**Maximal physical load, W**

**Patients' groups/ Parameter on veloergometry**

**1. Restenosis (n=656)**

**2. New stenosis**

**(n=146)**

**3. Without restenosis/ new stenosis (n=806)**

accordingly, in the first and third patients' group (p**<**0.05) (Figure 4.).

It was observed during patients follow-up, that a separate group of the patients is forming, which is characterized by no complaints of chest pain, but significant ST-segment changes on exercise test ECG (so-called, silent ischemia, poor prognostic factor). These are 22% of the patients (1608 patients), all of them underwent coronary angiography. Restenosis of coronary artery was detected in 656 patients (9% of the total number of patients) and new hemodinamically significant stenosis in coronary artery (> 50% of artery lumen) – in 146 patients (2%) of this patients group (Figure 2.).

### **4.2 New specific criteria in restenosis diagnostics**

Several new specific criteria were found in restenosis diagnostics field additionally to STsegment ischemic changes on ECG during exercise stress test – reduced load tolerance, decreased maximal heart rate and maximal systolic blood pressure, maximal rate-pressure product (double product) – Robinson index, also increased ST/pulse index (ST/p index).

Differences in parameters derived from exercise tests in patients with restenosis, new stenosis and in patients without restenosis/new stenosis on coronary angiography are shown in Figure 3.

Fig. 3. Results of exercise test in "silent" ischemia patients' group.

Patients with restenosis on coronary angiography (first group) showed definitely ischemic changes on exercise ECG at lower physical load 121.4±33.2 W compared with those patients' group with neither restenosis, nor new stenosis on coronary angiography (third group) – 160.0±25.8 W (p**<**0.05). Achieved maximal heart rate and systolic blood pressure during

It was observed during patients follow-up, that a separate group of the patients is forming, which is characterized by no complaints of chest pain, but significant ST-segment changes on exercise test ECG (so-called, silent ischemia, poor prognostic factor). These are 22% of the patients (1608 patients), all of them underwent coronary angiography. Restenosis of coronary artery was detected in 656 patients (9% of the total number of patients) and new hemodinamically significant stenosis in coronary artery (> 50% of artery lumen) – in 146

Several new specific criteria were found in restenosis diagnostics field additionally to STsegment ischemic changes on ECG during exercise stress test – reduced load tolerance, decreased maximal heart rate and maximal systolic blood pressure, maximal rate-pressure product (double product) – Robinson index, also increased ST/pulse index (ST/p index). Differences in parameters derived from exercise tests in patients with restenosis, new stenosis and in patients without restenosis/new stenosis on coronary angiography are

patients (2%) of this patients group (Figure 2.).

shown in Figure 3.

**4.2 New specific criteria in restenosis diagnostics**

Fig. 3. Results of exercise test in "silent" ischemia patients' group.

Patients with restenosis on coronary angiography (first group) showed definitely ischemic changes on exercise ECG at lower physical load 121.4±33.2 W compared with those patients' group with neither restenosis, nor new stenosis on coronary angiography (third group) – 160.0±25.8 W (p**<**0.05). Achieved maximal heart rate and systolic blood pressure during physical load also showed lower parameters in the first group, which is characterized by double rate-pressure product compared in both groups – 212.8±42.9 and 252.62±36.9, accordingly, in the first and third patients' group (p**<**0.05) (Figure 4.).

Fig. 4. Analysis of average parameters of veloergometry data (maximal heart rate, maximal systolic arterial pressure, maximal rate-pressure product – Robinson index).

Table 1. Analysis of average parameters of veloergometry data (achieved physical load, maximal heart rate, maximal systolic blood pressure, Robinson index, ST/pulse index).

The Role of Exercise Test After Percutaneous Coronary Intervention 255

24 (18.0) 41 (30.8) 51 (38.3)

51 (38.3) 54 (40.6) 28 (21.1)

47 (38.0) 47 (35.3)

Characteristics Prevalence Gender (males), n (%) 107 (80.5) Age, mea(±SD) 61.3 (± 9.8) Dyslipidemia, n (%) 96 (72.2) Arterial hypertension, n (%) 77 (57.9) Diabete mellitus, n (%) 11 (8.3)

Positive family history, n (%) 48 (36.1) Prior myocardial infarction, n (%) 60 (45.1) Prior PCI, n (%) 26 (19.5) Prior coronary artery bypass grafting, n (%) 7 (5.3)

**Characteristics Prevalence**

Complete/incomplete revascularization, % 40/27

 *PCI LCx*, n (%) 26 (19.5)  *PCI RCA*, n (%) 14 (10.5)  *PCI RIM*, n (%) 4 (3.0)  *PCI D1*, n (%) 3 (2.3) *PCI M1*, *RPL*, *RPD*, n (%) 1 (0.8)

*RPL*–right posterolateral branch; *RPD*-right posterodiaphragmal branch.

Table 4. Caracteristics of angiographic and PCI data of the patients (n=133).

*LM*–left main coronary artery; *LAD*–left anterior descending artery; *LCx*–left circumflex artery; *RCA*– right coronary artery; *RIM*–ramus intermedius; *D1*–first diagonal branch; *M1*–first marginal branch;

Table 3. Clinical characteristics of the patients (demographic parameters and risk factors of

Smoking status:

 Active smoker, n (%) Ex-smoker, n (%) Non-smoker, n (%)

coronary artery disease) (n=133).

Coronary artery disease: One-vessel disease, n (%) Two- vessel disease, n (%) Three- vessel disease, n (%)

*PCI LM* only, n (%) *PCI LM* and other artery:  *PCI LAD*, n (%)

Parameters of neither maximal heart rate, nor maximal systolic arterial blood pressure, and so Robinson index, accordingly, are significantly lower in patients' group witht coronary artery restenosis. The most important parameter, which can reflect patient's risk of restenosis more precisely is ST/pulse index. In restenosis group this parameter is the highest one (1.3±0.5) (Table 1. and 2.).

Table 2. Statistical analysis in comparison of different patients' groups.

### **4.3 Patients with left main coronary artery (LM) stenosis**

### **The database of the patients with LM stenosis was created.**

The group of the patients (n=400) with LM stenosis and performed PCI with drug-eluting stents (DES) was analyzed. In a period of years 2005-2010, 133 patients accomplished complete follow-up programme. Veloergometry was regularly performed in 3, 6, 12 and 24 months after PCI, also control coronarography was performed in 6-12 months after PCI.

### *Clinical characteristics of the patients:*

LM patients group – 80% of the patients are males, with mean age 61.3 ± 9.8 years. The most part of the patients is characterized with most important risk factors of coronary artery disease: in 96% of cases – dyslipidemia, in 77% of cases – arterial hypertension, smoking habits – active smokers (18%) or ex-smokers (30.8%). Previous myocardial infarction – in 45.1% of patients, positive family history (first-line relatives at young age with CAD) in 36.1% of cases (Table 3.).

All the patients underwent LM PCI: 47 patients (38%) underwent solely LM PCI and 86 patients (65%) – also PCI additionally in other artery (Table 4.).

The changes of the parameters registered on exercise test (maximal heart rate, maximal systolic blood pressure and Robinson index) in every follow-up period (independently of the follow-up data on coronary angiography) are showed in Table 5.

### **4.3.1 Association of veloergometry results with clinical events**

Recurrent hospitalization was ascertained for 14 patients (8.3%) in analysis of clinical events in follow-up period. The reasons for recurrent admission to the hospital: in two cases – myocardial infarction, in four cases – chest pain (angina) (three of these patients underwent recurrent coronary angiography), in two cases – next step PCI, in two cases – heart rhythm disorders (in one case – implantation of permanent pacemaker), in one case – stroke, in one case – elevated arterial blood pressure, in two cases – non-coronary reasons for hospitalization.

Parameters of neither maximal heart rate, nor maximal systolic arterial blood pressure, and so Robinson index, accordingly, are significantly lower in patients' group witht coronary artery restenosis. The most important parameter, which can reflect patient's risk of restenosis more precisely is ST/pulse index. In restenosis group this parameter is the

> **Maximal systolic blood pressure**

**< 0.05 < 0.05 0.012 < 0.05 < 0.05**

**< 0.05 < 0.05 < 0.05 < 0.05 < 0.05**

The group of the patients (n=400) with LM stenosis and performed PCI with drug-eluting stents (DES) was analyzed. In a period of years 2005-2010, 133 patients accomplished complete follow-up programme. Veloergometry was regularly performed in 3, 6, 12 and 24 months after PCI, also control coronarography was performed in 6-12 months after PCI.

LM patients group – 80% of the patients are males, with mean age 61.3 ± 9.8 years. The most part of the patients is characterized with most important risk factors of coronary artery disease: in 96% of cases – dyslipidemia, in 77% of cases – arterial hypertension, smoking habits – active smokers (18%) or ex-smokers (30.8%). Previous myocardial infarction – in 45.1% of patients, positive family history (first-line relatives at young age with CAD) in

All the patients underwent LM PCI: 47 patients (38%) underwent solely LM PCI and 86

The changes of the parameters registered on exercise test (maximal heart rate, maximal systolic blood pressure and Robinson index) in every follow-up period (independently of

Recurrent hospitalization was ascertained for 14 patients (8.3%) in analysis of clinical events in follow-up period. The reasons for recurrent admission to the hospital: in two cases – myocardial infarction, in four cases – chest pain (angina) (three of these patients underwent recurrent coronary angiography), in two cases – next step PCI, in two cases – heart rhythm disorders (in one case – implantation of permanent pacemaker), in one case – stroke, in one case – elevated arterial blood pressure, in two cases – non-coronary reasons for

0.396 0.118 0.48 **< 0.05 0.004**

**Robinson index**

**ST/pulse index**

**Maximal heart rate**

Table 2. Statistical analysis in comparison of different patients' groups.

**4.3 Patients with left main coronary artery (LM) stenosis The database of the patients with LM stenosis was created.**

patients (65%) – also PCI additionally in other artery (Table 4.).

the follow-up data on coronary angiography) are showed in Table 5.

**4.3.1 Association of veloergometry results with clinical events**

highest one (1.3±0.5) (Table 1. and 2.).

*Clinical characteristics of the patients:*

36.1% of cases (Table 3.).

hospitalization.

**Load, Watts**

p value (between patients' groups)

**First and second**

**Second and third**

**First and third**

**group**

**group**

**group**

Table 3. Clinical characteristics of the patients (demographic parameters and risk factors of coronary artery disease) (n=133).

*LM*–left main coronary artery; *LAD*–left anterior descending artery; *LCx*–left circumflex artery; *RCA*– right coronary artery; *RIM*–ramus intermedius; *D1*–first diagonal branch; *M1*–first marginal branch; *RPL*–right posterolateral branch; *RPD*-right posterodiaphragmal branch.

Table 4. Caracteristics of angiographic and PCI data of the patients (n=133).

The Role of Exercise Test After Percutaneous Coronary Intervention 257

In maximal systolic blood pressure analysis, almost statistically significant difference was observed (trend) between 'restenosis' group and 'non-restenosis' patients group on exercise

> **Maximal systolic blood pressure (mean ± SD)**

> > **'Nonrestenosis' group**

**Number of the patients**

**p (between groups)**

**p (between groups)**

**Number of the patients**

1-3 months 161.70 ± 23.64 10 182.27 ± 32.32 49 0.06 3-6 months 170.33 ± 27.55 15 185.00 ± 28.91 58 0.08 6-12 months 176.44 ± 37.51 16 182.67 ± 26.22 54 0.45 12-24 months 177.14 ± 30.76 14 184.16 ± 30.60 38 0.47 > 24 months 186.92 ± 32.27 13 183.39 ± 32.90 38 0.74

Table 7. Maximal systolic blood pressure in different exercise test control periods.

Robinson index changes between patients groups was not ascertained.

parameter to ST-segment changes in restenosis diagnostics (Table 8., Figure 5.).

The difference in analysis of double product (maximal rate-pressure product) or Robinson index was expected, on basis of previously obtained results. The following trend was observed – patients with coronary artery restenosis at control coronary angiography 1-3 months after performed PCI showed lower parameters of Robinson index. In turn, independently of stenosis location – LM or other coronary artery, or patients with new detected coronary artery stenosis – statistically significant difference and association with

Variability of Robinson index changes on exercise test could become possible additional

**Robinson index (mean ± SD)**

**'Restenosis' group 'Non-restenosis'**

Patients with angiographically detected coronary artery stenosis have achieved lower physical load (in Watts), not achieving submaximal pulse, because of termination the veloergometry, if ischemic changes or typical chest pain is appearing. This explains the curve difference of Robinson index in patients with and without coronary artery restenosis, also, statistically significant difference between mentioned groups is not present in analysis of maximal achieved heart rate and maximal systolic blood pressure. However, oscillations of Robinson index parameters are obviously seen in patiens of 'restenosis' group in relative

1-3 months 185.70 ± 32.96 217.51 ± 54.09 0.08 3-6 months 208.12 ± 56.00 226.73 ± 53.81 0.24 6-12 months 210.41 ± 51.57 223.22 ± 45.16 0.34 12-24 months 197.89 ± 27.17 223.41 ± 50.73 0.08 > 24 months 210.23 ± 46.75 221.48 ± 50.63 0.49

Table 8. Robinson index analysis in different exercise test control periods.

**group**

test 1-3 months and 3-6 months follow-ups (Table 7.).

**'Restenosis' group**

Exercise test control (months after PCI)

Exercise test control (months after PCI)

Table 5. Mean values of parameters analyzed on exercise test follow-up (maximal heart rate, maximal systolic blood pressure, Robinson index).

Indications for control angiography were defined according to ST-segment ischemic changes on ECG and/or typical patients' complaints during exercise test.

Control angiography in follow-up period was performed in 33.8% of cases – 3-6 months after PCI, in 36.8% and in 10.5% of cases – 6-12 months and 12-24 months after PCI, respectively.

### **4.3.2 Analysis of the results of control exercise tests (1-3 and 3-6 months after PCI) and coronary angiography**

There was no significant difference between patients group with LM restenosis and/or other coronary artery restenosis on control coronary angiography and patients group without diagnosed restenosis, analyzing maximal achieved physical load in early follow-up period (control exercise test performed 1-3 and 3-6 months after PCI).

Statistically significant difference (in maximal achieved physical load analysis) was observed comparing with the patients group with new coronary artery stenosis on control coronary angiography: these patients achieved lower maximal load on 1-3 months control exercise test – 90 ± 17 W vs. 129 ± 26 W, accordingly (p=0.027).

There was no significant difference observed between patients with and without LM restenosis (or other artery restenosis) in analysis of achieved maximal heart rate during exercise test 1-3 and 3-6 months after PCI, also between patients groups with and without diagnosed new artery stenosis on coronary angiography (Table 6.).

Table 6. Maximal heart rate analysis in different exercise test control periods.

(bpm ± SD) 118 ± 16 122 ± 17 121 ± 16 119 ± 15 119 ± 15

pressure (mmHg ± SD) 180 ± 31 181 ± 29 182 ± 29 183 ± 31 184 ± 32

Table 5. Mean values of parameters analyzed on exercise test follow-up (maximal heart rate,

Indications for control angiography were defined according to ST-segment ischemic changes

Control angiography in follow-up period was performed in 33.8% of cases – 3-6 months after PCI, in 36.8% and in 10.5% of cases – 6-12 months and 12-24 months after PCI,

**4.3.2 Analysis of the results of control exercise tests (1-3 and 3-6 months after PCI)**

There was no significant difference between patients group with LM restenosis and/or other coronary artery restenosis on control coronary angiography and patients group without diagnosed restenosis, analyzing maximal achieved physical load in early follow-up

Statistically significant difference (in maximal achieved physical load analysis) was observed comparing with the patients group with new coronary artery stenosis on control coronary angiography: these patients achieved lower maximal load on 1-3 months control

There was no significant difference observed between patients with and without LM restenosis (or other artery restenosis) in analysis of achieved maximal heart rate during exercise test 1-3 and 3-6 months after PCI, also between patients groups with and without

> **Maximal heart rate (mean ± SD)**

> > **'Nonrestenosis' group**

**Number of the patients**

**p (between groups)**

**Number of the patients**

1-3 months 114.70 ± 8.87 10 118.49 ± 19.96 49 0.49 3-6 months 120.93 ± 17.43 15 122.07 ± 16.92 58 0.82 6-12 months 119.06 ± 14.63 16 120.69 ± 15.39 55 0.71 12-24 months 112.79 ± 10.03 14 120.58 ± 15.71 38 0.09 > 24 months 112.4 6± 13.48 13 120.74 ± 15.90 38 0.10

Table 6. Maximal heart rate analysis in different exercise test control periods.

**1-3 months 3-6 months 6-12 months 12-24 months >24 months**

213.27±51.02 220.93±52.55 221.55±45.9 217.84±47.68 219.32±48.46

**Data of exercise test/ follow-up period**

Maximal heart rate

respectively.

**and coronary angiography**

Exercise test control (months after PCI)

Maximal systolic blood

Robinson index(max heart rate x max systolic blood pressure/100) ± SD

maximal systolic blood pressure, Robinson index).

on ECG and/or typical patients' complaints during exercise test.

period (control exercise test performed 1-3 and 3-6 months after PCI).

exercise test – 90 ± 17 W vs. 129 ± 26 W, accordingly (p=0.027).

diagnosed new artery stenosis on coronary angiography (Table 6.).

**'Restenosis' group**

In maximal systolic blood pressure analysis, almost statistically significant difference was observed (trend) between 'restenosis' group and 'non-restenosis' patients group on exercise test 1-3 months and 3-6 months follow-ups (Table 7.).

Table 7. Maximal systolic blood pressure in different exercise test control periods.

The difference in analysis of double product (maximal rate-pressure product) or Robinson index was expected, on basis of previously obtained results. The following trend was observed – patients with coronary artery restenosis at control coronary angiography 1-3 months after performed PCI showed lower parameters of Robinson index. In turn, independently of stenosis location – LM or other coronary artery, or patients with new detected coronary artery stenosis – statistically significant difference and association with Robinson index changes between patients groups was not ascertained.

Variability of Robinson index changes on exercise test could become possible additional parameter to ST-segment changes in restenosis diagnostics (Table 8., Figure 5.).

Table 8. Robinson index analysis in different exercise test control periods.

Patients with angiographically detected coronary artery stenosis have achieved lower physical load (in Watts), not achieving submaximal pulse, because of termination the veloergometry, if ischemic changes or typical chest pain is appearing. This explains the curve difference of Robinson index in patients with and without coronary artery restenosis, also, statistically significant difference between mentioned groups is not present in analysis of maximal achieved heart rate and maximal systolic blood pressure. However, oscillations of Robinson index parameters are obviously seen in patiens of 'restenosis' group in relative

The Role of Exercise Test After Percutaneous Coronary Intervention 259

**ST/pulse index (mean ± SD)**

Table 9. ST/pulse (ST/p) index in LM patients' group according to angiographic finding (restenosis, new stenosis of coronary artery or without detected restenosis or new stenosis of

Restenosis 50% 43% 7%

Table 10. Restenosis and ST-segment changes on exercise ECG prior the control coronary

The sensitivity of veloergometry test in 1-3 months – 29%, specificity – 100 %. Lower

Correlation of ST-segment changes with restenosis development is obvious also in later control of veloergometry (3-6 months after PCI). The sensitivity of veloergometry test – 50%, specificity – 86 %. All the patients with diagnosed new coronary artery stenosis (in other coronary artery) at control coronary angiography (3-6 months after PCI) showed STsegment depression on exercise ECG in early stress test control (1-3 months), but in patients group without restenosis ECG without any dynamical changes is observed in 92.9% of cases.

Basing on the previously obtained data and on the significance of exercise test in patients' follow-up after performed PCI, several algorithms were developed for evaluation of patients' functional status after PCI, also for evaluation of possible treatment strategy of

depression

parameters of Robinson index also were registered in this patients' group.

In LM patients' group analysis – 50% of cases of coronary artery restenosis are detected in early period (3-6 months after PCI), left 43% and 7% – 6-12 and 12-24 months after PCI, respectively. Angiographic results in early coronary angiography follow-up period (3-6 months after performed PCI) correlate with ECG changes on 1-3 months control of physical test: there is statistically significant difference between patients groups – ST-segment depression on exercise ECG is obvious in all patients with restenosis established at control

**'Without new stenosis' group**

1.07 ± 0.98 6 0.57 ± 0.34 53 0.01

0.80 ± 0.67 7 0.61 ± 0.40 66 0.27

0.76 ± 0.54 11 0.61 ± 0.40 60 0.28

3-6 months 6-12 months 12-24 months

ST-segment depression

**Number of the patients**

**p (between groups)**

ST-segment depression

**Number of the patients**

Exercise test control

1-3 months after PCI

3-6 months after PCI

6-12 months after PCI

coronary artery).

angiography.

**4.4 Algorithms**

coronary artery stenosis.

coronary angiography (Table 10.).

ST-segment changes ST-segment

The sensitivity of the test – 33%, specificity – 93 %.

**'New stenosis' group**

1 – without restenosis on control coronary angiography

2 – with restenosis on control coronary angiography

Fig. 5. Analysis of different exercise test parameters (Robinson index, maximal heart rate and maximal systolic blood pressure) during follow-ups in patients with and without coronary artery restsenosis (on control angiography).

risk period – 6-12 months follow-up. These curves repeatedly are establishing the role of targeted follow-up programme after performed PCI for more precise evaluation of risk of restenosis, taking into account not only patient's complaints and ischemic changes on ECG, but also the changes of Robinson index parameters in dynamics.

It is supposed, that the number of analyzed patients was not sufficient for statistical significance between groups in ST/p index analysis, in order to definitely conclude the role of this parameter in restenosis diagnostics (Table 9.)

Fig. 5. Analysis of different exercise test parameters (Robinson index, maximal heart rate and maximal systolic blood pressure) during follow-ups in patients with and without

risk period – 6-12 months follow-up. These curves repeatedly are establishing the role of targeted follow-up programme after performed PCI for more precise evaluation of risk of restenosis, taking into account not only patient's complaints and ischemic changes on ECG,

It is supposed, that the number of analyzed patients was not sufficient for statistical significance between groups in ST/p index analysis, in order to definitely conclude the role

> **ST/pulse index (mean ± SD)**

> > **'Non-restenosis' group**

0.76 ± 0.55 10 0.59 ± 0.44 49 0.28

0.72 ± 0.35 15 0.61 ± 0.45 58 0.36

0.76 ± 0.47 16 0.59 ± 0.41 55 0.16

**Number of the patients**

**p (between groups)**

**Number of the patients**

1 – without restenosis on control coronary angiography 2 – with restenosis on control coronary angiography

coronary artery restsenosis (on control angiography).

of this parameter in restenosis diagnostics (Table 9.)

**'Restenosis' group**

**Exercise test control**

1-3 months after PCI

3-6 months after PCI

6-12 months after PCI

but also the changes of Robinson index parameters in dynamics.

Table 9. ST/pulse (ST/p) index in LM patients' group according to angiographic finding (restenosis, new stenosis of coronary artery or without detected restenosis or new stenosis of coronary artery).

In LM patients' group analysis – 50% of cases of coronary artery restenosis are detected in early period (3-6 months after PCI), left 43% and 7% – 6-12 and 12-24 months after PCI, respectively. Angiographic results in early coronary angiography follow-up period (3-6 months after performed PCI) correlate with ECG changes on 1-3 months control of physical test: there is statistically significant difference between patients groups – ST-segment depression on exercise ECG is obvious in all patients with restenosis established at control coronary angiography (Table 10.).

Table 10. Restenosis and ST-segment changes on exercise ECG prior the control coronary angiography.

The sensitivity of veloergometry test in 1-3 months – 29%, specificity – 100 %. Lower parameters of Robinson index also were registered in this patients' group.

Correlation of ST-segment changes with restenosis development is obvious also in later control of veloergometry (3-6 months after PCI). The sensitivity of veloergometry test – 50%, specificity – 86 %. All the patients with diagnosed new coronary artery stenosis (in other coronary artery) at control coronary angiography (3-6 months after PCI) showed STsegment depression on exercise ECG in early stress test control (1-3 months), but in patients group without restenosis ECG without any dynamical changes is observed in 92.9% of cases. The sensitivity of the test – 33%, specificity – 93 %.

### **4.4 Algorithms**

Basing on the previously obtained data and on the significance of exercise test in patients' follow-up after performed PCI, several algorithms were developed for evaluation of patients' functional status after PCI, also for evaluation of possible treatment strategy of coronary artery stenosis.

The Role of Exercise Test After Percutaneous Coronary Intervention 261

**Exercise stress test**

**Incomplete revascularization**  (hemodinamically significant stenosis on coronary

**Next step PCI**  (invasive cardiologist visit)

exercise ECG

exercise ECG

Fig. 7. Exercise test algorithm in patients after PCI (incomplete revascularization).

Ischemic changes **Next step PCI**

control coronary angiography.

No ischemic changes **- Medical treatment - Exercise test every 6**

**months**

**Patients with incomplete revascularization ( Figure 7.):**

**Myocardial perfusion scintigraphy or stress echocardiography**

In case of angina and ischemic changes on exercise ECG patients should undergo

 Exercise test should be performed in 1-3 months after PCI in patients with incomplete revascularization (and hemodinamically sigfnificant stenosis, left on angiography); Myocardial perfusion scintigraphy investigation or stress echocardiography should be performed in case of no angina and no ischemic changes on exercise ECG. If ischemic

Fig. 6. Exercise test algorithm in patients after PCI (complete revascularization).

### **Patients with complete revascularization (Figure 6):**

**Complete revascularization** (without hemodinamically significant stenosis on coronary angiography)

**Myocardial perfusion scintigraphy or stress echocardiography (average 4 months after PCI)**

> **Control coronary angiography**

Ischemic changes **Control coronary angiography**

Fig. 6. Exercise test algorithm in patients after PCI (complete revascularization).

Exercise test should be performed in 1-3 months after PCI in patients with complete

Patients should continue medical treatment and exercise test control every 6 months, if

 Patients should undergo myocardial perfusion scintigraphy investigation or stress echocardiography in case of no angina, but with presentation of ischemic changes on exercise ECG. If ischemic changes are not present on additional examination tests, medical treatment shoul be continued and control of exercise test every 6 months;

**Patients with complete revascularization (Figure 6):**

**months**

**- Medical treatment - Exercise test every 6**

exercise ECG

**months**

revscularization (performed with PCI method);

No ischemic changes **- Medical treatment - Exercise test every 6**

**Exercise stress test after 1-3 and 6 months**

angina or ischemic changes on exercise ECG are not present;

Fig. 7. Exercise test algorithm in patients after PCI (incomplete revascularization).

 In case of angina and ischemic changes on exercise ECG patients should undergo control coronary angiography.

### **Patients with incomplete revascularization ( Figure 7.):**

The Role of Exercise Test After Percutaneous Coronary Intervention 263

 Patients should continue medical treatment and should perform exercise test every 6 months in case of no hemodinamically significant stenosis on coronary angiography; Myocardial perfusion scintigraphy investigation or stress echocardiography should be performed in case of ischemic changes on exercise ECG. If If ischemic changes are present (in additional investigations), coronary angiography should be performed. If ischemic changes are not present, patients should continue medical treatment and

 Patients with incomplete revascularization and angiographycally with hemodynamically significant stenosis are left, exercise test should be performed in 1-3 months after PCI. If ischemic changes are not present, patients continue medical treatment and perform exercise test every 6 months. In case of ischemic changes on exercise test, patient should

In this study we raised the question whether physical exercise test alone beside accurate diagnosis of obstructive lesions provides an opportunity to prognose cardiovascular risk. We claim that this is possible, which is demonstrated in our study by a significant number of patients with silent ischemia. The potential gain from reducing the risk of reverse cardiac events is actually greatest in those with silent ischemia at the time of follow-up presentation, because those patients are at especially high risk (Pepine and Deedwania, 1994). Nowadays it is clear that chest pain in history does not correlate tightly with ischemic ST-segment deviation following physical loading and with haemodynamically significant stenosis on

Published data as well as national and international guidelines state that physical exercise test following PCI is a useful method in diagnosis of restenosis in high risk or symptomatic patients and should be conducted six months after intervention (Gibbons et al., 2002). Our results showed that the exercise test should be done not later than three to six months after intervention. The highest rate of restenosis was observed in patients after interventional treatment of LM disease in 1-3 months after procedure. The importance of the physical test does not decrease later; more than third part of all documented restenosis was registered at six months after intervention (including the patients with newly diagnosed stenosis on coronary angiography). One year after PCI the specific weight of restenosis was 16.7% of all

The clinical value of exercise electrocardiograms following interventional therapy in the early period is high in evaluation of early post-interventional results (Roffi et al., 2003). This is supported with our results, which demonstrated high specificity of exercise test performed in the first six months after PCI. Exercise electrocardiograms 1–3 months after PCI did not show a shift of the ST-segment for all patients without restenosis. However, angiography depression of the ST-segment was registered on exercise electrocardiogram only for patients with restenosis. This demonstrates a clear correlation between ST-segment

Adequate implementation of drug therapies depending on patient clinical and functional status allow to reach goals set by national and international guidelines. Based on epidemiological studies, even small decreases in low density lipoprotein cholesterol and blood pressure levels translate into significant reductions in cardiovascular morbidity and mortality (LaRosa et al., 2005). Moreover, especially important is the patient compliance,

which can be achieved through frequently scheduled visits.

visit invasive cardiologist in order to make decision of next step PCI.

perform exercise test every 6 months;

**5. Discussion**

angiography either.

diagnosed restenosis.

depression and restenosis.

changes are present (in additional investigations), next step PCI should be performed. If ischemic changes are not present, patients should continue medical treatment and perform exercise test every 6 months;

 In case of ischemic changes on exercise ECG, independently of patient's complaints, next step PCI should be performed.

Fig. 8. Exercise test algorithm in patients after LM PCI.

### **Patients after left main coronary artery (LM) revascularization (Figure 8.):**

 Exercise test should be performed in 1-3 months after LM PCI. Myocardial perfusion scintigraphy could be performed in 4-6 months in case of inconclusive ECG;

### **5. Discussion**

262 Advances in Electrocardiograms – Clinical Applications

In case of ischemic changes on exercise ECG, independently of patient's complaints,

**Patients after left main coronary artery (LM) PCI**

> **Incomplete revascularization**  (hemodinamically significant stenosis on coronary angiography)

> > Ischemic changes **Next step PCI**  (invasive cardiologist visit)

No ischemic changes **- Medical treatment - Exercise test or myocardial perfusion scintigraphy every 6**

**months**

perform exercise test every 6 months;

next step PCI should be performed.

**Complete revascularization**  (without hemodinamically significant stenosis on coronary angiography)

No ischemic changes **- Medical treatment - Exercise test or myocardial perfusion scintigraphy every 6**

**months**

**Exercise stress test after 1-3 and 6 months or myocardial perfusion scintigraphy after 4-6 months**

> Ischemic changes **Myocardial perfusion scintigraphy or stress echocardiography**

Fig. 8. Exercise test algorithm in patients after LM PCI.

Ischemic changes **Coronary angiography**

**Patients after left main coronary artery (LM) revascularization (Figure 8.):**

**6 months**

Exercise test should be performed in 1-3 months after LM PCI. Myocardial perfusion

No ischemic changes **- Medical treatment - Exercise test or every**

scintigraphy could be performed in 4-6 months in case of inconclusive ECG;

changes are present (in additional investigations), next step PCI should be performed. If ischemic changes are not present, patients should continue medical treatment and

> In this study we raised the question whether physical exercise test alone beside accurate diagnosis of obstructive lesions provides an opportunity to prognose cardiovascular risk. We claim that this is possible, which is demonstrated in our study by a significant number of patients with silent ischemia. The potential gain from reducing the risk of reverse cardiac events is actually greatest in those with silent ischemia at the time of follow-up presentation, because those patients are at especially high risk (Pepine and Deedwania, 1994). Nowadays it is clear that chest pain in history does not correlate tightly with ischemic ST-segment deviation following physical loading and with haemodynamically significant stenosis on angiography either.

> Published data as well as national and international guidelines state that physical exercise test following PCI is a useful method in diagnosis of restenosis in high risk or symptomatic patients and should be conducted six months after intervention (Gibbons et al., 2002). Our results showed that the exercise test should be done not later than three to six months after intervention. The highest rate of restenosis was observed in patients after interventional treatment of LM disease in 1-3 months after procedure. The importance of the physical test does not decrease later; more than third part of all documented restenosis was registered at six months after intervention (including the patients with newly diagnosed stenosis on coronary angiography). One year after PCI the specific weight of restenosis was 16.7% of all diagnosed restenosis.

> The clinical value of exercise electrocardiograms following interventional therapy in the early period is high in evaluation of early post-interventional results (Roffi et al., 2003). This is supported with our results, which demonstrated high specificity of exercise test performed in the first six months after PCI. Exercise electrocardiograms 1–3 months after PCI did not show a shift of the ST-segment for all patients without restenosis. However, angiography depression of the ST-segment was registered on exercise electrocardiogram only for patients with restenosis. This demonstrates a clear correlation between ST-segment depression and restenosis.

> Adequate implementation of drug therapies depending on patient clinical and functional status allow to reach goals set by national and international guidelines. Based on epidemiological studies, even small decreases in low density lipoprotein cholesterol and blood pressure levels translate into significant reductions in cardiovascular morbidity and mortality (LaRosa et al., 2005). Moreover, especially important is the patient compliance, which can be achieved through frequently scheduled visits.

The Role of Exercise Test After Percutaneous Coronary Intervention 265

2. The database of the patients with left main coronary artery stenosis was analyzed, evaluating the efficacy of invasive treatment of left main stenosis, analyzing possible

3. New specific criteria were extracted for risk evaluation and detection with exercise

4. Algorithms were developed for CAD patients' clinical status evaluation after

5. Follow-up programme with targeted exercise test allows to personalize exact treatment

Arab D,Valeti V, Schunemann H, Lopez-Candales A (2000) Usefulness of the QTc Interval in

Babapulle M, Diodati J, Blankenship J, Huynh T, Cugno S, Puri R, Nguyen P, Eisenberg M

Bengtson J, Mark D, Honan M, et al (1990) Detection of Restenosis after Elective

Berntsen R, Gjestvang F, Rasmussen K (1995) QRS Prolongation as an Indicator of Risk of

Califf R, Mark D, Harrell F (1988) Importance of Clinical Measures of Ischemia in the

Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici P (2003) Coronary

Chalela W, Kreling J, Falcao A, Hueb W, Moffa P, Pereyra P, Ramires J (2006) Exercise Stress

Angioplasty. Brazilian Journal of Medical and Biological Research 39:475-482. Cerqueira M D, Weissman N J, Dilsizian V, Jacobs A K, Kaul S, Lasney W K, Pennel D J,

Erglis A et al. The guidelines of the Latvian Society of Cardiology on prevention and

Predicting Myocardial Ischemia in Patients undergoing Exercise Stress Testing. Am

(2007) Utility of Routine Exercise Treadmill Testing early after Percutaneous

Percutaneous Transluminal Coronary Angioplasty using the Exercise Treadmill

Ischemia-Related Ventricular Tachycardia and Fibrillation Induced by Exercise. Am

Prognosis of Patients with Documented Coronary Artery Disease J Am Coll

Microvascular Dysfunction and Prognosis in Hypertrophic Cardiomyopathy. N

Testing before and after successsful Multivessel Percutaneous Transluminal Coronary

Rumberger J A, Ryan T, Verani M S (2002) Standardized Myocardial Segmentation and Nomenclature for Tomographic Imaging of the Heart. A Statement for Healthcare Professionals From the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 105:539-542. Eisenberg M, Schechter D, Lefkovits J, Goudreau E, Deligonul U, Mak K, Del Core M, Duerr

R, Garzon P, Huynh T, Smilovitch M, Sedlis S, Brown D, Brieger D, Pilote L (2001) ROSETTA Investigators: Use of Routine Functional Testing after Percutaneous Transluminal Coronary Angioplasty: Results from the ROSETTA Registry. Am

management of stable coronary heart disease, Riga, 2007.Fletcher G, Balady G, Froelicher V, Hartley L, Haskell W, Pollock M (1995) Exercise Standards. A

progression of restenosis and evaluating following treatment steps.

strategy and risk factor correction for each patient individually.

Coronary Intervention. BMC Cardiovascular Disorders 7.

balloon angioplasty, etc.)

percutaneous coronary intervention.

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Cardiol 11:20-26.

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Test. Am J Cardiol 65:28-34.

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stress test.

**7. References**

with CAD, evolving different invasive treatment methods (with drug-eluting stents,

The clinical course and prognosis of patients with coronary artery disease can be modified favourably by successful translation of recommendations for secondary coronary prevention into effective clinical care. Crucial to the outcome of any preventive strategy is patient attitude to lifestyle modification and compliance with drug therapies over the long term. We tend to claim that an aggressive follow-up programme could help us to reach the goals in secondary prevention of coronary artery disease set by European Societies and Latvian Society of Cardiology.

The physical exercise test is a safe method with high specificity, but is limited by poor test sensitivity for the evaluation of efficacy of interventional and medical treatment for patients with coronary artery disease. A focussed exercise test performed on a regular basis indirectly influences clinical results and prognosis. Timely set diagnosis of restenosis provides necessary treatment measures, therefore, alienating adverse cardiac events such as unstable angina and myocardial infarction. Moreover, an exercise test performed on a regular basis provides essential corrections in drug therapy. After comparison of drug therapies recommended three months and one year after PCI, we can conclude that regular follow-ups provide the opportunity to sustain acceptable patient compliance and use of medications even twelve months after an intervention.

A focussed follow-up programme with an exercise test allows to evaluate clinical status of patients as well as to determine timely possible risk of restenosis, to adapt medication doses, to reduce risk factors and to influence positively patient compliance. The exercise test provides accurate estimation of possible restenosis in patients with complete revascularization. In patients with incomplete revascularization the exercise test specificity is reduced. Taking into account the results of the current study, we are sure, that focussed physical exercise test should be advised for all patients after interventional treatment. It is of high importance to achieve submaximal heart rate during the exercise test. In all cases when this is not possible for any reason, myocardial perfusion scintigraphy is indicated.

### **Advantages of the study (benefits)**

The results of this study can be used with a goal to determine possible risk of restenosis in a time, to prescribe medications according to patient's functional status, to correct possible risk factors, which can have negative influence on development of disease.

Regular patients' follow-ups increase the compliance of the patients and 'participation' in treatment process, thus increasing accuracy of data and foundation of the results.

### **Possible disadvantages (limits) of the study**

Irregular patients' follow-ups, thus exclusion from statistycal analysis.

Insufficient information about patient recurrent hospitalization at district hospital. Also the variability in medical treatment (general practitioner like "middle stage" between patient and cardiologist).

The lack of patients compliance in medication use, the lack of motivation in modification of their possible risk factors.

Low availability of myocardial perfusion scintigraphy, thus, not possibility to perform necessary investigation in position of diagnosis making and more detailed evaluation of clinical situation.

### **6. Conclusions**

1. Exercise test (veloergometry) is established as a safe method with high specificity, but lower sensitivity in evaluation of invasive and medical treatment efficiacy in patients with CAD, evolving different invasive treatment methods (with drug-eluting stents, balloon angioplasty, etc.)

### **7. References**

264 Advances in Electrocardiograms – Clinical Applications

The clinical course and prognosis of patients with coronary artery disease can be modified favourably by successful translation of recommendations for secondary coronary prevention into effective clinical care. Crucial to the outcome of any preventive strategy is patient attitude to lifestyle modification and compliance with drug therapies over the long term. We tend to claim that an aggressive follow-up programme could help us to reach the goals in secondary prevention of coronary artery disease set by European Societies and Latvian

The physical exercise test is a safe method with high specificity, but is limited by poor test sensitivity for the evaluation of efficacy of interventional and medical treatment for patients with coronary artery disease. A focussed exercise test performed on a regular basis indirectly influences clinical results and prognosis. Timely set diagnosis of restenosis provides necessary treatment measures, therefore, alienating adverse cardiac events such as unstable angina and myocardial infarction. Moreover, an exercise test performed on a regular basis provides essential corrections in drug therapy. After comparison of drug therapies recommended three months and one year after PCI, we can conclude that regular follow-ups provide the opportunity to sustain acceptable patient compliance and use of

A focussed follow-up programme with an exercise test allows to evaluate clinical status of patients as well as to determine timely possible risk of restenosis, to adapt medication doses, to reduce risk factors and to influence positively patient compliance. The exercise test provides accurate estimation of possible restenosis in patients with complete revascularization. In patients with incomplete revascularization the exercise test specificity is reduced. Taking into account the results of the current study, we are sure, that focussed physical exercise test should be advised for all patients after interventional treatment. It is of high importance to achieve submaximal heart rate during the exercise test. In all cases when this is not possible

The results of this study can be used with a goal to determine possible risk of restenosis in a time, to prescribe medications according to patient's functional status, to correct possible

Regular patients' follow-ups increase the compliance of the patients and 'participation' in

Insufficient information about patient recurrent hospitalization at district hospital. Also the variability in medical treatment (general practitioner like "middle stage" between patient

The lack of patients compliance in medication use, the lack of motivation in modification of

Low availability of myocardial perfusion scintigraphy, thus, not possibility to perform necessary investigation in position of diagnosis making and more detailed evaluation of

1. Exercise test (veloergometry) is established as a safe method with high specificity, but lower sensitivity in evaluation of invasive and medical treatment efficiacy in patients

Society of Cardiology.

medications even twelve months after an intervention.

for any reason, myocardial perfusion scintigraphy is indicated.

risk factors, which can have negative influence on development of disease.

Irregular patients' follow-ups, thus exclusion from statistycal analysis.

treatment process, thus increasing accuracy of data and foundation of the results.

**Advantages of the study (benefits)**

and cardiologist).

clinical situation.

**6. Conclusions**

their possible risk factors.

**Possible disadvantages (limits) of the study**

The Role of Exercise Test After Percutaneous Coronary Intervention 267

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**Part 4**

**Cardiotoxicology**

## **Part 4**

**Cardiotoxicology**

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**15**

*Romania*

**Toxic and Drug-Induced**

**Changes of the Electrocardiogram**

Catalina Lionte, Cristina Bologa and Laurentiu Sorodoc

There are numerous toxins and drugs that can cause, in overdose, electrocardiogram (ECG) changes, even in patients without history of cardiac pathology. The diagnosis and management of patients with an abnormal ECG encountered in a specific toxicity can challenge experienced physicians. One must have serious knowledge of basic cardiac physiology, in order to understand the ECG changes associated with various drugs and

The main mechanisms involved include membrane – depressant action (sodium channel blockers, slow calcium channel blockers, outward potassium (K+) channel blockers, and sodium-potassium adenosine-triphosphatase blockers), and action on autonomic nervous system and its sites of cardiovascular action (beta-adrenergic blockers and other sympathetic-inhibitors, sympathomimetic, anticholinergic and cholinomimetic substances). Many toxins and medications have actions that involve more than one of these mechanisms, including hypoxia, electrolyte and metabolic imbalances, and thus may result in a

In resting state, the myocardial cell membrane is impermeable to positively charged sodium ions (Na+). The Na+/K+ ATPase maintains a negative electric potential of approximately 90 mV in the myocyte. The rapid opening of Na+ channels and massive Na+ influx (phase 0 of action potential) explains depolarization of the cardiac cell membrane (fig.1), causing the rapid upstroke of the cardiac action potential, which is conducted through the ventricles and is expressed as the QRS complex of the ECG. The closure of Na+ channels and the transient opening of Ito K+ efflux channels (phase 1) mark the peak of the action potential. Then, phase 2 of the action potential occurs when the opening of slow calcium (Ca2+) channels produces an influx of positive ions with a steady maintenance of the membrane potential and myocardial contraction continues. The end of the cardiac cycle is marked by the closure of the Ca2+ channels and the activation of the K+ efflux channels, which allow the action potential to return to its resting potential of – 90 mV (phase 3). This K+ efflux from the myocardial cell is directly responsible for the QT interval on the ECG (Holstege et al., 2006). During phase 4 of the cardiac cell action potential, some cardiac fibers allow sodium ions to enter the cell, increasing the resting membrane potential, known as spontaneous diastolic depolarization. When the threshold in membrane potential is reached, the Na+ channels

**1. Introduction**

combination of electrocardiographic changes.

open and another action potential is generated.

toxins.

*"Gr.T.Popa" University of Medicine and Pharmacy, Iasi,*

## **Toxic and Drug-Induced Changes of the Electrocardiogram**

Catalina Lionte, Cristina Bologa and Laurentiu Sorodoc *"Gr.T.Popa" University of Medicine and Pharmacy, Iasi, Romania*

### **1. Introduction**

There are numerous toxins and drugs that can cause, in overdose, electrocardiogram (ECG) changes, even in patients without history of cardiac pathology. The diagnosis and management of patients with an abnormal ECG encountered in a specific toxicity can challenge experienced physicians. One must have serious knowledge of basic cardiac physiology, in order to understand the ECG changes associated with various drugs and toxins.

The main mechanisms involved include membrane – depressant action (sodium channel blockers, slow calcium channel blockers, outward potassium (K+) channel blockers, and sodium-potassium adenosine-triphosphatase blockers), and action on autonomic nervous system and its sites of cardiovascular action (beta-adrenergic blockers and other sympathetic-inhibitors, sympathomimetic, anticholinergic and cholinomimetic substances). Many toxins and medications have actions that involve more than one of these mechanisms, including hypoxia, electrolyte and metabolic imbalances, and thus may result in a combination of electrocardiographic changes.

In resting state, the myocardial cell membrane is impermeable to positively charged sodium ions (Na+). The Na+/K+ ATPase maintains a negative electric potential of approximately 90 mV in the myocyte. The rapid opening of Na+ channels and massive Na+ influx (phase 0 of action potential) explains depolarization of the cardiac cell membrane (fig.1), causing the rapid upstroke of the cardiac action potential, which is conducted through the ventricles and is expressed as the QRS complex of the ECG. The closure of Na+ channels and the transient opening of Ito K+ efflux channels (phase 1) mark the peak of the action potential. Then, phase 2 of the action potential occurs when the opening of slow calcium (Ca2+) channels produces an influx of positive ions with a steady maintenance of the membrane potential and myocardial contraction continues. The end of the cardiac cycle is marked by the closure of the Ca2+ channels and the activation of the K+ efflux channels, which allow the action potential to return to its resting potential of – 90 mV (phase 3). This K+ efflux from the myocardial cell is directly responsible for the QT interval on the ECG (Holstege et al., 2006). During phase 4 of the cardiac cell action potential, some cardiac fibers allow sodium ions to enter the cell, increasing the resting membrane potential, known as spontaneous diastolic depolarization. When the threshold in membrane potential is reached, the Na+ channels open and another action potential is generated.

Toxic and Drug-Induced Changes of the Electrocardiogram 273

Cardiotoxins are responsible of ECG changes through a combination of membrane depressant effects, autonomic disturbances and metabolic changes. The severity of a toxicinduced conduction block varies depending on the toxin involved and its site of action.

Inhibition of the fast Na+ channels, in the phase 0 of the action potential (AP), decreases the rate of rise and amplitude of the AP in Purkinje fibers, and in atrial and ventricular myocardial cells. As a result, the upslope of depolarization is slowed and the QRS complex becomes wide. In a toxicological situation, QRS complex widening likely results directly from Na+ channel blockage or indirectly from toxin-induced hyperkalemia (Holstege et al.,

5. Toxins: Quinine, Saxitoxin, Tetrodotoxin

Ventricular tachycardia (VT) and ventricular fibrillation (VF)

ST/T changes consistent with ischemia (cocaine toxicity)

1. Cardiovascular drugs:

Procainamide)

Moricizine)

Maprotiline)

3. Other drugs: - Amantadine

Asystole

Table 1. Na+ channel blockers and the resulting ECG changes.

ECG changes QRS widening

\*mechanism not involving the beta-receptor.

4. Illicit drugs: Cocaine

Right bundle branch pattern R wave elevation in aVR lead Rightward deviation of QRS axis

Bradycardia with wide QRS complex

**2. Membrane – depressant drugs and toxins**

**2.1 Sodium channel blockers**

Inhibitors of fast Na+

channels

Fig. 1. Cardiac cycle action potential with corresponding ion changes across the membrane and electrocardiographic tracing. Dotted line indicates the changes associated with Na+ channel blocker toxicity. Dashed line indicates the changes associated with K+ efflux blocker toxicity. Ito= transient outward K+ current; ICa= L-type Ca2+ current; INa= late sodium channel current; IKr= rapidly activating delayed-rectifier K+ current; IKs= slowly activating delayed rectifier K+ current; IK1= inward rectifier K+ current (adapted from Holstege et al., 2005).

The atrial and ventricular myocardium contraction, and the conduction in the His-Purkinje system depend on sodium entry via the fast sodium channels in phase 0 of the action potential, while the conduction in sinoatrial node and atrioventricular (AV) node depend on Ca2+ entry during phase 0 via the slow Ca2+ channels (Patel & Benowitz, 2005).

Cardiac activity is controlled, among other mechanisms, by the autonomic nervous system. Sympathetic fibers increase the heart rate, the rate of AV nodal conduction and the contracility of the myocardium. The norepinephrine released by postganglionic fibers leads to an interaction with beta 1-adrenergic cardiac receptors, and increasing cells' permeability to Na+ and Ca2+, with an increase of contractility, excitability, and conduction. The parasympathetic postganglionic fibers innervate the sinus node and AV node. Stimulation of muscarinic receptors via releasing of acetylcholine decreases atrial excitability and slows the conduction of impulses to the ventricles (Patel & Benowitz, 2005).

In the setting of drug overdose or of a toxic exposure, ECG abnormalities, especially arrhythmias, are produced by direct or indirect sympathomimetic effects, anticholinergic effects, the effects of altered central nervous system (CNS) regulation of peripheral autonomic system, and myocardial membrane depression. Genesis of arrhythmias in the poisoned patient is based on the same three mechanisms as in an ischemic patient: abnormal impulse formation, abnormal impulse conduction, and triggered activity. Contributing factors to ECG changes are hypotension, hypoxia, acid-base and electrolyte imbalances.

### **2. Membrane – depressant drugs and toxins**

Cardiotoxins are responsible of ECG changes through a combination of membrane depressant effects, autonomic disturbances and metabolic changes. The severity of a toxicinduced conduction block varies depending on the toxin involved and its site of action.

### **2.1 Sodium channel blockers**

272 Advances in Electrocardiograms – Clinical Applications

Fig. 1. Cardiac cycle action potential with corresponding ion changes across the membrane and electrocardiographic tracing. Dotted line indicates the changes associated with Na+ channel blocker toxicity. Dashed line indicates the changes associated with K+ efflux blocker toxicity. Ito= transient outward K+ current; ICa= L-type Ca2+ current; INa= late sodium channel current; IKr= rapidly activating delayed-rectifier K+ current; IKs= slowly activating delayed rectifier K+ current; IK1= inward rectifier K+ current (adapted from Holstege et al., 2005).

The atrial and ventricular myocardium contraction, and the conduction in the His-Purkinje system depend on sodium entry via the fast sodium channels in phase 0 of the action potential, while the conduction in sinoatrial node and atrioventricular (AV) node depend on

Cardiac activity is controlled, among other mechanisms, by the autonomic nervous system. Sympathetic fibers increase the heart rate, the rate of AV nodal conduction and the contracility of the myocardium. The norepinephrine released by postganglionic fibers leads to an interaction with beta 1-adrenergic cardiac receptors, and increasing cells' permeability to Na+ and Ca2+, with an increase of contractility, excitability, and conduction. The parasympathetic postganglionic fibers innervate the sinus node and AV node. Stimulation of muscarinic receptors via releasing of acetylcholine decreases atrial excitability and slows

In the setting of drug overdose or of a toxic exposure, ECG abnormalities, especially arrhythmias, are produced by direct or indirect sympathomimetic effects, anticholinergic effects, the effects of altered central nervous system (CNS) regulation of peripheral autonomic system, and myocardial membrane depression. Genesis of arrhythmias in the poisoned patient is based on the same three mechanisms as in an ischemic patient: abnormal impulse formation, abnormal impulse conduction, and triggered activity. Contributing factors to ECG changes are hypotension, hypoxia, acid-base and electrolyte imbalances.

Ca2+ entry during phase 0 via the slow Ca2+ channels (Patel & Benowitz, 2005).

the conduction of impulses to the ventricles (Patel & Benowitz, 2005).

Inhibition of the fast Na+ channels, in the phase 0 of the action potential (AP), decreases the rate of rise and amplitude of the AP in Purkinje fibers, and in atrial and ventricular myocardial cells. As a result, the upslope of depolarization is slowed and the QRS complex becomes wide. In a toxicological situation, QRS complex widening likely results directly from Na+ channel blockage or indirectly from toxin-induced hyperkalemia (Holstege et al.,

\*mechanism not involving the beta-receptor.

Table 1. Na+ channel blockers and the resulting ECG changes.

Toxic and Drug-Induced Changes of the Electrocardiogram 275

sign of severe poisoning, indicating that the Na+ channel blockade is so profound that tachycardia does not occur, despite the clinical muscarinic antagonism or adrenergic agonism (Holstege et al., 2006). Nevertheless, bradycardia may occur because of slowed

All CCBs (Table 2) inhibit the voltage sensitive L-type Ca2+ channel within the cell membrane. In the pacemaker cells of the sinoatrial node and AV node, the primary ion channel, which controls depolarization, is the slow Ca2+ channel. When inhibited, there is a slowing or an inhibition of the specialized tissue to conduct a cardiac impulse (Patel &

depolarization of pacemaker cells that depend on entry of Na+ ions.

1. Dihydropyridines:

2. Phenylalkylamine:

Reflex tachycardia (ex. Nifedipine) Varying degrees of AV block

Sinus arrest with AV junctional rhythm

In CCB toxicity initially occurs a sinus bradycardia, followed by various degrees of AV block (fig.4), and junctional and ventricular bradydysrhythmias on ECG. Depending on the agent involved, other dysrhythmias may be seen (Gordon, 2006): sinus tachycardia (specifically Nifedipine), atrial arrhythmias, and junctional rhythms (fig. 5, 6,7). A wide QRS complex may appear, caused by ventricular escape rhythms or by CCB-induced Na+ channel blockade which delays of phase 0 of depolarization. Sudden shifts from

In addition, ECG changes associated with cardiac ischemia (fig.8) may occur as a result of the hypotension and changes in the cardiovascular status, especially in patients with pre-

**2.2 Slow Calcium Channel Blockers (CCB)**

ECG changes Sinus bradycardia

Asystole

bradydysrhythmias to cardiac arrest have been reported.

Wide QRS complex ST/T changes

Table 2. Calcium channel blockers and the resulting ECG changes.

existing cardiac disease (Patel & Benowitz, 2005; Holstege et al., 2006).

Benowitz, 2005).

Inhibitors of slow Ca2+ channels

2005). Direct toxin-induced blockade of cardiac Na+ channels will cause QRS complex widening, and it has been described as a membrane stabilizing effect, a local anesthetic effect, or a quinidine-like effect. Some drugs in this category (Table 1) may also affect other myocardial ion transfers, such as the Ca2+ influx and K+ efflux (Holstege et al., 2006). Other abnormal QRS complex configurations are also possible. In the most severe cases, the QRS complex widening becomes so profound that the ultimate origin of the rhythm disturbance is impossible (fig. 2).

Fig. 2. Na+ channel blocker toxicity (patient with acute Propafenone overdose). Note the wide QRS complex, at a rate of 134/min, which suggests, at a first view, monomorphic VT.

R wave elevation in aVR ≥ 3 mm (fig.3) is the only ECG variable that significantly indicates the risk of seizures and arrhythmias in acute tricyclic antidepressant poisoning (Liebelt et al., 1995). In addition, QT interval prolongation can occur with tricyclic antidepressant poisoning, as well as rightward axis deviation of the terminal 40 msec of the frontal plane QRS axis, which is unknown in other Na+ channel blocking agents (Wolfe et al. 1989; Berkovitch et al, 1995). Continued prolongation of the QRS complex may result in a sine wave pattern and eventual asystole.

Fig. 3. Acute poisoning with Amitriptyline. ECG reveals sinus tachycardia 148/min, RBBB pattern, QRS complex ≥ 120 ms, as well as R wave elevation in aVR ≥ 3 mm.

Na+ channel blockers may determine slowed intraventricular conduction, unidirectional block, the development of a reentrant circuit, and a resulting VT as well as VF. Because many of the Na+ channel blocking agents have also anticholinergic or sympathomimetic effects, bradydisrrhythmias are rare. In Na+ channel blocker poisoning by anticholinergic and sympathomimetic drugs, the combination of a wide QRS complex and bradycardia is a

2005). Direct toxin-induced blockade of cardiac Na+ channels will cause QRS complex widening, and it has been described as a membrane stabilizing effect, a local anesthetic effect, or a quinidine-like effect. Some drugs in this category (Table 1) may also affect other myocardial ion transfers, such as the Ca2+ influx and K+ efflux (Holstege et al., 2006). Other abnormal QRS complex configurations are also possible. In the most severe cases, the QRS complex widening becomes so profound that the ultimate origin of the rhythm disturbance

Fig. 2. Na+ channel blocker toxicity (patient with acute Propafenone overdose). Note the wide QRS complex, at a rate of 134/min, which suggests, at a first view, monomorphic VT. R wave elevation in aVR ≥ 3 mm (fig.3) is the only ECG variable that significantly indicates the risk of seizures and arrhythmias in acute tricyclic antidepressant poisoning (Liebelt et al., 1995). In addition, QT interval prolongation can occur with tricyclic antidepressant poisoning, as well as rightward axis deviation of the terminal 40 msec of the frontal plane QRS axis, which is unknown in other Na+ channel blocking agents (Wolfe et al. 1989; Berkovitch et al, 1995). Continued prolongation of the QRS complex may result in a sine

Fig. 3. Acute poisoning with Amitriptyline. ECG reveals sinus tachycardia 148/min, RBBB

Na+ channel blockers may determine slowed intraventricular conduction, unidirectional block, the development of a reentrant circuit, and a resulting VT as well as VF. Because many of the Na+ channel blocking agents have also anticholinergic or sympathomimetic effects, bradydisrrhythmias are rare. In Na+ channel blocker poisoning by anticholinergic and sympathomimetic drugs, the combination of a wide QRS complex and bradycardia is a

pattern, QRS complex ≥ 120 ms, as well as R wave elevation in aVR ≥ 3 mm.

is impossible (fig. 2).

wave pattern and eventual asystole.

sign of severe poisoning, indicating that the Na+ channel blockade is so profound that tachycardia does not occur, despite the clinical muscarinic antagonism or adrenergic agonism (Holstege et al., 2006). Nevertheless, bradycardia may occur because of slowed depolarization of pacemaker cells that depend on entry of Na+ ions.

### **2.2 Slow Calcium Channel Blockers (CCB)**

All CCBs (Table 2) inhibit the voltage sensitive L-type Ca2+ channel within the cell membrane. In the pacemaker cells of the sinoatrial node and AV node, the primary ion channel, which controls depolarization, is the slow Ca2+ channel. When inhibited, there is a slowing or an inhibition of the specialized tissue to conduct a cardiac impulse (Patel & Benowitz, 2005).

Table 2. Calcium channel blockers and the resulting ECG changes.

In CCB toxicity initially occurs a sinus bradycardia, followed by various degrees of AV block (fig.4), and junctional and ventricular bradydysrhythmias on ECG. Depending on the agent involved, other dysrhythmias may be seen (Gordon, 2006): sinus tachycardia (specifically Nifedipine), atrial arrhythmias, and junctional rhythms (fig. 5, 6,7). A wide QRS complex may appear, caused by ventricular escape rhythms or by CCB-induced Na+ channel blockade which delays of phase 0 of depolarization. Sudden shifts from bradydysrhythmias to cardiac arrest have been reported.

In addition, ECG changes associated with cardiac ischemia (fig.8) may occur as a result of the hypotension and changes in the cardiovascular status, especially in patients with preexisting cardiac disease (Patel & Benowitz, 2005; Holstege et al., 2006).

Toxic and Drug-Induced Changes of the Electrocardiogram 277

Fig. 8. Same patient (Diltiazem poisoning), second day of evolution. ECG reveals atrioventricular dissociation, with escape junctional rhythm and some ventricular captures, and

Fig. 9. Drug-induced long QT interval, following interaction between Bisoprolol and Amiodarone. ECG shows long QT interval (0.80 sec), couples of PVB with R/T

phenomenon preceding a short episode of polymorphic VT.

Medications in the K+ efflux blocker category block the outward flow of K+ from intracellular to extracellular spaces. Blockade of the outward K+ currents may prolong the cardiac cycle action potential (Fig. 1). The primary electrocardiographic manifestation is QT interval prolongation (QTc interval greater than 0.45 seconds in men and 0.47 seconds in women). Delay of repolarization causes the myocardial cell to have less charge difference across its membrane, and result in the activation of the inward depolarization current (early after-depolarization), which is seen on ECG as prominent U waves (Murphy et al., 2007). This may promote triggered activity, which potentially can progress to re-entry and subsequent polymorphic VT. Toxin-induced blockade of K+ efflux channels during phase 3 of the action potential corresponding with repolarization and QT interval prolongation may place the patient at risk for polymorphic VT or torsades de pointes (Holstege et al., 2005; Holstege et al., 2006). The drugs and toxins reported to have this effect are listed in table 3. Risk factors for torsades de pointes (TdP) among patients treated with medications that prolong QT interval include, among others, female gender, hypokalemia, hypomagnesemia, bradycardia, overdose, drug interactions (fig.9), digitalis therapy, and background of the patient (preexisting cardiac disease, long QT interval or family history of long QT). (Murphy

signs of ischemia (in inferior and lateral leads).

**2.3 Outward potassium channel blockers**

et al., 2007; Roden, 2004)

Fig. 4. Acute poisoning with Verapamil in a 61-years old female. ECG reveals sinus bradycardia 41/min, minor right bundle ranch block (RBBB), first-degree AV block (PR 0.32 sec) and long QT interval (0.64 sec).

Fig. 5. Acute poisoning with Norvasc 300 mg in a 31-years old female. ECG reveals sinus tachycardia 114/min, signs of ischemia in infero-lateral leads, 14 hours after ingestion (systolic blood pressure 70 mmHg).

Fig. 6. Same patient, two days after ingestion. ECG reveals accelerated junctional rhythm (sinus coronary rhythm, or Zahn rhythm) 114/min, with negative P waves in leads DII, DIII, aVF, and disappearance of ischemic changes present at admission.

Fig. 7. Acute Diltiazem poisoning at admission. ECG reveals accelerated junctional rhythm 75/min, retrograde atrial conduction (negative P waves after QRS), and atrial premature beats.

Fig. 4. Acute poisoning with Verapamil in a 61-years old female. ECG reveals sinus

sec) and long QT interval (0.64 sec).

(systolic blood pressure 70 mmHg).

bradycardia 41/min, minor right bundle ranch block (RBBB), first-degree AV block (PR 0.32

Fig. 5. Acute poisoning with Norvasc 300 mg in a 31-years old female. ECG reveals sinus tachycardia 114/min, signs of ischemia in infero-lateral leads, 14 hours after ingestion

Fig. 6. Same patient, two days after ingestion. ECG reveals accelerated junctional rhythm (sinus coronary rhythm, or Zahn rhythm) 114/min, with negative P waves in leads DII, DIII,

Fig. 7. Acute Diltiazem poisoning at admission. ECG reveals accelerated junctional rhythm 75/min, retrograde atrial conduction (negative P waves after QRS), and atrial premature beats.

aVF, and disappearance of ischemic changes present at admission.

Fig. 8. Same patient (Diltiazem poisoning), second day of evolution. ECG reveals atrioventricular dissociation, with escape junctional rhythm and some ventricular captures, and signs of ischemia (in inferior and lateral leads).

### **2.3 Outward potassium channel blockers**

Medications in the K+ efflux blocker category block the outward flow of K+ from intracellular to extracellular spaces. Blockade of the outward K+ currents may prolong the cardiac cycle action potential (Fig. 1). The primary electrocardiographic manifestation is QT interval prolongation (QTc interval greater than 0.45 seconds in men and 0.47 seconds in women). Delay of repolarization causes the myocardial cell to have less charge difference across its membrane, and result in the activation of the inward depolarization current (early after-depolarization), which is seen on ECG as prominent U waves (Murphy et al., 2007). This may promote triggered activity, which potentially can progress to re-entry and subsequent polymorphic VT. Toxin-induced blockade of K+ efflux channels during phase 3 of the action potential corresponding with repolarization and QT interval prolongation may place the patient at risk for polymorphic VT or torsades de pointes (Holstege et al., 2005; Holstege et al., 2006). The drugs and toxins reported to have this effect are listed in table 3. Risk factors for torsades de pointes (TdP) among patients treated with medications that prolong QT interval include, among others, female gender, hypokalemia, hypomagnesemia, bradycardia, overdose, drug interactions (fig.9), digitalis therapy, and background of the patient (preexisting cardiac disease, long QT interval or family history of long QT). (Murphy et al., 2007; Roden, 2004)

Fig. 9. Drug-induced long QT interval, following interaction between Bisoprolol and Amiodarone. ECG shows long QT interval (0.80 sec), couples of PVB with R/T phenomenon preceding a short episode of polymorphic VT.

Toxic and Drug-Induced Changes of the Electrocardiogram 279

Many of these drugs have other effects that can result in significant electrocardiographic changes, such as antipsychotics, that can cause muscarinic acetylcholine receptor and alphaadrenergic receptor blockade and cardiac cell K+, Na+, and Ca2+ channel blockade (Holstege et al., 2006). These effects lead to sinus tachycardia (secondary to anticholinergic effect) or

Cardiac glycosides (table 4) inhibit the Na+/K+ adenosine triphosphatase (Na+/K+ATPase) pump. As a result, there is an inhibition of the active transport of Na+ and K+ across cell membrane, intracellular Na+ increases and the Na+/Ca2+exchanger is secondary activated. The intracellular Ca2+ level increases, and augments myofibril activity in cardiac myocytes, which results in a positive inotropic effect, and increased automaticity. The cardiac glycosides also increase vagal tone that may lead to a direct atrioventricular (AV) nodal depression (Holstege et al., 2006). Digitalis derivatives in therapeutic doses are used to increase myocardial contractility or slow AV conduction. They modify ECG, changes known as ''digitalis effect'', expressed by abnormal inverted or flattened T waves coupled with ST segment depression (most pronounced in leads with tall R waves), QT interval shortening (as a result of decreased ventricular repolarization time), PR interval lengthening (increased vagal activity), and prominent U-waves. Sagging ST segments, inverted T waves, and normal or shortened QT intervals are sometimes identified by their similar appearance to "Salvador Dali's mustache" (Clancy**,** 2007). These ECG changes are seen with therapeutic

reflex tachycardia (secondary to alpha-adrenergic blockade).

Digoxin levels and do not represent toxicity (Chung, 1981).

2. Plants producing cardiac glycosides:

3. Animals producing cardiac glycosides: - Bufadienolide type: *Bufo marinus* toads ECG changes - Excitant activity: atrial and junctional premature beats, atrial

Table 4. Na+/K+ ATPase blocking agents and ECG changes in intoxication (adapted from

*Digitalis lanata* and *Digitalis purpurea* (foxglove) – digoxin, digitoxin, *Nerium oleander* (oleander) – oleandrin, *Convallaria majalis* (Lily of the valley), *Apocynum cannabinum* (Dogbane), *Asclepias species.*

tachycardia, atrial flutter (rare), AF (rare), accelerated junctional rhythms, PVB, bigeminy and multifocal, VT, bi-directional VT, VF.  - Combination of these: atrial tachycardia with AV block, sinus bradycardia with junctional tachycardia, Wenckebach with junctional premature beats, regularization of ventricular rhythm

1. Drugs:

with AF.

Gordon, 2006; Lapostolle & Borron, 2007).

Na+/K+ ATPase

blockers

**2.4 Sodium–potassium ATPase blockers**

\*removed from the market; \*\* TdP reported.

Table 3. K+ efflux channel blockers, and the resulting ECG changes.

Fig. 10. Acute organophosphate poisoning, five days after ingestion. ECG shows long QT interval (0.60 sec), PVB with R/T phenomenon (arrows) preceding a short episode of TdP (TORS).

Doxepin, Imipramine, Nortriptyline, Maprotiline) - Other antidepressants (Citalopram, Venlafaxine)

\*\*)

1. Cardiovascular drugs:

Ibutilide, Sotalol, Vernakalant)

Terfenadine\*, Hydroxyzine)

Hydroxychloroquine, etc.)

4. Synthetic opioids: Levomethadyl 5. Opium alkaloids: Papaverine\*\*

Table 3. K+ efflux channel blockers, and the resulting ECG changes.

6. Toxins: Quinine, Organophosphates (fig.10)

Premature ventricular beats (PVB) followed by TdP

Fig. 10. Acute organophosphate poisoning, five days after ingestion. ECG shows long QT interval (0.60 sec), PVB with R/T phenomenon (arrows) preceding a short episode of TdP

Propafenone)

2. Psychiatric drugs:

T- or U-wave abnormalities

ECG changes QT interval prolongation

\*removed from the market; \*\* TdP reported.

(TORS).

Sinus tachycardia

Inhibitors of outward K+ channel

Many of these drugs have other effects that can result in significant electrocardiographic changes, such as antipsychotics, that can cause muscarinic acetylcholine receptor and alphaadrenergic receptor blockade and cardiac cell K+, Na+, and Ca2+ channel blockade (Holstege et al., 2006). These effects lead to sinus tachycardia (secondary to anticholinergic effect) or reflex tachycardia (secondary to alpha-adrenergic blockade).

### **2.4 Sodium–potassium ATPase blockers**

Cardiac glycosides (table 4) inhibit the Na+/K+ adenosine triphosphatase (Na+/K+ATPase) pump. As a result, there is an inhibition of the active transport of Na+ and K+ across cell membrane, intracellular Na+ increases and the Na+/Ca2+exchanger is secondary activated. The intracellular Ca2+ level increases, and augments myofibril activity in cardiac myocytes, which results in a positive inotropic effect, and increased automaticity. The cardiac glycosides also increase vagal tone that may lead to a direct atrioventricular (AV) nodal depression (Holstege et al., 2006). Digitalis derivatives in therapeutic doses are used to increase myocardial contractility or slow AV conduction. They modify ECG, changes known as ''digitalis effect'', expressed by abnormal inverted or flattened T waves coupled with ST segment depression (most pronounced in leads with tall R waves), QT interval shortening (as a result of decreased ventricular repolarization time), PR interval lengthening (increased vagal activity), and prominent U-waves. Sagging ST segments, inverted T waves, and normal or shortened QT intervals are sometimes identified by their similar appearance to "Salvador Dali's mustache" (Clancy**,** 2007). These ECG changes are seen with therapeutic Digoxin levels and do not represent toxicity (Chung, 1981).

Table 4. Na+/K+ ATPase blocking agents and ECG changes in intoxication (adapted from Gordon, 2006; Lapostolle & Borron, 2007).

Toxic and Drug-Induced Changes of the Electrocardiogram 281

In an acute poisoning, ECG changes, especially arrhythmias, can be explained by direct or indirect sympathomimetic effects, anticholinergic effects, and the effects of altered central nervous system (CNS) regulation of peripheral autonomic activity. Sympathetic fibers innervate most parts of the heart. Postganglionic fibers release norepinephrine, which interacts with the beta 1- adrenergic cardiac receptors, to increase permeability to Na+ and Ca2+, thus leading to increased excitability, conduction and contractility. The vagal postganglionic parasympathetic fibers locally release acetylcholine. Vagal stimulation of the muscarinic receptors primarily decreases excitability of the atria, and slows the conduction of impulse into the ventricles, to a complete blockade of transmission in the AV node, with

calcium channel blocking properties)

AV blocks (first-degree AV block is common)

Table 5. Beta-blockers and ECG changes in intoxication (adapted from Gordon, 2006;

Prolonged PR, and QTc intervals

Asystole (in severe poisoning) Mild tachycardia (Pindolol overdose)

Ventricular tachydysrhythmias (membrane stabilizing agents) - fig.14

Prolonged QRS complex (membrane stabilizing agents)

Multifocal ventricular extrasystoles, VT, VF (Sotalol)

**3. Drugs and toxins acting on autonomic nervous system**

modest direct effects on contractility (Patel & Benowitz, 2005).

sympathomimetic activity)

1st generation

activity)

ECG changes Sinus or nodal bradycardia

Holstege et al., 2006; Brubacher, 2007)

Beta-adrenergic

blockers

Electrocardiographic abnormalities with cardiac glycoside toxicity are the result of increased automaticity (from increased intracellular Ca2+) accompanied by slowed conduction through the AV node. In 10% to 15% of cases, ectopic rhythms will be the first sign of intoxication. AV block or an increase in ventricular automaticity are the most common manifestations of Digoxin toxicity and have been shown to occur in 30%to 40%of verified cases of toxicity. The nonspecific dysrhythmias consist of premature ventricular contractions (especially bigeminal and multiform), first-, second-, and third degree AV block, sinus bradycardia (fig.11), sinus tachycardia, sino-atrial block or arrest, atrial fibrillation (AF) with slow ventricular response (fig.12), atrial tachycardia, junctional escape rhythm, AV dissociation, ventricular bigeminy and trigeminy, VT (fig.13), TdP, and VF. The more specific dysrhythmias are AF with slow, regular ventricular rate (AV dissociation), nonparoxysmal junctional tachycardia (rate 70-130), atrial tachycardia with block (atrial rate is usually 150-200), and bi-directional VT. Bidirectional VT is particularly characteristic of severe toxicity and is the result of alterations of intraventricular conduction, junctional tachycardia with aberrant intraventricular conduction, or, on rare occasions, alternating ventricular pacemakers. Typically, in the young, slow rhythms and conduction defects predominate over ventricular ectopy, which is more prominent in older Digoxin-toxic patients. (Litonjua et al., 2005)

Fig. 11. Sinus bradicardia 47/min, with ST/T changes, 20 hours after attempted suicide with 10 mg Digoxin, in an 18 years old man.

Fig. 12. AF 56/min, with a pause of 2.96 sec, 15 hours after attempted suicide with Digoxin, in a 68 years old woman.

Fig. 13. PVB and a short episode of non-sustained VT 135/min, in a 56 years old male with Digoxin overdose in attempted suicide.

Electrocardiographic abnormalities with cardiac glycoside toxicity are the result of increased automaticity (from increased intracellular Ca2+) accompanied by slowed conduction through the AV node. In 10% to 15% of cases, ectopic rhythms will be the first sign of intoxication. AV block or an increase in ventricular automaticity are the most common manifestations of Digoxin toxicity and have been shown to occur in 30%to 40%of verified cases of toxicity. The nonspecific dysrhythmias consist of premature ventricular contractions (especially bigeminal and multiform), first-, second-, and third degree AV block, sinus bradycardia (fig.11), sinus tachycardia, sino-atrial block or arrest, atrial fibrillation (AF) with slow ventricular response (fig.12), atrial tachycardia, junctional escape rhythm, AV dissociation, ventricular bigeminy and trigeminy, VT (fig.13), TdP, and VF. The more specific dysrhythmias are AF with slow, regular ventricular rate (AV dissociation), nonparoxysmal junctional tachycardia (rate 70-130), atrial tachycardia with block (atrial rate is usually 150-200), and bi-directional VT. Bidirectional VT is particularly characteristic of severe toxicity and is the result of alterations of intraventricular conduction, junctional tachycardia with aberrant intraventricular conduction, or, on rare occasions, alternating ventricular pacemakers. Typically, in the young, slow rhythms and conduction defects predominate over ventricular ectopy, which is more

Fig. 11. Sinus bradicardia 47/min, with ST/T changes, 20 hours after attempted suicide with

Fig. 12. AF 56/min, with a pause of 2.96 sec, 15 hours after attempted suicide with Digoxin,

Fig. 13. PVB and a short episode of non-sustained VT 135/min, in a 56 years old male with

prominent in older Digoxin-toxic patients. (Litonjua et al., 2005)

10 mg Digoxin, in an 18 years old man.

Digoxin overdose in attempted suicide.

in a 68 years old woman.

### **3. Drugs and toxins acting on autonomic nervous system**

In an acute poisoning, ECG changes, especially arrhythmias, can be explained by direct or indirect sympathomimetic effects, anticholinergic effects, and the effects of altered central nervous system (CNS) regulation of peripheral autonomic activity. Sympathetic fibers innervate most parts of the heart. Postganglionic fibers release norepinephrine, which interacts with the beta 1- adrenergic cardiac receptors, to increase permeability to Na+ and Ca2+, thus leading to increased excitability, conduction and contractility. The vagal postganglionic parasympathetic fibers locally release acetylcholine. Vagal stimulation of the muscarinic receptors primarily decreases excitability of the atria, and slows the conduction of impulse into the ventricles, to a complete blockade of transmission in the AV node, with modest direct effects on contractility (Patel & Benowitz, 2005).

Table 5. Beta-blockers and ECG changes in intoxication (adapted from Gordon, 2006; Holstege et al., 2006; Brubacher, 2007)

Toxic and Drug-Induced Changes of the Electrocardiogram 283

Fig. 16. Acute Sotalol poisoning presenting with bradyarrhythmias, with severe QT

Cardiac disturbances caused by sympathetic-inhibiting drugs are listed in table 6.

ECG changes Sinus, atrial, junctional and ventricular

and imidazoline receptor stimulation (Murphy et al., 2007; Wiley II, 2007).

Table 6. Sympathetic-inhibitors and the resulting ECG changes.

**3.2 Other sympathetic – inhibitors (other than BB)**

Sympathetic-inhibiting agents Methyldopa

**3.3 Sympathomimetic toxicity**

exposure to a sympathomimetic.

(leads V1-V3).

prolongation, and monomorphic PVB, R/T phenomenon, and a couple of polymorphic PVB

Reserpine, Guanethidine

bradyarrhythmias First degree AV block

These drugs are used for their antihypertensive action, explained by central and peripheral alpha 2-adrenergic agonist effects. In acute overdose they cause ECG changes, along with hypotension, and cardiac failure. Cardiac arrests have been described in adults with Clonidine poisoning. Over-the-counter topical decongestants commonly contain imidazoline derivatives (naphzoline, tetrahydrozoline, oxymetazoline, and xylometazoline), and can cause systemic toxicity after topical exposure, or ingestion, with sympatholytic effects, such as bradyarrhythmias and hypotension, related to central alpha 2-adrenergic

Sympathetic overactivity can be caused by a number of drugs and toxins (table 7), such as illicit drugs, and hydrocarbon solvents, but also by sedative drug withdrawal syndromes. The typical ECG changes are sinus and atrial tachycardia, and occasionally ventricular dysrrhythmias (in massive exposures). Sinus tachycardia may be the first manifestation of

Prazosin and other alpha-blockers

Ventricular tachyarrhythmias

Clonidine and other imidazoline derivatives

### **3.1 Beta-adrenergic blockers (BB)**

BBs competitively inhibit various β-adrenergic receptors, and are listed in table 5.

They cause in most cases sinus bradycardia. Serious arrhythmias result from purely anticholinergic compound poisoning, especially in patients with underlying ischemic heart disease (e.g. atrial tachycardia and PVB). In acute BB overdose, the most pronounced effects are bradycardia (from decreased sinoatrial node function), varying degrees of AV block, and hypotension. Beta-adrenergic antagonists competitively antagonize the effects of catecholamines at the beta-adrenergic receptor and blunt the chronotropic and inotropic response to catecholamines (Bird, 2007).

Inhibition of the conducting system most commonly causes first-degree AV block, but higher levels of toxicity can promote second- and third-degree AV block (fig.15), junctional rhythms, and intraventricular conduction delays (Anderson, 2008).

Three beta-blockers are known to prolong QTc intervals: Sotalol (fig.16), Propranolol, and Acebutolol. Sotalol blocks K+ channels, thereby prolonging the action potential and the repolarization duration. The prolongation of the QTc interval predisposes the patient to ventricular tachyarrhythmias and TdP, which have been described after both Sotalol overdose and therapeutic administration. Propranolol overdose has caused QTc prolongation and torsades on rare occasion (Delk et al., 2006).

Fig. 14. Acute poisoning 3 hours after ingestion of 2 grams of Propranolol, presenting with accelerated idioventricular rhythm 115/min, in a young female. Note the absence of P waves, wide QRS complex (0.12 msec).

Fig. 15. Acute Metoprolol poisoning presenting with third degree AV block, with narrow QRS complex at a rate of 35/min. Atrial activity is represented by P waves, 80/min.

Beta-adrenergic antagonists also cause myocardial depression, at least in part, by an action independent of either catecholamine antagonism or membrane-depressant activity (Brubacher, 2007).

They cause in most cases sinus bradycardia. Serious arrhythmias result from purely anticholinergic compound poisoning, especially in patients with underlying ischemic heart disease (e.g. atrial tachycardia and PVB). In acute BB overdose, the most pronounced effects are bradycardia (from decreased sinoatrial node function), varying degrees of AV block, and hypotension. Beta-adrenergic antagonists competitively antagonize the effects of catecholamines at the beta-adrenergic receptor and blunt the chronotropic and inotropic

Inhibition of the conducting system most commonly causes first-degree AV block, but higher levels of toxicity can promote second- and third-degree AV block (fig.15), junctional

Three beta-blockers are known to prolong QTc intervals: Sotalol (fig.16), Propranolol, and Acebutolol. Sotalol blocks K+ channels, thereby prolonging the action potential and the repolarization duration. The prolongation of the QTc interval predisposes the patient to ventricular tachyarrhythmias and TdP, which have been described after both Sotalol overdose and therapeutic administration. Propranolol overdose has caused QTc

Fig. 14. Acute poisoning 3 hours after ingestion of 2 grams of Propranolol, presenting with accelerated idioventricular rhythm 115/min, in a young female. Note the absence of P

Fig. 15. Acute Metoprolol poisoning presenting with third degree AV block, with narrow QRS complex at a rate of 35/min. Atrial activity is represented by P waves, 80/min.

Beta-adrenergic antagonists also cause myocardial depression, at least in part, by an action independent of either catecholamine antagonism or membrane-depressant activity

BBs competitively inhibit various β-adrenergic receptors, and are listed in table 5.

rhythms, and intraventricular conduction delays (Anderson, 2008).

prolongation and torsades on rare occasion (Delk et al., 2006).

**3.1 Beta-adrenergic blockers (BB)**

response to catecholamines (Bird, 2007).

waves, wide QRS complex (0.12 msec).

(Brubacher, 2007).

Fig. 16. Acute Sotalol poisoning presenting with bradyarrhythmias, with severe QT prolongation, and monomorphic PVB, R/T phenomenon, and a couple of polymorphic PVB (leads V1-V3).

### **3.2 Other sympathetic – inhibitors (other than BB)**

Cardiac disturbances caused by sympathetic-inhibiting drugs are listed in table 6.

Table 6. Sympathetic-inhibitors and the resulting ECG changes.

These drugs are used for their antihypertensive action, explained by central and peripheral alpha 2-adrenergic agonist effects. In acute overdose they cause ECG changes, along with hypotension, and cardiac failure. Cardiac arrests have been described in adults with Clonidine poisoning. Over-the-counter topical decongestants commonly contain imidazoline derivatives (naphzoline, tetrahydrozoline, oxymetazoline, and xylometazoline), and can cause systemic toxicity after topical exposure, or ingestion, with sympatholytic effects, such as bradyarrhythmias and hypotension, related to central alpha 2-adrenergic and imidazoline receptor stimulation (Murphy et al., 2007; Wiley II, 2007).

### **3.3 Sympathomimetic toxicity**

Sympathetic overactivity can be caused by a number of drugs and toxins (table 7), such as illicit drugs, and hydrocarbon solvents, but also by sedative drug withdrawal syndromes. The typical ECG changes are sinus and atrial tachycardia, and occasionally ventricular dysrrhythmias (in massive exposures). Sinus tachycardia may be the first manifestation of exposure to a sympathomimetic.

Toxic and Drug-Induced Changes of the Electrocardiogram 285

Fig. 18. Atrial tachycardia 150/min, with variable AV block, in a female with a chronic

Either as a result of excessive circulating catecholamines observed with cocaine and sympathomimetics, or myocardial sensitization secondary to halogenated hydrocarbons or thyroid hormone, or increased second-messenger activity secondary to theophylline, the extreme inotropic and chronotropic effects cause dysrhythmias. Altered repolarization, increased intracellular Ca2+ concentrations, or myocardial ischemia may cause the dysrhythmia. Additionally, cocaine that produce focal myocardial ischemia, can lead to malignant ventricular dysrhythmias (Clancy, 2007). In high dose, along with its potent sympathomimetic action, cocaine blocks fast Na+ channels in the myocardium, with a depression of depolarization, and slowing of conduction velocity, manifested on ECG with

There are numerous and various anticholinergic drugs and toxins that may be ingested

Mandrake (Mandragora officinarum) - Toxic mushrooms: Amanita muscaria

Table 8. Drugs and toxins with anticholinergic effect, with induced ECG abnormalities.

They cause in most cases sinus tachycardia. Serious arrhythmias result from purely anticholinergic compound poisoning, especially in patients with underlying ischemic heart disease (e.g. atrial tachycardia and ventricular premature beats). Atropine, for example, increases myocardial oxygen demand secondary to tachycardia, and can lead to VT and fibrillation in patients after myocardial infarction. Patients presenting with anticholinergic

respiratory disease and Theophylline overdosage.

prolonged PR, QRS, and QT intervals (Murphy et al., 2007).

1. Drugs:

2. Toxins:

ECG changes Sinus and atrial tachycardia

Premature ventricular beats

**3.4 Anticholinergic toxicity**

Anticholinergic drugs and toxins

(table 8) and produce ECG abnormalities.

Table 7. Sympathomimetic drugs and toxins and the resulting ECG changes.

Fig. 17. Paroxysmal supraventricular tachycardia 169/min, in a young female with acute cannabis and ethanol poisoning.

However, other supraventricular or ventricular dysrhythmias may develop if an abnormal rhythm is generated in another part of the heart.

Sinoatrial slowing with escape junctional or ventricular rhythms

Myocardial ischemia or infarction (cocaine, amphetamines, or

sympathomimetics (decongestants containing phenylephrine,

pseudoephedrine, ephedrine)

Sympathomimetic drugs and toxins

1. Drugs:

Terbutaline)

Fig. 17. Paroxysmal supraventricular tachycardia 169/min, in a young female with acute

However, other supraventricular or ventricular dysrhythmias may develop if an abnormal

3. Toxins: - Ethanol

VT, VF

(solvent inhalation) Atrial tachycardia – fig. 18 Ventricular premature beats

hydrocarbons ingestion)

Table 7. Sympathomimetic drugs and toxins and the resulting ECG changes.

ECG abnormalities Sinus tachycardia

cannabis and ethanol poisoning.

rhythm is generated in another part of the heart.

2. Illicit drugs: - Amphetamines

Fig. 18. Atrial tachycardia 150/min, with variable AV block, in a female with a chronic respiratory disease and Theophylline overdosage.

Either as a result of excessive circulating catecholamines observed with cocaine and sympathomimetics, or myocardial sensitization secondary to halogenated hydrocarbons or thyroid hormone, or increased second-messenger activity secondary to theophylline, the extreme inotropic and chronotropic effects cause dysrhythmias. Altered repolarization, increased intracellular Ca2+ concentrations, or myocardial ischemia may cause the dysrhythmia. Additionally, cocaine that produce focal myocardial ischemia, can lead to malignant ventricular dysrhythmias (Clancy, 2007). In high dose, along with its potent sympathomimetic action, cocaine blocks fast Na+ channels in the myocardium, with a depression of depolarization, and slowing of conduction velocity, manifested on ECG with prolonged PR, QRS, and QT intervals (Murphy et al., 2007).

### **3.4 Anticholinergic toxicity**

There are numerous and various anticholinergic drugs and toxins that may be ingested (table 8) and produce ECG abnormalities.

Table 8. Drugs and toxins with anticholinergic effect, with induced ECG abnormalities.

They cause in most cases sinus tachycardia. Serious arrhythmias result from purely anticholinergic compound poisoning, especially in patients with underlying ischemic heart disease (e.g. atrial tachycardia and ventricular premature beats). Atropine, for example, increases myocardial oxygen demand secondary to tachycardia, and can lead to VT and fibrillation in patients after myocardial infarction. Patients presenting with anticholinergic

Toxic and Drug-Induced Changes of the Electrocardiogram 287

rare feature is acute myocardial infarction (fig.20), with a complex mechanism (fig.21) explaining its presence (coronary spasm induced by parasympathetic hyperactivity, direct

Fig. 19. Acute organophosphate poisoning, five days after exposure. ECG shows QT interval prolongation (0.60 sec), short episode of ventricular flutter (FLV), a couple of PVB, and one

Patients with clinical signs of cholinesterase inhibition and abnormal ECG (including long QT interval) should be monitored continuously, because of the risk of developing ventricular arrhythmias (Lionte et al., 2007). Reversible acetylcholinesterase inhibitors, such as Donepezil, have a high selectivity for neuronal acetylcholinesterase, and in accidental

Fig. 20. Acute organophosphate poisoning, four days after exposure, serum cholinesterase normalized with antidote. ECG shows acute ST segment elevation anterior myocardial infarction (with increased cardiac enzymes), sinus tachycardia 106/min, QT interval 0.32

overdose were reported to produce sinus bradycardia (Murphy et al., 2007).

toxic effect of pesticide on myocardium).

PVB with R on T phenomenon (R/T).

sec.

toxidrome (mydriasis, diminished bowel sounds, urinary retention, dry mouth, flushed skin, tachycardia, and agitation) may have ingested antihistamine-sympathomimetic combinations, or tricyclic antidepressants and neuroleptics, having both anticholinergic and membrane-depressant effects, which can explain the presence of serious cardiovascular disturbances (such as widening of the QRS complex, and a rightward deflection of the terminal 40 msec of the QRS complex, with prolongation of the QTc, which creates a substrate for the development of TdP). (Murphy et al., 2007; Juurlink, 2007)

### **3.5 Cholinomimetic toxicity**

Poisoning by cholinomimetic drugs and toxins (table 9) lead to different ECG aspects. The most common type of cholinomimetic toxicity is poisoning with organophosphate and carbamate pesticides, resulting in the excessive inhibition of the cholinesterase. The ECG changes are unpredictable and often change over the time course of the poisoning.

Table 9. Cholinomimetic drugs and toxins, and ECG changes induced in acute exposure.

Early in the course, tachycardia is present, due to acetylcholine stimulation of nicotinic receptors, followed by bradycardia, secondary to muscarinic receptor stimulation. In severe poisonings, advanced AV block, bradydysrhythmias and asystole may occur (Murphy et al., 2007). Up to 5 days after exposure, QTc interval prolongation is followed by ventricular tachyarrhythmias (fig.19), including TdP (fig.10), due to persistent imbalance between sympathetic and parasympathetic influences on the heart, as well as dyselectrolytemias. A

toxidrome (mydriasis, diminished bowel sounds, urinary retention, dry mouth, flushed skin, tachycardia, and agitation) may have ingested antihistamine-sympathomimetic combinations, or tricyclic antidepressants and neuroleptics, having both anticholinergic and membrane-depressant effects, which can explain the presence of serious cardiovascular disturbances (such as widening of the QRS complex, and a rightward deflection of the terminal 40 msec of the QRS complex, with prolongation of the QTc, which creates a

Poisoning by cholinomimetic drugs and toxins (table 9) lead to different ECG aspects. The most common type of cholinomimetic toxicity is poisoning with organophosphate and carbamate pesticides, resulting in the excessive inhibition of the cholinesterase. The ECG

Sinus tachycardia (seen in early stages of cholinesterase inhibition and

changes are unpredictable and often change over the time course of the poisoning.

volatile anesthetics, Ketamine)

Aminopyridines, Carbachol, Guanidine)

Atrial, junctional, or ventricular bradycardia

nicotine poisoning due to ganglionic stimulation) VT associated with QT interval prolongation

Table 9. Cholinomimetic drugs and toxins, and ECG changes induced in acute exposure.

Early in the course, tachycardia is present, due to acetylcholine stimulation of nicotinic receptors, followed by bradycardia, secondary to muscarinic receptor stimulation. In severe poisonings, advanced AV block, bradydysrhythmias and asystole may occur (Murphy et al., 2007). Up to 5 days after exposure, QTc interval prolongation is followed by ventricular tachyarrhythmias (fig.19), including TdP (fig.10), due to persistent imbalance between sympathetic and parasympathetic influences on the heart, as well as dyselectrolytemias. A

substrate for the development of TdP). (Murphy et al., 2007; Juurlink, 2007)

**3.5 Cholinomimetic toxicity**

1. Drugs:

Donepezil)

2. Toxins:

plant)

AV block

Asystole

Sinus bradycardia

Cholinomimetic drugs and toxins

ECG

abnormalities

rare feature is acute myocardial infarction (fig.20), with a complex mechanism (fig.21) explaining its presence (coronary spasm induced by parasympathetic hyperactivity, direct toxic effect of pesticide on myocardium).

Fig. 19. Acute organophosphate poisoning, five days after exposure. ECG shows QT interval prolongation (0.60 sec), short episode of ventricular flutter (FLV), a couple of PVB, and one PVB with R on T phenomenon (R/T).

Patients with clinical signs of cholinesterase inhibition and abnormal ECG (including long QT interval) should be monitored continuously, because of the risk of developing ventricular arrhythmias (Lionte et al., 2007). Reversible acetylcholinesterase inhibitors, such as Donepezil, have a high selectivity for neuronal acetylcholinesterase, and in accidental overdose were reported to produce sinus bradycardia (Murphy et al., 2007).

Fig. 20. Acute organophosphate poisoning, four days after exposure, serum cholinesterase normalized with antidote. ECG shows acute ST segment elevation anterior myocardial infarction (with increased cardiac enzymes), sinus tachycardia 106/min, QT interval 0.32 sec.

Toxic and Drug-Induced Changes of the Electrocardiogram 289

Myocardial injury from CO poisoning results from tissue hypoxia, and as damage at the cellular level. The affinity of hemoglobin for CO is 200 to 250 times greater than its affinity for oxygen. This results in competitive inhibition of oxygen release due to a shift in the oxygen-hemoglobin dissociation curve, reduced oxygen delivery, and subsequent tissue hypoxia. In CO poisoning, magnitude of ST/T changes doesn't correlate with the severity of the myocardial impairment, other tests, such as echocardiography, being necessary. All cardiovascular changes are more prominent in patients with underlying cardiac pathology

Fig. 22. ECG in acute CO poisoning, 24 hours after exposure (flattened T wave in DI, negative T wave in aVL, ST segment elevation and T wave changes in V1-V3).

Fig. 23. ECG in acute CO poisoning, same patient, 52 hours after exposure. Note the

Fig. 24. Same patient, 4 days after exposure. Note the evolution of ST/T changes in

evolution of ST/T changes in precordial leads.

precordial and lateral leads.

(Murphy et al., 2007; Satran et al., 2005).

Fig. 21. Cardiac manifestations of organophosphate poisoning and mechanisms involved.

### **4. Other substances inducing ECG changes**

### **4.1 Chemical asphyxiants**

Chemical asphyxiants act in one of two ways. Some prevent the uptake of oxygen in the blood. Carbon monoxide interferes with the transport of oxygen to the tissues by strongly binding with hemoglobin to form carboxyhemoglobin, which leaves inadequate hemoglobin available for oxygen transport. Hydrogen cyanide does not permit the normal oxygen transfer either from the blood to the tissues or within the cell itself, resulting in tissue hypoxia. Acute exposure to these agents leads to coma and metabolic acidosis, the last explaining in part ECG abnormalities (table 10) recorded in such poisoning.

Table 10. Major chemical asphyxiants and their effect on ECG in acute poisoning (adapted from Hall, 2007; Murphy et al., 2007; **Schraga** et al., 2008)

Fig. 21. Cardiac manifestations of organophosphate poisoning and mechanisms involved.

Chemical asphyxiants act in one of two ways. Some prevent the uptake of oxygen in the blood. Carbon monoxide interferes with the transport of oxygen to the tissues by strongly binding with hemoglobin to form carboxyhemoglobin, which leaves inadequate hemoglobin available for oxygen transport. Hydrogen cyanide does not permit the normal oxygen transfer either from the blood to the tissues or within the cell itself, resulting in tissue hypoxia. Acute exposure to these agents leads to coma and metabolic acidosis, the last

ST segment depression or elevation

Myocardial infarction (fig.22, 23, 24)

Table 10. Major chemical asphyxiants and their effect on ECG in acute poisoning (adapted

Arrhythmias occasionally (PVB, atrial fibrillation)

Erratic supraventricular and vntricular arrhythmias

Shortening of the ST segment with eventual fusion of the T wave

explaining in part ECG abnormalities (table 10) recorded in such poisoning.

Conduction disturbance

into the QRS complex.

Ventricular arrhythmias ST/T changes (fig.25)

Ischemic changes

Asystole

from Hall, 2007; Murphy et al., 2007; **Schraga** et al., 2008)

Bradicardia, heart block (late)

**4. Other substances inducing ECG changes**

**4.1 Chemical asphyxiants**

Chemical asphyxiants ECG changes

Hydrogen cyanide Tachycardia (early)

Zinc phosphide Atrial extrasystoles

Carbon monoxide (CO) T wave flattening or inversion

Myocardial injury from CO poisoning results from tissue hypoxia, and as damage at the cellular level. The affinity of hemoglobin for CO is 200 to 250 times greater than its affinity for oxygen. This results in competitive inhibition of oxygen release due to a shift in the oxygen-hemoglobin dissociation curve, reduced oxygen delivery, and subsequent tissue hypoxia. In CO poisoning, magnitude of ST/T changes doesn't correlate with the severity of the myocardial impairment, other tests, such as echocardiography, being necessary. All cardiovascular changes are more prominent in patients with underlying cardiac pathology (Murphy et al., 2007; Satran et al., 2005).

Fig. 22. ECG in acute CO poisoning, 24 hours after exposure (flattened T wave in DI, negative T wave in aVL, ST segment elevation and T wave changes in V1-V3).

Fig. 23. ECG in acute CO poisoning, same patient, 52 hours after exposure. Note the evolution of ST/T changes in precordial leads.

Fig. 24. Same patient, 4 days after exposure. Note the evolution of ST/T changes in precordial and lateral leads.

Toxic and Drug-Induced Changes of the Electrocardiogram 291

Atrial arrhythmias

Scombroid fish (scombrotoxin) Bradycardia, sinus tachycardia, ventricular

VF

acid, while others produce the poisoning because of improper fish handling.

Bradycardia

Table 11. ECG changes induced by natural products poisoning (adapted from Hahn, 2007;

In the pathogenesis of clinical syndrome produced by black widow spider bites was suggested to be also involved an excess of catecholamines, while in patients affected by

Fish-borne poisoning has multiple pathogenic mechanisms, depending on the toxin involved. Some of these toxins are heat stable, therefore unaffected by cooking, and gastric

Fig. 26. Scombroid fish poisoning, 1 hour after ingestion, in a young female, presenting chest pain and hypotension (BP 70/45 mmHg). ECG reveals signs of subendocardial myocardial

Aconite poisoning results from alkaloids contained in teas and herbs, which are not boiled enough before ingestion, such as aconitine and mesaconitine (Murphy et al., 2007).

infarction (sustained by enzymatic evidence), and sinus tachycardia 139/min.

changes with peaked T waves, QT prolongation, atrial and ventricular arrhythmias, myocardial infarction

Tachycardia, dysrhythmias, myocardial infarction

arrhythmias, acute myocardial infarction (fig.26)

VT (monomorphic or polymorphic)

Poisonous scorpion stings (venom) Sinus tachycardia, conduction abnormalities, ST/T

Poisonous animals and plants ECG abnormalities

Ciguatera fish (ciguatoxin) Bradycardia, arrhythmias Puffer fish (tetrodotoxin) Bradycardia, arrhythmias

Black widow spider bites (venom) Tachycardia

Lionte, 2010; Murphy et al., 2007; Wandersee, 2006).

*Hymenoptera* stings, histamine plays a role in pathogenesis.

*Hymenoptera* (bees and wasps)

Aconite poisoning (Chinese herbs or teas that contain *Aconitum carmichaelii* or *A. kusnezoffii*)

stings (venom)

In humans, cyanide produces histotoxic hypoxia by combining with the ferric ion in mitochondrial cytochrome oxidase, preventing electron transport in the cytochrome system and bringing oxidative phosphorylation and ATP production to a halt. The inhibition of oxidative metabolism puts increased demands on anaerobic glycolysis, which results in lactic acid production and may produce severe acid-base imbalance. Myocardial depression with decreased cardiac output produces stagnation hypoxia. Abnormal heartbeat can occur in cases of severe poisoning. Bradycardia, intractable low blood pressure, and death may result (Hall, 2007).

Fig. 25. Attempted suicide with zinc phosphide ingestion in a 19 years old female, presenting circulatory collapse and dyspnea. ECG (leads aVR, aVL, aVF, V1-V3) reveals tachycardia 160 /min with wide QRS complex, multiple PVC (trigeminy), some with R/T phenomenon, and ST/T changes.

Zinc phosphide is a highly effective insecticide and rodenticide. It is mediated by phosphine, which inhibits cytochrome C oxidase. It has been shown recently in nematodes that phosphine rapidly perturbs mitochondrial morphology, inhibits oxidative respiration by 70%, and causes a severe drop in mitochondrial membrane potential. This failure of cellular respiration is likely to be due to a mechanism other than inhibition of cytochrome C oxidase. In addition, phosphine and hydrogen peroxide can interact to form the highly reactive hydroxyl radical and phosphine also inhibits catalase and peroxidase; both mechanisms result in hydroxyl radical associated damage such as lipid peroxidation. The major lethal consequence of zinc phosphide ingestion, profound circulatory collapse, is secondary to factors including direct effects on cardiac myocytes, fluid loss, and adrenal gland damage. There is usually only a short interval between ingestion and the appearance of systemic toxicity. Phosphine-induced impairment of myocardial contractility and fluid loss leads to circulatory failure, and pulmonary edema. Metabolic acidosis, or mixed metabolic acidosis and respiratory alkalosis, are frequent, and contribute to ECG changes (Lionte et al., 2004; Proudfoot, 2009).

### **4.2 Natural products**

Many natural products and toxins have cardiovascular effects, leading to ECG changes (table 11). The clinical and myocardial histological manifestations of scorpion sting resemble those of catecholamine infusion. Myocardial infarction has been documented in scorpion envenomation with a pathophysiological mechanism involving transient myocardial "stunning" (Thomas et al., 2007).

In humans, cyanide produces histotoxic hypoxia by combining with the ferric ion in mitochondrial cytochrome oxidase, preventing electron transport in the cytochrome system and bringing oxidative phosphorylation and ATP production to a halt. The inhibition of oxidative metabolism puts increased demands on anaerobic glycolysis, which results in lactic acid production and may produce severe acid-base imbalance. Myocardial depression with decreased cardiac output produces stagnation hypoxia. Abnormal heartbeat can occur in cases of severe poisoning. Bradycardia, intractable low blood pressure, and death may

Fig. 25. Attempted suicide with zinc phosphide ingestion in a 19 years old female, presenting circulatory collapse and dyspnea. ECG (leads aVR, aVL, aVF, V1-V3) reveals tachycardia 160 /min with wide QRS complex, multiple PVC (trigeminy), some with R/T

Zinc phosphide is a highly effective insecticide and rodenticide. It is mediated by phosphine, which inhibits cytochrome C oxidase. It has been shown recently in nematodes that phosphine rapidly perturbs mitochondrial morphology, inhibits oxidative respiration by 70%, and causes a severe drop in mitochondrial membrane potential. This failure of cellular respiration is likely to be due to a mechanism other than inhibition of cytochrome C oxidase. In addition, phosphine and hydrogen peroxide can interact to form the highly reactive hydroxyl radical and phosphine also inhibits catalase and peroxidase; both mechanisms result in hydroxyl radical associated damage such as lipid peroxidation. The major lethal consequence of zinc phosphide ingestion, profound circulatory collapse, is secondary to factors including direct effects on cardiac myocytes, fluid loss, and adrenal gland damage. There is usually only a short interval between ingestion and the appearance of systemic toxicity. Phosphine-induced impairment of myocardial contractility and fluid loss leads to circulatory failure, and pulmonary edema. Metabolic acidosis, or mixed metabolic acidosis and respiratory alkalosis, are frequent, and contribute to ECG changes

Many natural products and toxins have cardiovascular effects, leading to ECG changes (table 11). The clinical and myocardial histological manifestations of scorpion sting resemble those of catecholamine infusion. Myocardial infarction has been documented in scorpion envenomation with a pathophysiological mechanism involving transient myocardial

result (Hall, 2007).

phenomenon, and ST/T changes.

(Lionte et al., 2004; Proudfoot, 2009).

"stunning" (Thomas et al., 2007).

**4.2 Natural products**

Table 11. ECG changes induced by natural products poisoning (adapted from Hahn, 2007; Lionte, 2010; Murphy et al., 2007; Wandersee, 2006).

In the pathogenesis of clinical syndrome produced by black widow spider bites was suggested to be also involved an excess of catecholamines, while in patients affected by *Hymenoptera* stings, histamine plays a role in pathogenesis.

Fish-borne poisoning has multiple pathogenic mechanisms, depending on the toxin involved. Some of these toxins are heat stable, therefore unaffected by cooking, and gastric acid, while others produce the poisoning because of improper fish handling.