A R T I C L E  I N F O		ABSTRACT
REVIEW ARTICLE		Introduction: Extreme weather or climate, including heat waves and cold waves, is considered a health issue causing adverse effects on health, such as cardiovascular diseases (CVDs), mortality and morbidity. Thus, this systematic review aimed to study the impacts of extreme ambient temperature on cardiovascular outcomes. Material and Methods: This study was carried out based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. Papers about the ambient temperature and cardiovascular outcomes were searched in the scientific database, including ISI, PubMed, Scopus, and Google Scholar, from January 1970 up to the end of 2020. We used the key terms, such as “heat wave”, “cold wave”, “extreme event”, “cardiovascular disease”, “mortality”, and “morbidity”. The thematic analysis method was used to determine all themes and analyze the data. Results: Among the 7631 searched and extracted papers, 20 articles met the eligibility criteria for including the process of final analysis. Effects of extreme events included mortality, morbidity, and hospitalization due to CVD. A relationship between extreme events and CVD mortality was confirmed for cerebrovascular diseases, including congestive heart failure (CHF), ischemic heart diseases (IHD), myocardial infarction (MI), cardiac arrhythmia, coronary heart disease (CHD), out-of-hospital cardiac arrest (OHCA), acute coronary syndrome (ACS), and blood pressure. Conclusion: The present study indicated the impact of extreme ambient temperature on CVD outcomes. The findings provided adaptation and preventive measures and strategies which can be used for CVD patients and managers to prevent CVD due to ambient temperature.
Article History: Received: 14 August 2021 Accepted: 20 October 2021
*Corresponding Author: Mohsen Dowlati Email: dowlati.m@iums.ac.ir Tel: +982188797301
Keywords: Temperature, Heat Wave, Cold Wave, Cardiovascular Disease.

Introduction
Extreme weather or extreme climate, including heat waves and cold waves, related to excessive extreme temperatures in cold and warm season, is expected to impact health, such as increased cardiovascular diseases (CVDs), mortality, and morbidity ^{1, 2}. CVD sharing the characteristics of acute attack and hard recovery, has become an main health issue³. CVDs are a group of diseases that include both the heart and blood vessels⁴. CVDs are one of the main causes of global mortality. According to estimation of World Health Organization (WHO), more than 17.9 million people die from cardiovascular, annually⁵. CVDs cause adverse economic effects, such as disability, affect the productivity of active labor force, and result in reduced gross domestic product (GDP) and national income⁶. One of the main factors of CVD is exposure to extreme events, such as cold and heat waves. Both cold and heat temperatures are related to increased death due to CVDs.  In addition, insignificant excess hospital emergency admissions due to CVDs are considered on both heat and cold waves⁷. Based on the latest measurement of CVD mortality rate vs. GDP per capita, 2017, CVD mortality rate is measured as the number of deaths per 100,000 individuals versus GDP per capita⁸.
The relation between heat wave and hospitalization is urgent and of short-term period, whereas that of cold waves is postponed but would last longer. Extreme ambient temperature events, especially heat waves, have been proved as the most hazardous of all environmental hazards and claim the largest numbers of patients⁷. The World Meteorological Organization (WMO) described heat wave as the daily maximum temperature that is higher than 32 °C and period of more than 3 days⁹. Exposure to heat waves composed with physical exertion can at the same time effect in systems of sympathetic and parasympathetic, increasing the possibility of atrial fibrillation¹⁰. Dehydration, raised hypotension and even endothelial cell damage, blood viscosity, and a higher possibility of thromboembolic diseases are the major pathophysiological mechanisms of the heat impacts on health ¹¹. Moreover, heat waves may impair the endothelial function, enhancing the risk for cardiovascular events¹².
Cold waves can affect CVD stress due to blood pressure, vasoconstriction, rising  in blood viscosity and count of red blood cell, plasma fibrinogen and cholesterol¹³. Cold stress is associated with increased blood pressure and platelet aggregation; raised vasoconstriction; increased blood viscosity and count of red blood cell, plasma fibrinogen and cholesterol; and higher hem concentration, all of which could causes thrombosis⁷. Numerous researches have proven extreme ambient temperature to be related to raise CVD mortality and morbidity. Several research studies have confirmed the effect of extreme events, such as cold and heat waves on cardiovascular mortality^14-16. All of studies have evaluated the raised risk of CVD outcomes under various conditions, such as duration and intensity¹⁶. Vulnerable group, including elderly people, women, and outdoor employees are at higher risk than the other groups. Harmful impacts of heat waves among the older people and women are more severe than younger people and males¹⁶. The present systematic review aimed to study the effects of ambient temperature (heat and cold waves) on CVD outcomes, such as mortality, morbidity, and hospitalization.
Materials and Methods
In this research, the systematic review of papers related to ambient temperature and CVD was conducted based on the PRISMA guidelines¹⁷.
Strategy of search and data sources
Strategy of search was conducted based on the Cochrane protocol¹⁸. The key terms were firstly selected by authors based on the Medical Subject Headings (MeSH). Then, the syntax of search strategy was designed in partnership with an academic librarian expert. The scientific international databases included ISI, PubMed, Cochrane Library, and Scopus, within the period of Jan 1^st, 1970 to Dec 31^st, 2020. Furthermore, the gray literature was searched through the Open Grey online database and Google Scholar. As well as, the reference lists of the retrieved papers were checked to identify any further studies. Finally, the EndNote was used to screen and control the whole searched paper followed by the removal of duplicate and irrelevant papers.
Syntax of search strategy was as follows: ("Heat Wave" OR "Cold Wave" OR “Extreme Event" OR "Ambient temperature" OR "Cold Temperature”, “Hot temperature" OR” climate change” AND "cardiovascular disease" OR “Heart Diseases” OR "Cardiovascular Infections" OR "Cardiovascular Abnormalities” OR "acute coronary syndrome" OR "acute myocardial infarction" OR "coronary event" OR "heart attack" OR "heart failure" OR "hospital admissions" ''congestive heart failure'' OR ``heart infarct*” OR hospitalization)
Criteria for Eligibility
In this research, the papers were selected and remained based on the criteria as follows:
1) The papers apparently addressing the ambient temperature and CVD.
2) Full texts of papers are available freely.
3) The papers published in English language.
4) The studies that included in all types of methodologies published in peer-reviewed journals.
5) The papers encompassing all types of CVD associated in ambient temperature.
The exclusion criteria were as follows:
1) The books, letters to the editor, editorials, clinical studies, abstracts, conference papers, presentations, theses, and commentaries.
2) The studies with irrelevant subjects and duplicate data.
3) The studies with ambiguous methodology or without results.
4) The studies including the association between ambient temperature with other diseases, such as respiratory or renal.
Study selection
Initially, duplicate studies were removed using the EndNote software. Remaining studies were assessed based on titles and abstracts and some irrelevant articles were removed. In the next step, two authors assessed the full texts of the retrieved studies critically based on eligibility criteria, independently. Then, the results of assessment were compared and in the case of any disagreement, they were resolved through consensuses. In case of any disagreement of opinions between the two previous authors, a third author was requested independently for final decision.
Data extraction
The determined information was extracted from the selected final studies using standard data extraction form.     The collected data included 1) first author name 2) publication year 3) tittle 4) location 5) purpose of study 6) study design 7) exposure (heat wave/cold wave) 8) types of CVD 9) outcome 10) key results of articles along with the corresponding standard deviations were exploited from the selected studies.
Quality assessment and risk of bias
Assessment of quality for the final studies was conducted to separate low-quality articles from others and to avoid risk of bias. Given that the low-quality studies were of high level of bias, they were all removed from this study.  Quality assessment or risk of bias for all of the assessed full texts of articles was independently and critically performed by two authors through the critical appraisal skills program (CASP) ¹⁹, the strengthening the reporting of observational studies in epidemiology (STROBE) tools²⁰, and checklists.
Ethical Issue
This research was completed in accordance
with the ethical principles of, and was approved by, the research ethics committee of Iran University of Medical Sciences (IR.IUMS.REC. 1397.1376).
Results
A total of 7631 studies were found from the scientific databases and 8 articles were identified from other sources. Firstly, 2378 papers were removed using the EndNote because of duplication. Then, 5253 papers were assessed based on titles and abstracts for eligibility and 5127 papers were excluded. Then, full texts of the 126 remained papers were reviewed. Finally, 20 papers met the eligibility criteria for including the process of systematic review after considering type of articles and quality assessment as shown in Table 1. This table reveals first author name, publication year, tittle, location, aim of study, study design, exposure (heat wave/cold wave), types of CVD, outcome and key results of articles. Figure 1 demonstrates PRISMA flowchart encompassing study identification and selection process. PRISMA primarily focuses on review reports evaluating the study selection process. This process includes number of records identified through searching databases and additional documents searched through other database, records removed after duplicates, records screened, full-text papers reviewed for eligibility, full-text papers excluded with causes, and final studies included in article.

 

Key results	Period	Outcome	Location	Exposure (heat wave/cold wave)	Study methods and design	Year	First author	Reference Number
Cold waves may be a main factor in bringing on the onset of CVD, even in mild winters region. Public health measures highlighting cold exposure while out of homes may play an main role in encouraging the decrease of cold stress, especially among elderly and those already at higher risk of CVD.	1980–2001	cardiac mortality	USA	Cold wave	Cross sectional	2005	A. CAGLE	[14]
Ambient temperature is a main factor of AMI death even in the mild weather of a Mediterranean region, its effects being predominantly evident in the older people.	2001	MI	Greece	Heat and cold	Cross sectional	2006	Dilaveris	[30]
A direct relationship between the daily temperature range and ACS admissions was highlighted.	2000-2003	acute coronary syndrome	Taiwan	Heat and cold	Longitudinal study	2008	Liang	[48]
Relationship between heat waves with increases in short-term risk of CVD mortality was confirmed. But relationship between cold waves with increased risk of CVD was not found.	1984-1993	Congestive Heart Failure	Canada	Heat and cold	Case-crossover design	2010	Stefanie Kolb	[48]
Heat waves higher of 20°C was related to increased risk of MI after 1-6 hours exposure.	2003-09	MI	England and Wales	Heat	Case-crossover study	2012	Krishnan Bhaskaran	[31]
Cold waves have no effect on acute MI.	2003-2007	MI	Portugal	Cold wave	Poisson regression	2013	Vasconcelos	[33]
Mortality due to IHD is associated to heat waves. But heat wave no effect on hospital admissions due to IHD.	2001–2010	Ischemic heart diseases	Germany	Heat waves	Time series	2014	Stefan Zacharias	[27]
Heat waves is associated to CVD mortality in Cyprus. Therefore, proper interventions should be developed.	2004-2010	Cardiovascular mortality	Cyprus	Heat wave	Non-linear model	2015	Lubczyńska	[15]
Mortality due to CVD is associated to higher blood pressure.	2004-2008	Blood pressure	China	cold	Cross sectional	2015	LingYang	[54]
Heat and cold waves are related to high risk of OHCA in China.	2008-2012	Out-of-hospital cardiac Arrest	China	Heat and cold	Time-series	2016	Yue Niu	[45]
Cold and heat waves and higher DTR are associated to arrhythmia exacerbations. Thus, proper measures should be performed with aim of risk reduction for vulnerable groups to reduce cold waves exposure.	2008-2011	Cardiac arrhythmias	South Korea	Heat and cold	Cross sectional	2016	Jayeun Kim	[37]
Heat and cold waves were effects on the blood pressure.	2006-2011	Blood pressure	China	Heat and cold	Regression model	2016	Lina Madaniyazi	[52]
Heat wave is associated to mortality due to CVD in Beijing, China.	2010- 2012	Cardiovascular disease mortality	China	Heat wave	A generalized additive model (GAM)	2017	Qian Yin	[16]
Heat and cold waves are associated to increasing of hospitalization due to AMI.	1960–1989	Acute MI hospitalizations	USA	Extreme heat events	Case-crossover	2017	Fisher	[35]
Heat and cold wave have direct relationship with hospitalization due to heart failure in Hong Kong.	2002- 2011	HF	Hong Kong	Heat and cold	Time-series	2017	Goggins	[23]
Heat and cold waves are associated to increasing of hospitalization due to AMI in Ontario.	1996- 2013	Coronary heart disease	Canada	Heat and cold	Cross sectional	2017	Li Bai	[41]
Heat and cold waves have direct relationship with increasing risk of ACS hospital admission in Rasht, Iran.	2005 -2014	ACS	Iran	Heat and cold	Time-series	2018	Moghadamnia	[49]
Heat and cold waves have direct association to higher blood pressure. Thus, appropriate protective measures should be conducted during cold wave especially.	2013-2016	Blood pressure	China	Heat and cold	Lag nonlinear model	2019	Dandan Xua	[53]
Heat and cold and AMI have direct relationship in Vietnam.	2008–2015	Hospital admissions for acute MI	Vietnam	Heat and cold	Time-series	2019	Thu Dang	[34]
Heat and cold are associated to hospitalization due to cardiac arrhythmia in Brazil.	2000–2015	Cardiac arrhythmia	Brazil	Heat and cold	Case-crossover	2019	Qi Zhao	[38]

Discussion
The purpose of present study was to systematic review and summarize key findings related to the impact of extreme events on cardiovascular outcomes, including mortality, CVD, and hospitalization attributed to CVD. The systematic review of the 20 included publications demonstrated that extreme events play a significant role in the cardiovascular outcomes. Several studies have proved increased risk of cardiovascular outcomes, such as mortality, CVD, and hospitalization. An association between extreme events and CVD mortality was observed for cerebrovascular diseases, congestive heart failure, ischemic heart disease, myocardial infarction, cardiac arrhythmia, coronary heart disease, out-of-hospital cardiac arrest, acute coronary syndrome, and blood pressure. (Figure 2)
Congestive Heart Failure
A syndrome in which the heart is not able to pump blood sufficiently named Heart failure (HF) that causes MI and hypertension²¹. CHF is a disease that results in pulmonary vascular congestion and decreased heart output. CHF is a chronic status that the pumping power of cardiac muscle is affected²². One of the risk factors of CHF is weather, especially heat wave. Many papers have studied relation between extreme temperature events and morbidity, mortality, and hospitalizations raise during heat and cold waves²³. Based on some studies, the mortality rate due to CHF increased significantly at ambient high temperature^{24, 25}.
Ischemic Heart Disease (IHD)
The inadequate condition of oxygen within the heart muscles due to an imbalance between oxygen supply and demand, named IHD. This illness determined by reduced blood supply to the cardiac muscle. This event results from the obstruction in coronary arteries by atherosclerosis and thrombus²⁶. Many research studies have shown the impact of heat wave on death due to IHD. Intensity and duration of heat waves feature stronger influences on IHD deaths. The period of heat waves has main effects on mortality. Heat waves with a period of three days shown an average IHD mortality raise of about 10%, days during longer heat waves are related to higher death rate of up
to 19%.²⁷
Myocardial infarction
MI, or heart attack, is due to an atherosclerotic plaque rupture, leading to partial or complete thrombotic vessel occlusion²⁸. Acute MI is one of the leading reasons of death worldwide. An MI causes impairment in diastolic and systolic function, making the patient prone to arrhythmias²⁹. Ambient temperature is a major risk factor of AMI mortality³⁰. Heat waves with temperature of above a threshold of 20°C to be related to an raised risk of MI 1-6 hours after exposure³¹. In cold weather the blood pressure decreases in the peripheral parts of the body. It increases viscosity and concentration of blood which may leading to higher clotting and, so, a greater rate of thrombosis³². Negative effects of cold wave on acute MI have been demonstrated in some studies³³. Furthermore, some studies have shown that exposure to extremely high and extremely low temperature increases the rate of hospitalization due to AMI. Risks of heat waves may be different in population subgroups^{34, 35}.
Cardiac arrhythmia
Cardiac arrhythmia is considered a major
risk factor for mortality due to CVDs, especially
in the older people, in whom disorder
heart function may aggravate pre-existing abnormalities. ³⁶. 
Cardiac arrhythmias, including atrial fibrillation and flutter, are one of the types of CVDs in which the heartbeat is abnormal, very rapid, or slow. Some arrhythmias have no symptoms, and their particular reason may sometimes be unknown³⁷. Based on recent evidence, acute exposure to heat and cold raise the possibility of cardiac arrhythmia, which is mainly due to paroxysmal tachycardia and other cardiac arrhythmias³⁸. Also, emergency department (ED) visits due to arrhythmia is strongly related extreme ambient temperature. Arrhythmia-related emergency department visits decrease during fall and winter³⁷.
Coronary heart disease
CHD is one of the types of CVD that creates when the arteries of the cardiac cannot transfer sufficient oxygen-rich blood to the cardiac. CHD is developed by the buildup of plaque, a waxy substance, inside the lining of larger coronary arteries. This buildup can partially or totally block blood flow in the large arteries of the cardiac^{39, 40}. Risks of CHD hospitalizations with both heat and cold waves were investigated and confirmed⁴¹. Also, there are limited epidemiological studies quantifying the ambient temperature-related burden of CVD death, especially CHD⁴².
Out-of-hospital cardiac arrest
OHCA is considered an important global human health challenge. The loss of mechanical heart function and the absence of systemic circulation are described as OHCA ⁴³. Cessation of cardiac mechanical activity that occurs outside of the hospital is named OHCA and is approved by the absence of symptom of circulation⁴⁴.The potential effects of seasonal variation and ambient temperature on OHCA were investigated⁴⁵. Some studies have shown that both clod and heat
waves were significantly related to raised
hospital emergency admission and death due to OHCA⁴⁵.
Acute coronary syndrome
ACS is one of the types CVD and leading numerous mortalities globally. ACS often shown a level of destruction to the coronary arteries by atherosclerosis; plaque rupture, thrombosis, and inflammation^{46, 47}. There was a significant seasonal fluctuation in the rate of ACS, and extreme ambient temperature may affect the onset of ACS⁴⁸. Ambient temperature range associated significantly with daily emergency hospitalization due to ACS ^{48, 49}. Diurnal ambient temperature fell below 17.0°C or the diurnal temperature range exceeded a threshold of 5.8°C. The risk level of ACS was higher than baseline data⁴⁸.
Blood Pressure
Hypertension or blood pressure is one of the most important risk factors for CVD and is a one of the main causes of precocious death globally. Blood pressure is a crucial medical status that significantly raises the risks of heart, brain, kidney, and other illness. Based on the estimation of the WHO 1.13 billion people worldwide have hypertension⁵⁰. Cold wave leading to vasoconstriction and tachycardia, both of which contribute to raised blood pressure and heart load⁵¹. Several studies have confirmed that blood pressure changes with temperature and extreme ambient temperature imparts a very short-term impact on blood pressure^52-54.

Figure 2: Cardiovascular outcomes due to extreme ambient temperature

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