REVIEW For reprint orders, please contact: [email protected]
The current literature regarding the cardiovascular effects of electronic cigarettes Bhargava Nelluri1, Katie Murphy2, Farouk Mookadam*,1 & Martina Mookadam3
Smoking is the leading cause of preventable morbidity and mortality globally. Electronic cigarettes are marketed both as nicotine substitutes and recreational devices. The popularity of electronic cigarettes has superseded other forms of nicotine replacement therapy. They are also popular in ‘never smokers.’ This review summarizes the available data regarding the cardiovascular effects of electronic cigarettes. The existing literature is limited and short term with a lack of high-quality studies and adequate follow-up. The available literature suggests that electronic cigarettes have sympathomimetic effects related to nicotine exposure, however, electronic cigarettes also contain other chemicals that require further investigation. Sparse data suggest vascular injury may be another concern. Further research is needed before broad recommendations can be made. First draft submitted: 29 September 2015; Accepted for publication: 26 November 2015; Published online: 26 February 2016 Background The 2014 Surgeon General Report attributes more than 20 million deaths in the USA between 1965 and 2014 to active and passive smoking [1] . Of these, approximately 8 million deaths are due to cardiovascular and metabolic diseases; 7 million deaths are due to cancers; 3.8 million deaths are due to pulmonary diseases, 108,000 deaths are due to perinatal conditions and 2.4 million deaths are due to secondhand smoke [1] . Approximately 70% of current adult smokers are interested in stopping smoking completely while 52% of smokers have tried to quit in the preceding year with only 6% achieving this successfully [2] . Various therapies are available to alleviate the withdrawal symptoms associated with nicotine withdrawal. Pharmacotherapy approved for smoking cessation includes bupropion and varenicline, which work by acting on norepinephrine, dopamine and neuronal acetyl choline receptors. Both of these have limitations because of side effects including tachycardia, nausea and weight gain [3] . The newest agent available for nicotine replacement therapy is the electronic cigarette (EC), invented by Hon Lik, a Chinese pharmacist, in 2004. In 2007, ECs entered the USA market [4] . ECs are now being used both as nicotine replacement therapy and as a recreational product. The basic mechanism involved in the EC is that of a battery, a heating chamber and the cigarette liquid. The heating of the coil is triggered by various mechanisms including puffing on the cigarette. The liquid is then inhaled as an aerosol [5] .
KEYWORDS
• coronary artery disease • E cigarette • electronic cigarette • heart • heart disease • myocardial function • vascular disease
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA 2 Department of Family Medicine, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA 3 Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA *Author for correspondence: Tel.: +1 480 301 6907; Fax: +1 480 301 8018; [email protected] 1
10.2217/fca.15.83 © 2016 Future Medicine Ltd
Future Cardiol. (2016) 12(2), 167–179
part of
ISSN 1479-6678
167
Review Nelluri, Murphy, Mookadam & Mookadam There are three generations of EC available. The first-generation devices resemble a conventional cigarette (CC). The second-generation devices are filled with liquid, the coils replaced and the power adjusted. Third-generation devices are more adaptable, for example, with adaptable voltage giving higher nicotine doses and potentially more sympathomimetic effects. The liquid can also have different flavors added. Some devices also come with software to monitor use [6] . Reports show that EC use has been increasing exponentially [7,8] . There was a notable increase in use among young previously nonsmokers [9] . The USA market for ECs was worth US$1.5 billion in 2014 and was estimated to be worth US$2 billion in 2015 by Wells Fargo [10] . While the hazards of smoking traditional cigarettes are widely known, the risks of ECs are not known. Furthermore, these products are not currently US FDA regulated, although the US FDA has the power to regulate them and has announced plans for regulation [11] . The composition of the EC fluid is not always clear and varies by brand. Some of the chemical compounds found in ECs are known carcinogens or have teratogenic potential. Others are known to be addictive [12,13] . Figure 1 shows a selection of these compounds [12] . The European Parliament has introduced rules governing the content and sale of ECs, which will take effect in May 2016. In addition, laws regarding advertising of tobacco products will also apply to ECs [14] . This review will specifically focus on the potential benefits and risks of ECs with regard to cardiovascular health. Methods PubMed, Embase, Medline, Cinahl and Cochrane collaboration electronic databases were searched from 1 January 2005 to 11 June 11 2015 to identify studies on the relationship between the ECs and cardiovascular risks using the search terms ‘heart disease,’ ‘coronary artery disease,’ ‘vascular disease,’ ‘electronic cigarettes,’ ‘e cigarettes.’ The search was repeated by a qualified librarian using the same search engines and criteria. We included articles involving adult humans, English language, published in the last 10 years. We included case reports, case series, reviews and meta-analyses. A flow sheet detailing our methods is given in Figure 2. We identified ten papers directly related to our topic. There were two major categories – randomized trials and case reports. We assessed
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Future Cardiol. (2016) 12(2)
the quality of the trials (n = 4) with the Jadad criteria and found the quality to be suboptimal with scores of 0 or 1 (Supplementary Table 1) . Our results encompass the randomized trials and the case reports with a further discussion of the other papers to provide the most comprehensive overview of the available literature possible. Results We identified four randomized trials and six case reports that evaluated the cardiovascular effects of ECs. Although some of the trials also looked at respiratory signs, symptoms and parameters, we focused on the cardiovascular findings. A total of 210 patients were included in these articles. Farsalinos et al. in 2014 conducted a study with 76 subjects – 36 smokers and 40 EC users (using ECs for at least 1 month). The study used echocardiographic and hemodynamic parameters to evaluate the acute effects of traditional and ECs on myocardial function. The subjects had a baseline echocardiogram performed. All subjects then smoked a tobacco cigarette or used an EC for 7 min. All participants were then rested for 5 min and had a repeat echocardiogram performed. It was found that systolic blood pressure, heart rate and rate pressure product were elevated following the use of traditional cigarettes. This increase was not seen in those who used an EC.. In the CC group, systolic blood pressure increased 6.6 mmHg (±5.2; p < 0.001), heart rate increased 5.9 bpm (±4.7; p < 0.001) and rate pressure product increased by 1248 ± 840 (p < 0.001). Diastolic blood pressure increased in both groups after smoking without a statistically significant difference (3.0 ± 3.6 in EC group; 4.4 ± 3.3 in CC group). With regard to echocardiographic parameters, Doppler echocardiography showed a significant increase in isovolumetric relaxation time (IVRT) (IVRTc: corrected for heart rate) in the group consuming CCs compared with the EC group (10.4 ± 10.1 ms EC; -1.2 ± 6.9 ms CC; p < 0.001). IVRT also showed a significant increase in the CC group compared with the EC group (5.6 ± 9.2 ms CC group; -1.0 ± 5.7 ms EC group; p = 0.001), myocardial performance index increased in the CC group compared with the EC group, however, the change was not significant in the EC group (0.03 ± 0.04 CC group; p = 0.02; -0.01 ± 0.04 in EC group; p = 0.330; p-value for difference = 0.001).
future science group
The current literature regarding the cardiovascular effects of electronic cigarettes
Review
Nicotine
Volatile organic compounds
Aldehydes • Formaldehyde • Acetaldehyde • Acrolein • o-methyl benzaldehyde • Acetone
• Toluene p, m-xylene • Propylene glycol • Glycerin • 3-methylbutyl-3methylbutanoate
Chemical evaluation of electronic cigarettes
Polycyclic aromatic hydrocarbons
Tobacco specific nitrosamines • N-nitrosonornicotine • 4-(N-nitrosomethylamino) -1-(3-pyridyl)-1-butanone • N-nitrosoanatabine • N-nitrosoanabasine
• Anthracene • Phenanthrene • 1-methyl phenanthrene • Pyrene
Tobacco alkaloids
Metals
• Cotinine • Myosmine • Anatabine • Anabasine • β-nicotyrine • Nornicotine
• Cadmium • Nickel • Lead • Chromium • Arsenic
Figure 1. Chemical compounds found in electronic cigarettes. Data taken from [12].
Doppler tissue measurements showed a significant reduction in early diastolic peak velocity of the mitral valve (E velocity) in the CC group compared with the EC group (-0.7 ± 1.4 cm/s CC group; 0.2 ± 0.7 cm/s EC group; p < 0.001). In addition, there was a significant decrease in the ratio of early to late annular mitral velocity (-0.08 ± 0.13 CC group; -0.01 ± 0.13 EC group; p = 0.011) and increase in myocardial performance index utilizing pulsed-wave tissue Doppler (0.03 ± 0.05 CC group; -0.01 ± 0.04 EC
future science group
group; p < 0.001). Regarding longitudinal deformation measurements, early diastolic strain rate (SRe) was significantly reduced in CC compared with EC (-0.08 ± 0.12 CC group; 0.01 ± 0.08 EC group; p < 0.001). In essence, these findings show impaired diastolic function in the patients smoking CCs compared with EC use, suggesting an impairment in myocardial relaxation not seen in patients using ECs [15] . In 2013, Battista et al. conducted a study with 12 EC smokers to examine the acute
www.futuremedicine.com
169
Review Nelluri, Murphy, Mookadam & Mookadam hemodynamic effects of ECs. Subjects included in the study smoked their own favored brand of ECs, which varied in nicotine strength between 4 and 9 mg/ml. Blood pressure, heart rate and oxygen saturation levels were measured at rest, 2 min, and 4 min post-EC smoking while echocardiographic measurements (cardiac output and systemic vascular resistance) were performed in parallel. The results showed an increase in cardiac output, diastolic blood pressure and mean arterial pressure after 4 min of EC smoking compared with baseline. Systemic vascular resistance decreased after 2 and 4 min of EC smoking. No changes were noted in oxygen saturation levels. Unfortunately the exact measurements were not available for review, nor were details of statistical significance [16] . Vakali et al. in 2013 conducted a study with 53 participants to determine the effects of the usage of a single EC on symptoms, vital signs Records identified in PubMed (n = 7)
Records identified in Ovid EMBASE (n = 64)
Records identified in Ovid MEDLINE (n = 5)
Records identified in Cochrane (n = 1)
and indices of airway inflammation. Participants were divided into two groups. There were two ECs used. The first had a nicotine strength of 11 mg. The second was a placebo with a strength of 0 mg. Group A consisted of ten nonsmokers and 24 healthy smokers. Each subject smoked a single EC (nicotine strength: 11 mg) for a period of 10 min. Group B consisted of 11 nonsmokers and nine healthy smokers. Each subject in this group smoked a single EC (nicotine strength: 0 mg) for 10 min. It was found that increased heart rate and palpitations were related to the use of ECs [17] . Tsikrika et al. in 2013 conducted a study with 62 participants to determine the effects of ECs on symptoms, vital signs including heart rate and exhaled carbon monoxide. The participants included 52 CC smokers and ten nonsmokers. Of the smokers, 16 suffered from chronic obstructive pulmonary disease (COPD) and 12 Records identified in CINAHL (n = 1)
Total records identified (n = 78)
Records excluded as duplicates (n = 19)
Total records after screening for duplicates (n = 59)
Records assessed for relevance to topic of discussion (n = 59)
Records excluded as irrelevant (n = 49)
Records that were relevant and directly related to topic (n = 10)
Figure 2. Study selection strategy.
170
Future Cardiol. (2016) 12(2)
future science group
future science group
[18]
12
64
62
Battista et al. (2013)
Vakali et al. (2013)
Tsikrika et al. (2013)
www.futuremedicine.com
BP: Blood pressure; CC: Conventional cigarette; CO: Cardiac output; EC: Electronic cigarette; HR: Heart rate; SVR: Systemic vascular resistance.
Overall increase in HR and palpitations, more seen in smokers
[17]
Increased HR and palpitations reported more frequently in users of EC as compared with placebo
Group A: 12 nonsmokers, 29 healthy smokers smoked for 10 min a single 11-mg EC. Group B: 14 nonsmokers and 9 healthy smokers smoked a single 0-mg. Both groups used same brand of EC Participants smoked an EC (strength: 11 mg) for 10 min
[16]
Increased CO and decreased SVR were noted after 2 and 4 min. Diastolic BP and mean arterial pressure increased after 4 min of EC smoking
[15]
Impaired myocardial relaxation and diastolic function in CC smokers compared with EC users
Baseline echocardiogram carried out, followed by use of conventional tobacco cigarette or EC for 7 min. Participants then rested for 5 min and had a repeat echocardiogram carried out Cardiovascular parameters were measured at rest, 2 min and 4 min during use of an EC
Review
Comparison of CC Hemodynamic measurements, smokers with users of ECs echocardiographic including 2D echocardiographic measurements, Doppler flow, tissue Doppler, longitudinal deformation measurements Evaluation of changes BP, HR, SVR, CO in hemodynamic and echocardiographic parameters following use of ECs. All volunteers were users of ECs Effect of single-EC use on symptoms, vital signs and airway inflammatory markers after inhaling either 0 mg or 11 mg of nicotine Participants included Changes in vital signs, clinical both nonsmokers and symptoms and exhaled carbon smokers. Effects of a monoxide were measured. single EC were evaluated Farsalinos et al. 76 (2014)
Cardiovascular effects reported Methods Parameters measured Study design
The majority of the available research regarding the cardiovascular toxicity of electronic cigarettes has focused on the effect of nicotine; however, there are multiple other components of EC liquid that may have adverse cardiovascular effects. There is also variation in the chemical composition of different brands. A review of multiple analyses by Cheng in 2014 found multiple compounds that have been identified in EC aerosols, including aldehydes, metals, volatile organic compounds and tobacco specific nitrosamines. Figure 1 details the compounds found. While some of these compounds, such as acrolein and formaldehyde, are found in CCs, some compounds are unique to ECs and long-term toxicity data are unavailable.
No. of subjects
●●Chemical evaluation of ECs
Study (year)
Other data evaluated
Table 1. Summary of clinical trials evaluating cardiovascular effects of electronic cigarettes.
from asthma. The remaining 24 smokers were free from airway diseases. Participants smoked a single EC (nicotine strength: 11 mg) for a period of 10 min. A significant increase in heart rate and palpitations following use of the EC was noted, with a greater increase noted in smokers [18] . Table 1 summarizes the studies that we evaluated. We identified six case reports involving seven patients where adverse cardiovascular effects of ECs were described. Only one of the cases involved the intended use of ECs. In the remaining cases the cigarette or EC liquid was used improperly, as it was ingested or injected, either accidentally or with suicidal intent. One patient was excluded from our analysis as he was a child. These case reports are summarized in Table 2. Table 3 consolidates the cardiovascular effects of the ECs. As detailed, echocardiographic findings were of impaired myocardial relaxation, or diastolic function seen more in CC users compared with EC users. Hemodynamic findings in subjects consuming ECs were mainly of hypertension and tachycardia and hypokalemia consistent with the sympathomimetic effect of lower dose nicotine intoxication. Bradycardia was also seen, which can be associated with higher dose exposures. The cardiopulmonary arrest [22] was associated with a serum nicotine level well above that seen in the other cases, achieved with intravenous injection of EC liquid. Unfortunately detailed information regarding the study participants is not available as three out of the four trials were published only as conference abstracts.
Ref.
The current literature regarding the cardiovascular effects of electronic cigarettes
171
Review Nelluri, Murphy, Mookadam & Mookadam Table 2. Case reports involving adverse cardiovascular effects of electronic cigarette exposure. Study (year)
Patient
Eberlein et al. (2014) Monroy et al. (2012) Valento et al. 2013
Reason for exposure
Cardiovascular effects
Treatment
Outcome
Ref.
24-year-old male Ingestion 180 mg nicotine
Suicidal
Hypertension, tachycardia
Full recovery
[19]
70-year-old Inhalation, volume female unknown 22-year-old male Ingestion 30 ml of EC liquid (nicotine strength: 24 mg/ml) = 720 mg nicotine and dermal application of 30 ml of liquid 29-year-old male Intravenous injection unknown volume of EC liquid
Nicotine replacement Suicidal
Atrial fibrillation
Activated charcoal, supportive treatment Diltiazem, cessation of EC use Supportive therapy, skin decontamination
Full recovery Full recovery
[20]
Suicidal
Cardiopulmonary arrest (patient also had intractable seizures)
Therapeutic hypothermia, treatment of seizures
[22]
Christensen et al. 36-year-old (2013) female
Suicidal
Hypotension (103/69 mmHg)
Activated charcoal, supportive treatment
Death, attributed to anoxic brain injury Full recovery
Schipper et al. (2014)
Suicidal
Hypertension, tachycardia
Activated charcoal, supportive treatment
Full recovery
[24]
Thornton et al. (2013)
Method and volume of exposure
Ingestion 50 ml EC liquid (nicotine strength: 30 mg/ml) = 1500 mg nicotine 27-year-old male Ingestion of EC liquid containing 420 mg of nicotine
Bradycardia
[21]
[23]
EC: Electronic cigarette.
Furthermore, the composition of different EC aerosols differs between brands and so the risk may vary [12] . Acrolein is an oxidizing agent that has been linked with increased cardiovascular risk [25] . It has been found in analysis of the EC aerosol [12] . In addition propylene glycol is an ingredient used in the EC liquid. It is a known carcinogen [26] and also has been shown to have cardiovascular effects with vagal stimulation and efferent sympathetic inhibition [27] . It is not found in appreciable amounts in CCs and may represent an additional risk associated with the use of ECs that has not previously been identified in smokers of CCs. Effects of long-term exposure are unknown. Particulate matter in CCs and in air pollution has also been shown to have adverse cardiovascular effects. The American Heart Association advises increased risk with exposure to particles
The current literature regarding the cardiovascular effects of electronic cigarettes Bhargava Nelluri1, Katie Murphy2, Farouk Mookadam*,1 & Martina Mookadam3
Smoking is the leading cause of preventable morbidity and mortality globally. Electronic cigarettes are marketed both as nicotine substitutes and recreational devices. The popularity of electronic cigarettes has superseded other forms of nicotine replacement therapy. They are also popular in ‘never smokers.’ This review summarizes the available data regarding the cardiovascular effects of electronic cigarettes. The existing literature is limited and short term with a lack of high-quality studies and adequate follow-up. The available literature suggests that electronic cigarettes have sympathomimetic effects related to nicotine exposure, however, electronic cigarettes also contain other chemicals that require further investigation. Sparse data suggest vascular injury may be another concern. Further research is needed before broad recommendations can be made. First draft submitted: 29 September 2015; Accepted for publication: 26 November 2015; Published online: 26 February 2016 Background The 2014 Surgeon General Report attributes more than 20 million deaths in the USA between 1965 and 2014 to active and passive smoking [1] . Of these, approximately 8 million deaths are due to cardiovascular and metabolic diseases; 7 million deaths are due to cancers; 3.8 million deaths are due to pulmonary diseases, 108,000 deaths are due to perinatal conditions and 2.4 million deaths are due to secondhand smoke [1] . Approximately 70% of current adult smokers are interested in stopping smoking completely while 52% of smokers have tried to quit in the preceding year with only 6% achieving this successfully [2] . Various therapies are available to alleviate the withdrawal symptoms associated with nicotine withdrawal. Pharmacotherapy approved for smoking cessation includes bupropion and varenicline, which work by acting on norepinephrine, dopamine and neuronal acetyl choline receptors. Both of these have limitations because of side effects including tachycardia, nausea and weight gain [3] . The newest agent available for nicotine replacement therapy is the electronic cigarette (EC), invented by Hon Lik, a Chinese pharmacist, in 2004. In 2007, ECs entered the USA market [4] . ECs are now being used both as nicotine replacement therapy and as a recreational product. The basic mechanism involved in the EC is that of a battery, a heating chamber and the cigarette liquid. The heating of the coil is triggered by various mechanisms including puffing on the cigarette. The liquid is then inhaled as an aerosol [5] .
KEYWORDS
• coronary artery disease • E cigarette • electronic cigarette • heart • heart disease • myocardial function • vascular disease
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA 2 Department of Family Medicine, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA 3 Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA *Author for correspondence: Tel.: +1 480 301 6907; Fax: +1 480 301 8018; [email protected] 1
10.2217/fca.15.83 © 2016 Future Medicine Ltd
Future Cardiol. (2016) 12(2), 167–179
part of
ISSN 1479-6678
167
Review Nelluri, Murphy, Mookadam & Mookadam There are three generations of EC available. The first-generation devices resemble a conventional cigarette (CC). The second-generation devices are filled with liquid, the coils replaced and the power adjusted. Third-generation devices are more adaptable, for example, with adaptable voltage giving higher nicotine doses and potentially more sympathomimetic effects. The liquid can also have different flavors added. Some devices also come with software to monitor use [6] . Reports show that EC use has been increasing exponentially [7,8] . There was a notable increase in use among young previously nonsmokers [9] . The USA market for ECs was worth US$1.5 billion in 2014 and was estimated to be worth US$2 billion in 2015 by Wells Fargo [10] . While the hazards of smoking traditional cigarettes are widely known, the risks of ECs are not known. Furthermore, these products are not currently US FDA regulated, although the US FDA has the power to regulate them and has announced plans for regulation [11] . The composition of the EC fluid is not always clear and varies by brand. Some of the chemical compounds found in ECs are known carcinogens or have teratogenic potential. Others are known to be addictive [12,13] . Figure 1 shows a selection of these compounds [12] . The European Parliament has introduced rules governing the content and sale of ECs, which will take effect in May 2016. In addition, laws regarding advertising of tobacco products will also apply to ECs [14] . This review will specifically focus on the potential benefits and risks of ECs with regard to cardiovascular health. Methods PubMed, Embase, Medline, Cinahl and Cochrane collaboration electronic databases were searched from 1 January 2005 to 11 June 11 2015 to identify studies on the relationship between the ECs and cardiovascular risks using the search terms ‘heart disease,’ ‘coronary artery disease,’ ‘vascular disease,’ ‘electronic cigarettes,’ ‘e cigarettes.’ The search was repeated by a qualified librarian using the same search engines and criteria. We included articles involving adult humans, English language, published in the last 10 years. We included case reports, case series, reviews and meta-analyses. A flow sheet detailing our methods is given in Figure 2. We identified ten papers directly related to our topic. There were two major categories – randomized trials and case reports. We assessed
168
Future Cardiol. (2016) 12(2)
the quality of the trials (n = 4) with the Jadad criteria and found the quality to be suboptimal with scores of 0 or 1 (Supplementary Table 1) . Our results encompass the randomized trials and the case reports with a further discussion of the other papers to provide the most comprehensive overview of the available literature possible. Results We identified four randomized trials and six case reports that evaluated the cardiovascular effects of ECs. Although some of the trials also looked at respiratory signs, symptoms and parameters, we focused on the cardiovascular findings. A total of 210 patients were included in these articles. Farsalinos et al. in 2014 conducted a study with 76 subjects – 36 smokers and 40 EC users (using ECs for at least 1 month). The study used echocardiographic and hemodynamic parameters to evaluate the acute effects of traditional and ECs on myocardial function. The subjects had a baseline echocardiogram performed. All subjects then smoked a tobacco cigarette or used an EC for 7 min. All participants were then rested for 5 min and had a repeat echocardiogram performed. It was found that systolic blood pressure, heart rate and rate pressure product were elevated following the use of traditional cigarettes. This increase was not seen in those who used an EC.. In the CC group, systolic blood pressure increased 6.6 mmHg (±5.2; p < 0.001), heart rate increased 5.9 bpm (±4.7; p < 0.001) and rate pressure product increased by 1248 ± 840 (p < 0.001). Diastolic blood pressure increased in both groups after smoking without a statistically significant difference (3.0 ± 3.6 in EC group; 4.4 ± 3.3 in CC group). With regard to echocardiographic parameters, Doppler echocardiography showed a significant increase in isovolumetric relaxation time (IVRT) (IVRTc: corrected for heart rate) in the group consuming CCs compared with the EC group (10.4 ± 10.1 ms EC; -1.2 ± 6.9 ms CC; p < 0.001). IVRT also showed a significant increase in the CC group compared with the EC group (5.6 ± 9.2 ms CC group; -1.0 ± 5.7 ms EC group; p = 0.001), myocardial performance index increased in the CC group compared with the EC group, however, the change was not significant in the EC group (0.03 ± 0.04 CC group; p = 0.02; -0.01 ± 0.04 in EC group; p = 0.330; p-value for difference = 0.001).
future science group
The current literature regarding the cardiovascular effects of electronic cigarettes
Review
Nicotine
Volatile organic compounds
Aldehydes • Formaldehyde • Acetaldehyde • Acrolein • o-methyl benzaldehyde • Acetone
• Toluene p, m-xylene • Propylene glycol • Glycerin • 3-methylbutyl-3methylbutanoate
Chemical evaluation of electronic cigarettes
Polycyclic aromatic hydrocarbons
Tobacco specific nitrosamines • N-nitrosonornicotine • 4-(N-nitrosomethylamino) -1-(3-pyridyl)-1-butanone • N-nitrosoanatabine • N-nitrosoanabasine
• Anthracene • Phenanthrene • 1-methyl phenanthrene • Pyrene
Tobacco alkaloids
Metals
• Cotinine • Myosmine • Anatabine • Anabasine • β-nicotyrine • Nornicotine
• Cadmium • Nickel • Lead • Chromium • Arsenic
Figure 1. Chemical compounds found in electronic cigarettes. Data taken from [12].
Doppler tissue measurements showed a significant reduction in early diastolic peak velocity of the mitral valve (E velocity) in the CC group compared with the EC group (-0.7 ± 1.4 cm/s CC group; 0.2 ± 0.7 cm/s EC group; p < 0.001). In addition, there was a significant decrease in the ratio of early to late annular mitral velocity (-0.08 ± 0.13 CC group; -0.01 ± 0.13 EC group; p = 0.011) and increase in myocardial performance index utilizing pulsed-wave tissue Doppler (0.03 ± 0.05 CC group; -0.01 ± 0.04 EC
future science group
group; p < 0.001). Regarding longitudinal deformation measurements, early diastolic strain rate (SRe) was significantly reduced in CC compared with EC (-0.08 ± 0.12 CC group; 0.01 ± 0.08 EC group; p < 0.001). In essence, these findings show impaired diastolic function in the patients smoking CCs compared with EC use, suggesting an impairment in myocardial relaxation not seen in patients using ECs [15] . In 2013, Battista et al. conducted a study with 12 EC smokers to examine the acute
www.futuremedicine.com
169
Review Nelluri, Murphy, Mookadam & Mookadam hemodynamic effects of ECs. Subjects included in the study smoked their own favored brand of ECs, which varied in nicotine strength between 4 and 9 mg/ml. Blood pressure, heart rate and oxygen saturation levels were measured at rest, 2 min, and 4 min post-EC smoking while echocardiographic measurements (cardiac output and systemic vascular resistance) were performed in parallel. The results showed an increase in cardiac output, diastolic blood pressure and mean arterial pressure after 4 min of EC smoking compared with baseline. Systemic vascular resistance decreased after 2 and 4 min of EC smoking. No changes were noted in oxygen saturation levels. Unfortunately the exact measurements were not available for review, nor were details of statistical significance [16] . Vakali et al. in 2013 conducted a study with 53 participants to determine the effects of the usage of a single EC on symptoms, vital signs Records identified in PubMed (n = 7)
Records identified in Ovid EMBASE (n = 64)
Records identified in Ovid MEDLINE (n = 5)
Records identified in Cochrane (n = 1)
and indices of airway inflammation. Participants were divided into two groups. There were two ECs used. The first had a nicotine strength of 11 mg. The second was a placebo with a strength of 0 mg. Group A consisted of ten nonsmokers and 24 healthy smokers. Each subject smoked a single EC (nicotine strength: 11 mg) for a period of 10 min. Group B consisted of 11 nonsmokers and nine healthy smokers. Each subject in this group smoked a single EC (nicotine strength: 0 mg) for 10 min. It was found that increased heart rate and palpitations were related to the use of ECs [17] . Tsikrika et al. in 2013 conducted a study with 62 participants to determine the effects of ECs on symptoms, vital signs including heart rate and exhaled carbon monoxide. The participants included 52 CC smokers and ten nonsmokers. Of the smokers, 16 suffered from chronic obstructive pulmonary disease (COPD) and 12 Records identified in CINAHL (n = 1)
Total records identified (n = 78)
Records excluded as duplicates (n = 19)
Total records after screening for duplicates (n = 59)
Records assessed for relevance to topic of discussion (n = 59)
Records excluded as irrelevant (n = 49)
Records that were relevant and directly related to topic (n = 10)
Figure 2. Study selection strategy.
170
Future Cardiol. (2016) 12(2)
future science group
future science group
[18]
12
64
62
Battista et al. (2013)
Vakali et al. (2013)
Tsikrika et al. (2013)
www.futuremedicine.com
BP: Blood pressure; CC: Conventional cigarette; CO: Cardiac output; EC: Electronic cigarette; HR: Heart rate; SVR: Systemic vascular resistance.
Overall increase in HR and palpitations, more seen in smokers
[17]
Increased HR and palpitations reported more frequently in users of EC as compared with placebo
Group A: 12 nonsmokers, 29 healthy smokers smoked for 10 min a single 11-mg EC. Group B: 14 nonsmokers and 9 healthy smokers smoked a single 0-mg. Both groups used same brand of EC Participants smoked an EC (strength: 11 mg) for 10 min
[16]
Increased CO and decreased SVR were noted after 2 and 4 min. Diastolic BP and mean arterial pressure increased after 4 min of EC smoking
[15]
Impaired myocardial relaxation and diastolic function in CC smokers compared with EC users
Baseline echocardiogram carried out, followed by use of conventional tobacco cigarette or EC for 7 min. Participants then rested for 5 min and had a repeat echocardiogram carried out Cardiovascular parameters were measured at rest, 2 min and 4 min during use of an EC
Review
Comparison of CC Hemodynamic measurements, smokers with users of ECs echocardiographic including 2D echocardiographic measurements, Doppler flow, tissue Doppler, longitudinal deformation measurements Evaluation of changes BP, HR, SVR, CO in hemodynamic and echocardiographic parameters following use of ECs. All volunteers were users of ECs Effect of single-EC use on symptoms, vital signs and airway inflammatory markers after inhaling either 0 mg or 11 mg of nicotine Participants included Changes in vital signs, clinical both nonsmokers and symptoms and exhaled carbon smokers. Effects of a monoxide were measured. single EC were evaluated Farsalinos et al. 76 (2014)
Cardiovascular effects reported Methods Parameters measured Study design
The majority of the available research regarding the cardiovascular toxicity of electronic cigarettes has focused on the effect of nicotine; however, there are multiple other components of EC liquid that may have adverse cardiovascular effects. There is also variation in the chemical composition of different brands. A review of multiple analyses by Cheng in 2014 found multiple compounds that have been identified in EC aerosols, including aldehydes, metals, volatile organic compounds and tobacco specific nitrosamines. Figure 1 details the compounds found. While some of these compounds, such as acrolein and formaldehyde, are found in CCs, some compounds are unique to ECs and long-term toxicity data are unavailable.
No. of subjects
●●Chemical evaluation of ECs
Study (year)
Other data evaluated
Table 1. Summary of clinical trials evaluating cardiovascular effects of electronic cigarettes.
from asthma. The remaining 24 smokers were free from airway diseases. Participants smoked a single EC (nicotine strength: 11 mg) for a period of 10 min. A significant increase in heart rate and palpitations following use of the EC was noted, with a greater increase noted in smokers [18] . Table 1 summarizes the studies that we evaluated. We identified six case reports involving seven patients where adverse cardiovascular effects of ECs were described. Only one of the cases involved the intended use of ECs. In the remaining cases the cigarette or EC liquid was used improperly, as it was ingested or injected, either accidentally or with suicidal intent. One patient was excluded from our analysis as he was a child. These case reports are summarized in Table 2. Table 3 consolidates the cardiovascular effects of the ECs. As detailed, echocardiographic findings were of impaired myocardial relaxation, or diastolic function seen more in CC users compared with EC users. Hemodynamic findings in subjects consuming ECs were mainly of hypertension and tachycardia and hypokalemia consistent with the sympathomimetic effect of lower dose nicotine intoxication. Bradycardia was also seen, which can be associated with higher dose exposures. The cardiopulmonary arrest [22] was associated with a serum nicotine level well above that seen in the other cases, achieved with intravenous injection of EC liquid. Unfortunately detailed information regarding the study participants is not available as three out of the four trials were published only as conference abstracts.
Ref.
The current literature regarding the cardiovascular effects of electronic cigarettes
171
Review Nelluri, Murphy, Mookadam & Mookadam Table 2. Case reports involving adverse cardiovascular effects of electronic cigarette exposure. Study (year)
Patient
Eberlein et al. (2014) Monroy et al. (2012) Valento et al. 2013
Reason for exposure
Cardiovascular effects
Treatment
Outcome
Ref.
24-year-old male Ingestion 180 mg nicotine
Suicidal
Hypertension, tachycardia
Full recovery
[19]
70-year-old Inhalation, volume female unknown 22-year-old male Ingestion 30 ml of EC liquid (nicotine strength: 24 mg/ml) = 720 mg nicotine and dermal application of 30 ml of liquid 29-year-old male Intravenous injection unknown volume of EC liquid
Nicotine replacement Suicidal
Atrial fibrillation
Activated charcoal, supportive treatment Diltiazem, cessation of EC use Supportive therapy, skin decontamination
Full recovery Full recovery
[20]
Suicidal
Cardiopulmonary arrest (patient also had intractable seizures)
Therapeutic hypothermia, treatment of seizures
[22]
Christensen et al. 36-year-old (2013) female
Suicidal
Hypotension (103/69 mmHg)
Activated charcoal, supportive treatment
Death, attributed to anoxic brain injury Full recovery
Schipper et al. (2014)
Suicidal
Hypertension, tachycardia
Activated charcoal, supportive treatment
Full recovery
[24]
Thornton et al. (2013)
Method and volume of exposure
Ingestion 50 ml EC liquid (nicotine strength: 30 mg/ml) = 1500 mg nicotine 27-year-old male Ingestion of EC liquid containing 420 mg of nicotine
Bradycardia
[21]
[23]
EC: Electronic cigarette.
Furthermore, the composition of different EC aerosols differs between brands and so the risk may vary [12] . Acrolein is an oxidizing agent that has been linked with increased cardiovascular risk [25] . It has been found in analysis of the EC aerosol [12] . In addition propylene glycol is an ingredient used in the EC liquid. It is a known carcinogen [26] and also has been shown to have cardiovascular effects with vagal stimulation and efferent sympathetic inhibition [27] . It is not found in appreciable amounts in CCs and may represent an additional risk associated with the use of ECs that has not previously been identified in smokers of CCs. Effects of long-term exposure are unknown. Particulate matter in CCs and in air pollution has also been shown to have adverse cardiovascular effects. The American Heart Association advises increased risk with exposure to particles
