Air pollution from lung to heart

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Peer reviewed article




                     Air pollution: from lung to heart
                     Nino Künzlia, Ira B. Tagerb
                     a
                         Department of Preventive Medicine, Keck School of Medicine, University of Southern California,
                         Los Angeles, CA
                     b
                         Division of Epidemiology, School of Public Health, University of California, Berkeley, CA




                     Summary
                         Epidemiological, clinical, and experimental          cumulated exposure include adverse effects on
                     evidence correlates current levels of ambient air        lung growth, chronic bronchitis, lung cancer, and
                     pollution with both respiratory and cardiovascular       probably the development of asthma and athe-
                     effects. Oxidative stress, inflammation, induction       rosclerosis. These morbidities ultimately lead to
                     of a pro-coagulatory state and dysfunction of the        shorter life expectancy. Host factors including
                     autonomic nervous system appear to play a major          genotype are important modifiers of the effects of
                     role. Acute effects include changes in lung func-        air pollution. Further research will help identify
                     tion, heart rate, blood pressure and inflammatory        susceptible subgroups and disentangle specific
                     state, and clinical measures such as respiratory         effects and mechanisms associated with various
                     symptoms, thrombosis, myocardial infarction,             constituents and sources of air pollution.
                     arrhythmia, stroke, and death. In addition, there
                     is an increase in the use of health care resources       Key words: particulate matter; ozone; environmental
                     due to these effects. Long-term consequences of          health




                     Introduction
                          Extreme air pollution events such as the his-       review articles and restrict references to single
                     toric London fog in 1952 made it clear that both         studies, to recently published studies or to those
                     the lung and the heart can be affected by high lev-      with a high impact. The distinction between acute
                     els of ambient air pollution. A large body of epi-       and long-term effects is important both from a
                     demiological, clinical and toxicological data have       biologic and public health perspective. We define
                     accumulated indicating that cardiovascular and           acute effects of air pollution as all those that occur
                     respiratory physiological processes and health are       within one or a few days of exposure, sub-acute ef-
                     adversely affected by air pollutants despite the im-     fects as those that occur within several weeks, and
                     proved air quality since the 1950s [1]. In this re-      long-term effects are the consequences of sub-
                     view, we summarise the effects of acute and long-        clinical effects on chronic processes that ultimately
                     term exposure on both organ systems, emphasis-           lead to manifest morbidity and/or death. Effects
                     ing the effects of long-term exposure on cardiovas-      of air pollution on reproductive health are not
                     cular health. We refer primarily to other related        addressed herein.




                     Effects of acute air pollution exposure
                          A large number of studies have investigated         inal European APHEA project (Air Pollution and
                     whether daily changes in air quality are followed        Health: A European Approach) or the U.S. coun-
                     by acute changes in the health state of children and     terpart NMMAPS (National Mortality and Mor-
                     adults. Outcomes of various levels of severity have      bidity Air Pollution Study) are particularly rele-
 N. Künzli is sup-   been investigated that range from sub-clinical           vant [3, 4]. Small but significant increases in the
 ported by NIEHS     functional changes to symptoms, impaired activi-         daily total, respiratory, and/or cardiovascular mor-
 (P30 ES07048 and
 5P01ES 11627)       ties (eg school absences), doctors’ or emergency         bidity and mortality have been observed in asso-
 and the Hastings    room visits, hospitalisations and death [1, 2] (see      ciation with the fluctuations of daily pollution. As
 Foundation.
                     table 1). Large multi-city projects such as the sem-     a rule of thumb, the acute increment of death per
Air pollution: from lung to heart                                                                                                                 698

Table 1                    Lung                                                      Heart / vasculatur
List of respiratory        Physiologic & structural changes
and cardiovascular            Forced expiratory volume and flows                     Heart rate (2)
physiologic, struc-
                              Inflammatory mediators (local and systemic)            Heart rate variability (4)
tural, and clinical
outcomes reported
                              Air way remodelling                                    Blood pressure
to be associated with                                                                Blood coagulation factors
exposure to ambient                                                                  Vascular reactivity
air pollution                                                                        Inflammatory mediators
(? means evidence                                                                    Vessel structure
is sparse).
                           Acute clinical measures of effect
                              Upper respiratory symptoms                             Thrombosis
                              Lower respiratory symptoms                             Myocardial infarction
                              Acute exacerbations of chronic bronchitis, asthma      Arrhythmia
                              Asthma medication use                                  Stroke
                              Death                                                  Death
                              School / work absences                                 Use of health care resources due to all of the above
                              Use of health care resources due to all of the above
                           Cumulative clinical effects
                              Reduced lung growth                                    Reduced life expectancy
                              Reduced small airway function                          (premature cardiovascular death)
                              Chronic bronchitis                                     ? Atherosclerosis
                              Lung cancer
                              Reduced life expectancy
                              ? Asthma onset


                           10 mg/m3 increase in the daily levels of ambient                       correlated with higher hospital admissions and
                           particulate matter is approximately 0.5%, whereas                      emergency room visits due to respiratory and car-
                           inclusion of sub-acute effects leads to estimates                      diovascular events, including myocardial infarc-
                           three to four times larger. Particles have most often                  tion, arrhythmias, and stroke [6]. Increased blood
                           been used to characterise pollution, but gaseous                       viscosity and blood pressure, decreased heart rate
                           pollutants almost certainly contribute to the risks.                   variability (HRV) and changes in the repolarisa-
                           In fact, recent reviews have concluded that ambi-                      tion patterns have all been shown to correlate with
                           ent ozone at levels usually observed during sum-                       pollution. Moreover, discharges of implanted car-
                           mer periods are associated with higher death rates,                    dioverter-defibrillators (evidence of ventricular
                           that are not explained by other pollutants or tem-                     tachycardia and/or fibrillation) increase in an ex-
                           perature [5].                                                          posure-response manner with the daily level of
                               Increases in daily levels of air pollution are also                ambient particulate matter [6].




                           Biologic mechanisms
                                Causality is supported by an increasing, albeit                   inflammation with alterations in the vascular sys-
                           fragmentary, body of research that addresses bio-                      tem. Moreover, inflammation itself is a potent
                           logic mechanisms of the observed effects [6, 7]. Ev-                   source of oxidant stress which leads to DNA dam-
                           idence is strongest for (interrelated) pathways of                     age.
                           action – namely, oxidative stress and inflammation,                         Autonomic function: Activation of pulmonary
                           induction of a pro-coagulatory state, dysfunction                      neural reflexes due to interactions between pollu-
                           of the autonomic nervous system, and ischaemic                         tants and lung receptors may initiate changes in the
                           responses in the myocardium [2, 6]. The observa-                       autonomic function and partly explain the ob-
                           tion of ambient particulate matter in the heart                        served cardiovascular effects. Studies show a rather
                           muscle cells and the brain may also suggest diffu-                     immediate decrease in heart rate variability (HRV)
                           sion of particles which may lead to direct toxic ef-                   after exposure to ambient particles, and the de-
                           fects. In fact, studies with artificial ultrafine parti-               creased parasympathetic input may explain the
                           cles had demonstrated direct penetration into the                      increase in arrhythmias and cardiovascular mortal-
                           blood stream [2].                                                      ity associated with ambient pollution [6].
                                Oxidative stress and inflammation: High con-                           A recent panel study conducted among elderly
                           centrations of oxidants and pro-oxidants contained                     highlights the complexity of interrelated mecha-
                           in ambient air pollution, such as particulate com-                     nisms [8]. As shown before, Schwartz et al. ob-
                           ponents of various sizes and compositions (eg ul-                      served a decrease in HRV with increasing pollu-
                           trafine PM, transition metals, reactive organic                        tion. However, effects were absent in subjects
                           compounds), and gases such as ozone (O3) or ni-                        treated with statins – lipid-lowering and anti-
                           trogen oxides (NO, NO2) promote oxidative stress                       inflammatory medication. Moreover, HRV was
                           and respiratory inflammatory responses [7]. Medi-                      affected only among genotypes with reduced abil-
                           ated through cytokines and chemokines, the pul-                        ities to balance oxidative stress, namely those with
                           monary responses also lead to sub-clinical systemic                    the GSTM-null polymorphism.
                                                      S W I S S M E D W K LY 2 0 0 5 ; 1 3 5 : 6 9 7 – 7 0 2 · w w w . s m w . c h   699


Long-term cumulative effects of air pollution
     The question arises whether and to what ex-            among children engaging in outdoor sports [11].
tent acute sub-clinical effects of air pollution may        Recent studies observed higher asthma prevalence
contribute to the long-term development of respi-           among children living along busy roads suggestive
ratory and cardiovascular diseases. Cohort studies          of a role of fresh exhaust pollutants in the develop-
are essential to address chronic exposure effects.          ment of asthma [12]. As shown by Gilliland et al.
The largest one, the American Cancer Society                in a chamber study conducted with allergic pa-
Study (ACS), followed some 150,000 adults over              tients, complex interactions of pollutants (diesel
more than 15 years [9]. Investigators reported              in this case), allergens, and genetic factors may be
strong associations of long-term levels of ambient          important in the genesis of this multifactorial com-
air pollution with cardiovascular death [9]. More           plex disease [13].
sophisticated individual residential assignment of               The incidence of chronic bronchitis has been
pollutants using geostatistical techniques led to           investigated in a Californian cohort study only,
considerably larger estimates such as a 24% change          [14] whereas the Swiss cross-sectional findings of
in cardiovascular death for a 10 µg/m3 contrast in          higher prevalence of bronchitis in communities
long-term residential outdoor PM2.5 [10].                   with higher pollution cannot unambiguously dis-
     However, these mortality studies raise the             tinguish acute from chronic effects [15]. Lung
question as to whether air pollution only triggers          cancer is an established long-term consequence of
events among those with underlying susceptibili-            ambient air pollution and exposure to traffic
ties due to other causes (eg COPD, diabetes, hy-            emissions may be of particular importance [16].
perlipidaemia, smoking) or whether air pollution                 One of the most intriguing findings at the in-
contributes in a sustained, chronic manner to the           terface of chronic respiratory and cardiovascular
long-term pathophysiologic processes that ulti-             diseases originates from investigations of associa-
mately lead to morbidity and mortality, independ-           tions between forced expiratory lung function (LF)
ent of the level of pollution at the time of the event.     and long-term exposure to ambient air pollution.
The much larger associations between pollution              Reduced lung capacity (FVC, FEV1) is a well es-
and death observed in cohort studies as compared            tablished marker of both respiratory and cardio-
to acute effect studies are suggestive but do not           vascular health. In fact, prospective studies show
proof such chronic effects [9]. More proximal out-          not only a very strong association between FEV1
comes, namely chronic functional or structural              and respiratory death but also with the concomi-
changes and the incidence of chronic diseases need          tant risks of hospitalisation and death due to car-
to be investigated to clarify this issue.                   diovascular causes. Thus, the finding in the 8-year
     Cross-community comparisons have usually               follow-up of Southern Californian children show-
failed to see a clear association between asthma in-        ing lung growth being affected by ambient urban
cidence or prevalence and urban air pollution, de-          air pollution is very relevant [17]. Those growing
spite the known causal role of pollution in trigger-        up in the most polluted towns were left with
ing attacks among asthmatics. The California                substantial deficits at age 18. The cross-sectional
Children Health Study suggests that high oxidant            results of the SAPALDIA study (age 18 to 65) with
pollution may contribute to the onset of asthma             lower levels of LF in more polluted towns indicate

Figure 1
Model of the interre-     LUNG
lated pulmonary, sys-
temic, and vascular                  Oxidative                                                Chronic                          Respira-
                                                                   Lung
chronic inflammatory                    stress                                                  lung                             tory
responses to air pol-
                                                                 function
                                   Inflammation                                               diseases                          death
lution. Lung function
and artery wall thick-
ness are examples
of markers of the
continuous chronic
process from health       LIVER
to disease. (Thin
lines denote correla-
tions established           systemic inflammation
in epidemiological
studies).                 BONE    M.




                                    endothelial                     Artery                     Cardio-                        Cardio -
                                    dysfunction                      wall                     vascular                       vascular
                                   inflammation                   thickness                   diseases                         death


                          A RTERIES
Air pollution: from lung to heart                                                                                                   700

                           that the functional deficit remains into adulthood.     ing urban air may be considered a continuous and
                           We observed significant associations between life-      non-voluntary type of “low grade” smoking with
                           time ambient ozone and pulmonary function               qualitatively similar long-term effects on chronic
                           among college students but studies on chronic           respiratory and cardiovascular diseases.
                           effects of ozone are not consistent [18].                   The link between air pollution-induced in-
                                The repeated acute inflammatory insults            flammation and atherogenesis has been investi-
                           observed in experimental and epidemiological            gated experimentally in rabbits [19]. Four-week
                           studies may contribute to the long-term develop-        exposure to ambient PM resulted in dose-depend-
                           ment and course of chronic diseases. The reduc-         ent alveolar and systemic inflammatory responses
                           tion in LF involves various mechanisms but sys-         and the progression of atherosclerosis in the coro-
                           temic factors including systemic inflammation are       nary arteries and the aorta. The atherogenic effects
                           likely to play a role as all major non-pulmonary in-    were associated with the extent of PM phagocy-
                           flammatory diseases – such as diabetes, metabolic       tosed by alveolar macrophages in the lung and cou-
                           syndrome, atherosclerosis, rheumatoid arthritis or      pled with an enhanced release of bone marrow
                           bowl diseases – are associated with reduced LF [2].     monocytes. These precursors of macrophages play
                           We suggest the model shown in figure 1 to link          an important role in atherogenic inflammatory
                           acute effects with chronic pulmonary and cardio-        responses. So far, only one study investigated the
                           vascular ailments. The model puts local and sys-        association between ambient pollution and ather-
                           temic inflammation into the centre but other            osclerosis in humans [20]. The study used baseline
                           mechanisms may be relevant as well (eg direct toxic     data from two clinical trials conducted in the Los
                           effects on DNA that lead to cell death). There is       Angeles area. Carotid intima-media thickness
                           ample experimental and/or epidemiological evi-          (CIMT), an established marker of atherosclerosis,
                           dence for all the links indicated with arrows and       was the primary outcome. Novel spatial models of
                           lines. Pulmonary inflammation sustains sub-clini-       ambient fine particle surfaces allowed the assign-
                           cal systemic inflammation, which plays a pivotal        ment of pollution concentrations to each parti-
                           role in atherosclerosis as the primary underlying       cipant’s home. For a contrast of 10 mg/m3 in am-
                           mechanism of cardiovascular morbidity and mor-          bient PM2.5, CIMT was approximately 4–5%
                           tality. All outcomes shown in the model are known       thicker. These results open new avenues in the in-
                           to be associated with smoking. Ambient air pollu-       vestigation of the link between air pollution, lung
                           tion may act on these same pathways, and breath-        function and atherosclerosis (figure 1).




                           Four relevant open questions
                           Who is susceptible?                                     What pollutants and sources are most
                                The tobacco disease epidemics have made it         relevant?
                           very clear that susceptibility to health effects re-         The health consequences are unlikely to be the
                           lated to airborne toxicant vary considerably among      consequence of one or a few single pollutants but,
                           individuals. This paradigm is likely to hold for        more likely, are the result of the complex mixture
                           ambient air pollution as well. Studies suggest acute    of primary and secondary interacting constituents
                           effects of air pollutants to be stronger among the      that lead to the observed effects through common
                           elderly and subjects with preexisting diseases such     (eg oxidant stress) and/or distinct (direct toxicity)
                           as diabetes, asthma, chronic bronchitis, diagnosed      pathways. Experimental studies are unable to
                           cardiovascular diseases or a history of myocardial      mimic fully the ambient mixture, whereas epi-
                           infarction, and, possibly, also among the obese.        demiological studies have limited capabilities to
                           Of interest are interactions with genetic factors, in   disentangle effects of specific constituents or
                           particular polymorphisms of genes that regulate         sources of pollutants. Thus the question cannot be
                           the response to oxidative stress and inflammation       answered with any certainty [12]. A causal role of
                           [7]. The same polymorphisms that modify the ef-         particles and of ozone can be inferred from many
                           fect of air pollution on HRV mentioned above [8]        studies, whereas NO2 may amplify effects of other
                           determine the atherogenic potential of smoking          pollutants or allergens [23]. The characterisation
                           [21], and amplify the effect of in utero smoking        of exposure to traffic emissions has been improved
                           on the occurrence of asthma and wheezing in off-        considerably in recent studies; and it becomes
                           spring [22]. It remains to be shown whether all         increasingly apparent that living within 0–100 me-
                           conditions that sustain sub-clinical systemic in-       ters to the emissions from busy roads may impose
                           flammation such as diabetes, metabolic syndrome,        a health threat [12, 24].
                           hypercholesteraemia, rheumatoid arthritis, or
                           bowl diseases were to amplify effects of air pollu-     Is the magnitude of the reported risks
                           tion.                                                   relevant?
                                                                                       It is clear that current levels of air pollution
                                                                                   lead to increases in adverse health effects (table 1)
                                                                S W I S S M E D W K LY 2 0 0 5 ; 1 3 5 : 6 9 7 – 7 0 2 · w w w . s m w . c h   701

of only a few percent or less across the typical                      [28]. Even subtle improvements in air quality as
ranges of ambient exposure observed in developed                      observed in Switzerland over the past 10 years led
countries. This may mislead clinicians to consider                    to reductions in respiratory symptoms among chil-
air pollution an irrelevant issue. However, the size                  dren [29], and preliminary findings of the SAPAL-
of the risk gradient is only one determinant of pub-                  DIA study suggest these air quality changes corre-
lic health relevance. The number of people af-                        late with reduced age-related lung function decline
fected is the other key factor in the equation. Given                 rates in adults [30]. Lung growth of children mov-
no evidence for safe “thresholds of no effect” all                    ing into cleaner areas during the Children’s Health
people living in environments with ambient pollu-                     Study follow-up also improved whereas those
tion above natural background are, in theory,                         moving into more polluted communities experi-
exposed to some finite increased risk, conditional                    enced reduced growth rates [31]. A recent experi-
on susceptibility factors noted above. As a conse-                    ment has shown that a non-specific intervention
quence, estimates of the public health burden of                      such as a particle filter on a diesel engine, com-
ambient air pollution are substantial. A tri-national                 bined with the use of low sulphur diesel fuel can
European study attributed some 6% of all deaths                       reduce drastically, if not eliminate, a myriad of
and ~2% of hospital admissions to ambient air pol-                    pollutants and toxic reactions observed in the lungs
lution [25], and studies not available at that time                   of mice after exposure to diesel exhaust [32].
indicate that these rough estimates may have been                          In summary, evidence is increasing that ambi-
conservative [10, 24].                                                ent air pollutants affect the autonomic nervous sys-
     Small shifts in the population mean of physio-                   tem and contribute to oxidative stress and systemic
logical markers such as blood pressure, lung func-                    inflammation leading to cardio-respiratory effects
tion, or intima-media thickness (CIMT) ulti-                          [2]. This supports a causal interpretation of obser-
mately translate into substantial changes in the                      vations made in many epidemiological studies. Fu-
number of people with clinically relevant condi-                      ture research will need to clarify the life-time
tions [26]. It has been estimated that a 10% in-                      course of these effects, the relevance of cumulative
crease in CIMT increases the risk for future my-                      exposure, as well as identify the most susceptible
ocardial infarction or stroke by approximately                        time periods and populations, and the pathophys-
15% [27].                                                             iologic link between lung and cardiovascular
                                                                      ailments. Last but not least, pollution needs to be
Do reductions of ambient pollution                                    reduced, and air quality and health need to be
concentrations reduce risk?                                           monitored to be aware of trends and consequences.
     As a public health conclusion from the above,
stringent clean air quality policies are required on
both the national and international level to curb air                        Correspondence:
pollution as a primary preventive strategy. An in-                           Nino Künzli, MD, PhD
creasing body of “intervention-type” studies con-                            Associate Professor,
firms that improvements in air quality, in fact, do                          Keck School of Medicine University of Southern
lead to health benefits in the population. The 1991                          California,
coal ban in Dublin was followed by an immediate                              1540 Alcazar, CHP 236,
decline in pollution and a sustained ~10% decrease                           Los Angeles, CA 90033 – USA
in cardiovascular mortality, corresponding to                                E-Mail: Kuenzli@usc.edu
~240–250 fewer cardiovascular deaths per year




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Impact factor Swiss Medical Weekly
 2
1.8
                                                                      1.537          E ditores M edicorum H elveticorum
1.6
1.4
1.2                                                           1.162
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