyopathy, myocarditis… Did authors perform some other diagnostic procedures other than coronary angiography to be sure that diagnosis in all patients is MINOCA? 

Answer:

  • Patients were required to meet the modified criteria for acute myocardial infarction (AMI) based on the "Fourth Universal Definition of Myocardial Infarction." This included: 1) A rise or fall in cardiac troponin levels with at least one value above the 99th percentile; 2)Clinical evidence of MI, such as symptoms of myocardial ischemia, new ischemic changes on ECG, pathological Q waves, new regional wall motion abnormalities, evidence of new loss of viable myocardium, or a coronary thrombus detected via angiography. Coronary artery obstruction was excluded in patients undergoing angiography if stenosis in major epicardial vessels was <50%, and no subsequent interventions were performed. Among the study population, 22 patients (5.9%) were diagnosed with Takotsubo syndrome (TTS), and 48 patients (12.9%) were diagnosed with myocarditis. The definition of MINOCA in our study followed the 2023 ACS Guidelines. Other diagnostic procedures, such as cardiac magnetic resonance (CMR), were performed in 68 patients (17.5%). However, the lack of systematic implementation of CMR remains a limitation of our study, as noted in the limitations section.

 

  1. Results:  I will only suggest modifying Kaplan Meier curves  (for better curve visibility) (Figure 3).

Answer:

  • Thank you for your suggestion to improve the Kaplan-Meier curves for better visibility. We have made the necessary modifications, as shown in the updated Figure 3.
  1. What about other predictors for in-hospital and long-term adverse events? As I can see, authors performed only basic analysis, not univariate and multivariate analysis that will include troponin level with other baseline, clinical, echocardiographic variables…..

Answer:

  • We conducted a comprehensive investigation into the impact of demographics, clinical characteristics, ECG findings, medical history, laboratory values, and medications on both in-hospital and long-term outcomes, please see tables below.

 

 

 

 

 

 

 

Table 6: univariate and multiple Logistic Regression Analysis for in-hospital outcome 

Variable 

Univariate analysis 

 

Multivariable analysis 

 

OR 

95% CI 

P value 

OR 

95% CI 

P value 

Age  

1.03 

1.018-1.050 

<0.001 

 

1.00 

0.959-1.047 

0.919 

 

Male 

1.24 

0.809-1.892 

0.327 

 

 

 

 

 

BMI 

1.01 

0.974-1.052 

0.537 

 

 

 

 

 

Symptoms 

 

 

 

 

 

 

 

 

Angina pectoris 

0.24 

0.150-0.373 

<0.001 

 

0.19 

0.054-0.627 

0.007 

 

Dyspnea 

1.56 

1.086-2.574 

0.020 

 

2.20 

0.524-8-955 

0.270 

 

Palpations 

3.33 

1.753-6.324 

<0.001 

 

7.68 

1.377-42.839 

0.020 

 

Clinic parameter 

 

 

 

 

 

 

 

 

Systolic BP 

1.00 

0.987-1.004 

0.280 

 

 

 

 

 

Diastolic BP 

0.10 

1.012-1.026 

0.097 

 

 

 

 

 

Heart rate  

1.03 

1.021-1.040 

<0.001 

 

1.04 

1.016-1.072 

0.002 

 

ECG Data  

 

 

 

 

 

 

 

 

ST-segment elevation 

0.64 

0.341-1.216 

0.175 

 

 

 

 

 

Inversed T-Waves 

0.74 

0.481-1.131 

0.162 

 

 

 

 

 

Medical history  

 

 

 

 

 

 

 

 

Current Smoker  

0.67 

0.392-1.133 

0.134 

 

 

 

 

 

Diabetes mellitus  

1.39 

0.803-2.397 

0.241 

 

 

 

 

 

Obesity (BMI > 30 kg/m2) 

1.20 

0.761-1.906 

0.427 

 

 

 

 

 

Arterial Hypertension 

2.31 

1.407-3.806 

<0.001 

 

2.22 

0.453-10.942 

0.325 

 

Pulmonary disease  

1.492 

0.895-2.490 

0.125 

 

 

 

 

 

Dyslipidemia  

0.89 

0.549-1.451 

0.647 

 

 

 

 

 

Malignancy 

1.31 

0.702-2.458 

0.393 

 

 

 

 

 

Neurological disease  

1.33 

0.813-2.163 

0.258 

 

 

 

 

 

Kidney disease  

1.50 

0.830-2.704 

0.180 

 

 

 

 

 

Autoimmune disease 

2.17 

0.815-5.757 

0.121 

 

 

 

 

 

Psychiatric disease  

0.80 

0.391-1.635 

0.540 

 

 

 

 

 

Malignant cardiac arrhythmias 

1.11 

0.261-4.721 

0.887 

 

 

 

 

 

Supraventricular arrhythmias 

5.86 

3.157-10.864 

<0.001 

 

3.70 

0.721-19-023 

0.117 

 

Laboratory values 

 

 

 

 

 

 

 

 

Troponin

1.00 

0.999-1.000 

0.164 

 

 

 

 

 

Creatine phosphokinase 

1.00 

1.000-1.002 

0.657 

 

 

 

 

 

BNP 

1.00 

1.000-1.003 

0.037 

 

1.00 

0.999-1.017 

0.095 

 

Creatinine 

1.02 

1.009-1.023 

<0.001 

 

1.03 

1.001-1.050 

0.042 

 

TSH  

1.12 

0.891-1.287 

0.094 

 

 

 

 

 

fT3 

0.83 

0.534-1.284 

0.399 

 

 

 

 

 

fT4 

1.04 

0.896-1.214 

0.587 

 

 

 

 

 

Echocardiography data, n (%)

 

 

 

 

 

 

 

 

LVEF ≥50% 

0.29 

0.169-0.505 

<0.001 

 

3.38 

0.624-18.301 

0.158 

 

LVEF 40-49% 

2.35 

1.099-5.020 

0.028 

 

6.48 

0.862-48.796 

0.069 

 

LVEF ≤ 40 % 

2.72 

1.459-5.066 

0.002 

 

0.42 

0.058-2.966 

0.381 

 

Tricuspid valve regurgitation 

2.86 

1.752-4.673 

<0.001 

 

2.35 

0.451-12.271 

0.310 

 

Mitral valve regurgitation 

2.74 

1.719-4.368 

<0.001 

 

0.29 

0.046-1.762 

0.177 

 

Aortic valve regurgitation 

1.68 

0.862-3.289 

0.127 

 

 

 

 

 

Drugs on admission 

 

 

 

 

 

 

 

 

ß-Blocker 

1.92 

1.237-2.990 

0.004 

 

1.61 

0.435-5.963 

0.476 

 

ACE inhibitor 

1.28 

0.814-2.005 

0.286 

 

 

 

 

 

Sartane 

2.16 

1.223-3.826 

0.008 

 

0.27 

0.053-1.374 

0.115 

 

Ca-Blocker 

1.43 

0.848-2.403 

0.180 

 

 

 

 

 

Diuretics 

2.44 

1.523-3.894 

<0.001 

 

1.56 

0.407-5.970 

0.518 

 

Statin 

0.92 

0.548-1.535 

0.742 

 

 

 

 

 

Anticoagulants 

3.17 

1.784-5.631 

<0.001 

 

2.42 

0.416-14.051 

0.326 

 

Aspirin 

0.65 

0.377-1.125 

0.124 

 

 

 

 

 

Antiarrhythmics  

1.23 

0.342-4.452 

0.749 

 

 

 

 

 

OR, Odds ratio; CI, confidence interval; BP, blood pressure; ECG, Electrocardiogram; BMI, body mass index; BNP, brain natriuretic Peptide; LVEF, left ventricular ejection fraction; ACE, Angiotensin-converting-enzyme 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 7: univariate and multiple Logistic Regression Analysis for long-term outcome 

Variable 

Univariate analysis 

 

Multivariable analysis 

 

OR 

95% CI 

P value 

OR 

95% CI 

P value 

Age  

1.09 

1.060-1.112 

<0.001 

 

1.07 

1.013-1.137 

0.017 

 

Male 

0.55 

0.333-0.898 

0.017 

 

0.28 

0.064-1.252 

0.096 

 

BMI 

0.99 

0.727-1.351 

0.954 

 

 

 

 

 

Symptoms 

 

 

 

 

 

 

 

 

Angina pectoris 

0.85 

0.511-1.421 

0.540 

 

 

 

 

 

Dyspnea 

2-39 

1.448-3.954 

<0.001 

 

3.09 

0.753-12.694 

0.117 

 

Palpations 

0.52 

0.216-1.248 

0.143 

 

 

 

 

 

Clinic parameter 

 

 

 

 

 

 

 

 

Systolic BP 

1.00 

0.991-1.004 

0.505 

 

 

 

 

 

Diastolic BP 

0.99 

0.976-1.007 

0.296 

 

 

 

 

 

Heart rate  

1.00 

0.991-1.008 

0.922 

 

 

 

 

 

ECG Data  

 

 

 

 

 

 

 

 

ST-segment elevation 

0.92 

0.453-1.881 

0.825 

 

 

 

 

 

Inversed T-Waves 

1.86 

1.131-3.062 

0.015 

 

1.33 

0.391-4.511 

0.649 

 

Medical history  

 

 

 

 

 

 

 

 

Current Smoker  

0.44 

0.230-0.845 

0.014 

 

1.24 

0.241-6.383 

0.798 

 

Diabetes mellitus  

2.51 

1.362-4.624 

0.003 

 

14.00 

2.181-89.933 

0.005 

 

Obesity (BMI > 30 kg/m2) 

1.33 

0.792-2.231 

0.281 

 

 

 

 

 

Arterial Hypertension 

1.78 

1.021-3.091 

0.042 

 

0.50 

0.079-3.113 

0.454 

 

Pulmonary disease  

2.13 

1.187-3.836 

0.011 

 

0.43 

0.077-2.378 

0.331 

 

Dyslipidemia 

1.18 

0.685-2.045 

0.546 

 

 

 

 

 

Malignancy 

1.34 

0.705-2.527 

0.375 

 

 

 

 

 

Neurological disease  

3.15 

1.811-5.461 

<0.001 

 

0.80 

0.207-3.072 

0.743 

 

Kidney disease  

2.21 

1.154-4.235 

0.017 

 

    

 

 

Autoimmune disease 

0.88 

0.298-2.622 

0.825 

 

 

 

 

 

Malignant cardiac arrhythmias 

2.64 

0.579-12.031 

0.210 

 

 

 

 

 

Supraventricular arrhythmias 

2.78 

1.387-5.553 

0.004 

 

 

 

 

 

Laboratory values 

 

 

 

 

 

 

 

 

Troponin 

0.99 

0.939-1.053 

0.848 

 

 

 

 

 

Creatine phosphokinase 

1.00 

1.000-1.001 

0.724 

 

 

 

 

 

BNP 

1.00 

1.000-1.001 

0.015 

 

0.83 

0.124-5.511 

0.843 

 

Creatinine 

2.00 

1.014-3.938 

0.045 

 

3.64 

0.346-38.301 

0.282 

 

TSH  

0.86 

0.693-1.068 

0.172 

 

 

 

 

 

fT3 

0.59 

0.237-1.474 

0.260 

 

 

 

 

 

fT4 

1.16 

0.935-1.445 

0.176 

 

 

 

 

 

Echocardiography data, n (%)

 

 

 

 

 

 

 

 

LVEF ≥50%  

0.78 

0.418-1.439 

0.420 

 

 

 

 

 

LVEF 40-49% 

0.54 

0.193-1.510 

0.240 

 

 

 

 

 

LVEF ≤ 40 % 

1.90 

0.959-3.760 

0.066 

 

 

 

 

 

Tricuspid valve regurgitation 

0.90 

0.512-1.583 

0.715 

 

 

 

 

 

Mitral valve regurgitation 

1.04 

0.612-1.777 

0.878 

 

 

 

 

 

Aortic valve regurgitation 

1.03 

0.488-2.189 

0.931 

 

 

 

 

 

Drugs on admission 

 

 

 

 

 

 

 

 

ß-Blocker 

1.74 

1.054-2.880 

0.030 

 

0.38 

0.092-1.558 

0.179 

 

ACE inhibitor 

1.78 

1.056-2.991 

0.030 

 

1.78 

0.450-7.069 

0.410 

 

Sartans 

1.31 

0.684-2.511 

0.416 

 

 

 

 

 

Ca-Blocker 

1.61 

0.988-3.330 

0.055 

 

 

 

 

 

Diuretics 

2.28 

1.344-3.877 

0.002 

 

0.65 

0.152-2.743 

0.552 

 

Statins 

1.03 

0.566-1.869 

0.925 

 

 

 

 

 

Anticoagulants 

1.81 

0.955-3.440 

0.069 

 

 

 

 

 

Aspirin 

1.89 

1.055-3.395 

0.032 

 

3.33 

0.593-18.698 

0.172 

 

Antiarrhythmics  

2.05 

0.784-5.334 

0.143 

 

 

 

 

 

OR, Odds ratio; CI, confidence interval; BP, blood pressure; ECG, Electrocardiogram; BMI, body mass index; BNP, brain natriuretic Peptide; LVEF, left ventricular ejection fraction; ACE, Angiotensin-converting-enzyme 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reviewer 4 Report

Comments and Suggestions for Authors

The study examines long-term outcomes in patients with troponin elevation without obstructive coronary lesions, focusing on age-related differences over an 11-year period. Divided into four age groups, the study analyzes baseline characteristics, in-hospital complications, and cardiovascular outcomes. Results indicate that older patients experience more in-hospital adverse events and have higher long-term cardiovascular mortality compared to younger patients. However, non-sustained ventricular arrhythmias were more common in the 51-60 age group.

1. Early definitions of terms such as MINOCA, troponin elevation, and obstructive vs. non-obstructive coronary disease would improve clarity, especially for readers less familiar with these distinctions.

2. Provide more detail on patient selection criteria and exclusion parameters, particularly why certain conditions like stroke and renal failure were excluded.

3. Expand on the significance of non-sustained ventricular tachycardia (nsVT) in the 51-60 age group. Discuss why this might occur more frequently in this age group and its potential implications.

4. Discuss the baseline characteristics (e.g., hypertension, smoking rates) more thoroughly to relate them to observed outcomes and age differences in complications.

Author Response

The study examines long-term outcomes in patients with troponin elevation without obstructive coronary lesions, focusing on age-related differences over an 11-year period. Divided into four age groups, the study analyzes baseline characteristics, in-hospital complications, and cardiovascular outcomes. Results indicate that older patients experience more in-hospital adverse events and have higher long-term cardiovascular mortality compared to younger patients. However, non-sustained ventricular arrhythmias were more common in the 51-60 age group.

  1. Early definitions of terms such as MINOCA, troponin elevation, and obstructive vs. non-obstructive coronary disease would improve clarity, especially for readers less familiar with these distinctions.

Response:

- Thank you for your feedback. We have revised and improved the definitions of terms such as MINOCA, troponin elevation, and obstructive vs. non-obstructive coronary artery disease (CAD) in the Materials and Methods section to enhance clarity for readers less familiar with these distinctions:

MINOCA was defined in accordance with the 2023 ACS Guidelines of the European Society of Cardiology (ESC).

To meet the inclusion criteria, patients first had to fulfill the modified criteria for acute MI according to the ’’Fourth Universal Definition of Myocardial Infarction’’[11]. Additionally, there had to be clinical evidence of MI, as indicated by at least one of the following: symptoms of MI, new ischemic changes on the electrocardiogram, pathological Q waves, evidence of new loss of viable myocardium, new regional wall motion abnormalities suggestive of an ischemic cause, or evidence of coronary thrombus identified through angiography or autopsy.

Obstructive CAD was defined as the presence of one or more coronary stenoses with a diameter reduction of ≥50%. Nonobstructive CAD was further classified based on angiographic findings as stenoses <50% or no angiographic evidence of coronary disease.

  1. Provide more detail on patient selection criteria and exclusion parameters, particularly why certain conditions like stroke and renal failure were excluded.

Response:

  • In accordance with the 2023 ACS guidelines, troponin elevation without obstructive CAD can result from underlying coronary, non-coronary cardiac, and non-cardiac causes. Non-cardiac causes include acute respiratory distress syndrome (ARDS), allergic reactions, end-stage renal failure, inflammation, pulmonary embolism, sepsis, and stroke.

In our study, patients had to meet the inclusion criteria by fulfilling the modified criteria for acute myocardial infarction (MI) as defined by the "Fourth Universal Definition of Myocardial Infarction" [11]. This required clinical evidence of MI, as indicated by at least one of the following: symptoms of MI, new ischemic changes on the electrocardiogram, pathological Q waves, evidence of new loss of viable myocardium, new regional wall motion abnormalities suggestive of an ischemic cause, or evidence of coronary thrombus identified through angiography or autopsy.

Conditions like stroke and renal failure were excluded to ensure a more specific evaluation of troponin elevation related to MINOCA and to avoid confounding factors caused by non-cardiac or systemic illnesses. Additional details are provided in the Materials and Methods section.

  1. Expand on the significance of non-sustained ventricular tachycardia (nsVT) in the 51-60 age group. Discuss why this might occur more frequently in this age group and its potential implications.

Response:

  • Some conditions, such as Takotsubo syndrome (TTS) and hypertrophic cardiomyopathy (HCM), occurred in this age range. In one study, the median age of HCM diagnosis was 45.8 years. Another study reported that 1,194 patients (56.9%) were between 51 and 74 years old. Myocarditis occurred also in this age range. In our study, troponin levels in this group were higher compared to older age groups. Additionally, the left ventricular ejection fraction (LVEF) on admission was reported to be 37.5 ± 25, which may also contribute to the higher occurrence of non-sustained ventricular tachycardia (nsVT) in this group. These factors are discussed in greater detail in the Discussion
  1. Discuss the baseline characteristics (e.g., hypertension, smoking rates) more thoroughly to relate them to observed outcomes and age differences in complications..

Response:

  • We conducted a comprehensive investigation into the impact of demographics, clinical characteristics, ECG findings, medical history, laboratory values, and medications on both in-hospital and long-term outcomes. In the multivariate analyses for both in-hospital and long-term outcomes, hypertension and smoking rates were not identified as predictors.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Congratulations to the authors on the improvements made to the manuscript following the revision.

However, in Lines 285–290, there is a lack of citations. I recommend updating the bibliography accordingly to address this issue.

Author Response

Comments and Suggestions for Authors

Congratulations to the authors on the improvements made to the manuscript following the revision.

However, in Lines 285–290, there is a lack of citations. I recommend updating the bibliography accordingly to address this issue.

Response: Thank you for pointing this out. We have added the necessary citation in Lines 285–290 and updated the bibliography accordingly to address this issue.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you to the authors for the revisions made, which I believe have enhanced the quality of the final manuscript.

I have no further comments.

Author Response

Comments and Suggestions for Authors

Thank you to the authors for the revisions made, which I believe have enhanced the quality of the final manuscript.

I have no further comments.

Response: Thank you for your positive feedback and for taking the time to review our manuscript. We are pleased to hear that the revisions have improved the quality of the work.

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