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Cardiac & Cardiovascular Systems
Cardiovascular diseases (CVDs), such as arterial hypertension, myocardial infarction, stroke, heart failure, atrial fibrillation, etc., still represent the main cause of morbidity and mortality worldwide. They significantly modify the patients’ quality of life with a tremendous economic impact. It is well established that cardiovascular risk factors increase the probability of fatal and non-fatal cardiac events. These risk factors are classified into modifiable (smoking, arterial hypertension, hypercholesterolemia, low HDL cholesterol, diabetes, excessive alcohol consumption, high-fat and high-calorie diet, reduced physical activity) and non-modifiable (sex, age, family history, of previous cardiovascular disease).
- cardiovascular diseases
- conventional risk factors
- cardiovascular prevention
1. Introduction
Despite tremendous advancements in prevention and treatment, CVDs are still the leading causes of mortality and the major contributors to disability in industrialized countries, with a huge impact on social and economic systems. Since the first observations from the Framingham Heart Study started in 1948 [1], several other epidemiological studies have confirmed the impact of the so-called conventional CV risk factors, such as age, blood pressure, glucose blood levels, lipid profile, and smoking status, as major determinants of CV disease development and clinical outcome [2]. Based on all these data, the current guidelines on cardiovascular prevention using the SCORE algorithm define the risk of fatal and non-fatal events in a 10-year period [3]. The achievement of targets for all the modifiable risk factors is the primum movens in prevention [3]. However, despite the major effort in promoting a healthy lifestyle and keeping the cardiovascular risk factors at target, in 2019, an estimated 17.9 million people died from CVDs, representing 32% of all global deaths. Of these deaths, 85% were related to heart attack and stroke [4,5,6,7]. Thus, the optimistic expectation of cardiologists to reduce the CVD burden because of improved prevention strategies and treatment of the modifiable risk factors has been largely unmet. Several aspects should be taken into account to explain the reasons of such failure. In December 2022, the American College of Cardiology (ACC) announced the publication of “The Global Burden of Cardiovascular Diseases and Risk: A Compass for Future Health”. In this document, 18 specific CV conditions and 15 risk factors across 21 global regions were analyzed to provide an up-to-date overview of the global burden of CVD [8]. This document includes data from 204 countries, analyzing the major global modifiable CVD risk factors, how they contribute to disease burden, and recent strategies for prevention [8]. Based on this analysis, hypertension, hypercholesterolemia, dietary lifestyle, and air pollution were the leading causes of CVD worldwide. A total of 15 leading risks for CV diseases were included and divided in three categories: environmental (air pollution, household air pollution, low and high temperature); metabolic (systolic blood pressure, low-density lipoprotein cholesterol, body mass index, fasting plasma glucose, kidney dysfunction); and behavioral (dietary, smoking, alcohol use, physical activity). This report has also evaluated the disability-adjusted life years (DALYs), looking at the years of life lost because of premature mortality, and years lived with disability [8]. As a main result of this analysis, ischemic heart disease remains the major cause of CV death, with up to 9.44 million deaths in 2021 and 185 million DALYs. Hypertension remains the modifiable risk factor mainly associated with premature CV deaths, with up to 10.8 million CV deaths and 11.3 million deaths overall in 2021 [8]. A dietary lifestyle evaluation has considered under-consumed food, such as vegetables, fruits, fiber, vegetables, and over-consumed food, such as meats, sodium, and sugar-sweetened beverages. This analysis reveals an association of 6.58 million CV deaths and 8 million deaths overall in 2021 [8]. However, the conventional risk factors evaluated in this latest document may explain only part of the cardiovascular disease burden. In the last few years, several epidemiological and experimental studies have linked the development of CVDs to novel and emerging risk factors [9], such as homocysteine and vitamin D levels, gut microbiota, sleep apnea, sleep duration, uric acid plasma concentration over the air pollution, and climate change, as already stated by the ACC document [8].
2. Metabolic Risk Factors
2.1. Homocysteine: The Never-Ending Debate in Cardiovascular Prevention
Homocysteine is a sulphur amino acid that originates from the metabolism of methionine. Methionine, an essential food-derived amino acid, plays a vital role in cellular processes through the donation of methyl groups [10]. The first metabolite originating from methyl transfer is S-adenosyl methionine, which is subsequently converted to S-adenosyl homocysteine, the immediate precursor of homocysteine. The latter can be ‘recycled’ by taking the methylation route, resulting in the regeneration of methionine, or alternatively, it can be eliminated renally via the transulfuration route, leading to the formation of cysteine. Both processes are mediated by enzymes whose cofactors are vitamin B12, folic acid, and vitamin B6 [11,12]. Under physiological conditions, there is a balance between homocysteine formation and elimination [12]. If homocysteine can accumulate in the body, the biochemical transformation process fails, leading to a serum level increase [12]. Serum homocysteine values between 5 and 15 micromol/L are considered normal while mild hyperhomocysteinemia is defined as values between 15 and 30 micromol/L; moderate, between 30 and 100 micromol/L; and severe, if greater than 100 micromol/L [13]. In the healthy population, blood levels of homocysteine do not appear to be significantly influenced by dietary intake [14]. Hyperhomocysteinemia has many causes, with genetic profiles playing a dominant role: several genetic polymorphisms have been recognized [15] as responsible for the deficiency of enzymes involved in homocysteine metabolism [16]. The most frequent polymorphisms involve the gene coding for methylenetetrahydrofolate reductase and the one coding for cystathionine beta synthase [17]. Other causes include vitamin B12, B6 and folic acid deficiency [18]; advanced age; male sex; menopause; lifestyle habits, such as alcohol abuse and smoking [19]; and certain diseases, including cancers [15], chronic kidney disease [20], hypothyroidism [21], and inflammatory bowel disease [22]. Mention should be made of drugs that may interfere with the metabolism of homocysteine or its enzymatic cofactors: these include methotrexate, carbamazepine, nitrates, fibrates, and metformin [23].
Over the past few decades, the correlation of homocysteine with the incidence of cardio- and cerebrovascular events as well as its potential role in the pathogenesis of atherosclerosis have been the subject of countless debates [24,25,26]. The first correlation between serum homocysteine levels and the incidence of coronary artery disease is dated 1956 [27]. Numerous clinical studies and meta-analyses have subsequently supported this theory, reporting a 20% increase in the risk of new coronary events for every 5 micromol/L increase above normal serum homocysteine levels [28] and an increased risk of fatal and non-fatal coronary [29,30,31] and cerebrovascular events [30,32]. Further analyses corroborate these data, showing a 25% reduction in homocysteine levels (approximately 3 micromol/L) correlates with a lower risk of cardiac ischemic events and stroke [32].
The relationship between hyperhomocysteinemia and mortality for coronary artery diseases or cardiovascular causes or all causes has been evaluated in a meta-analysis of 20 prospective studies reporting that elevated homocysteine levels were an independent predictor of cardiovascular events, mortality from cardiovascular causes, and mortality from all causes [33].
Other studies have correlated hyperhomocysteinemia with an increased risk for and recurrence of venous thromboembolic events [34,35,36], peripheral artery diseases [37], and congestive heart failure [38].
Based on this evidence, hyperhomocysteinemia has been proposed as an independent cardiovascular risk factor [38,39].
Several cellular mechanisms have been proposed to explain how hyperhomocysteinemia is implicated in the etiology of cardio- and cerebrovascular events. Endothelial dysfunction, increased arterial stiffness, and a prothrombotic state are common in patients with hyperhomosysteinemia [40]. The main pathways associated with this endothelial impairment are: a) increased oxidative stress [41]; b) a reduction in the expression of the endothelial isoform of nitric oxide synthetase (eNOS) and increase in the cellular expression of caveolin-1 that is an inhibitor of eNOS, thus leading to a reduced release of nitric oxide [42]; and c) the upregulation of cell adhesion molecules, resulting in an increased chemotaxis of monocytes on the endothelium and increased endothelial expression of IL-8, which favor inflammatory processes [43].
Hyperhomocysteinemia is also associated to collagen synthesis [44] and vessel smooth muscle cell proliferation [45], through activation of cyclin A, protein kinase C, and the proto-oncogenes c-myc and c-fos [45,46] as well as increased production of phospholipids [46] and increased expression of platelet growth factor [47]. This smooth muscle cells proliferation as well as increased collagen deposition and alterations in elastic tissue composition [48] is responsible for increased arterial wall stiffness [49,50,51]. This phenomenon is facilitated by the inactivation of eNOS and the reduced production of nitric oxide [52]. A schematic view of homocysteine pathways involved in CVD is provided in Figure 1.
Figure 1. Possible role of homocysteine in CVD.
Moreover, several studies have also linked hyperhomocysteinemia to increased prothrombotic state [53]. This effect has been mainly related to: (a) factor XII and factor V activation [54]; (b) tissue factor expression [55]; (c) thrombomodulin inhibition [56] that results in a reduction of protein C activation [57]; (d) a reduction in the anticoagulant effect of antithrombin III, thus altering the binding capacity of endothelial heparan sulphate with the latter [58]; and (e) the reduction of plasminogen activator function and increased expression of its inhibitor [59].
In light of these basic findings, several clinical studies have investigated whether the treatment of hyperhomocysteinemia might result in cardiovascular benefits in terms of cardio- and cerebrovascular event reduction with conflicting results.
2.2. Uric Acid: Still a Controversial Cardiovascular Risk Factor?
Uric acid (UA) is the final product of purine metabolism. The increase in its blood levels may depend either on an increased production or on a reduced elimination [60]. If hyperuricemia develops, urate crystals accumulation may occurs in the joints leading to the clinical manifestations of gout, subsequently also affecting the renal parenchyma and the excretory tracts with the picture of gouty nephropathy and nephro/urolithiasis [61]. Beyond this known effect, several other clinical studies have also investigated the relationship between high blood levels of UA and the development of CVDs [62] and, as for homocysteine, with conflicting results. The Framingham Heart Study did not indicate hyperuricemia as an independent risk factor for coronary artery disease, cardiovascular death, and death from all causes [63,64]. Some epidemiological studies have described a J- or U-shaped relationship between UA levels and cardiovascular risk, meaning that patients with either very low or very high UA values have an increased cardiovascular risk [65]. More recently, clinical studies seem to support the role of hyperuricemia in atherosclerosis, systemic arterial hypertension, atrial fibrillation, and chronic kidney disease as the pathophysiological processes promoted by UA, such as oxidative stress and inflammation that are the basis of endothelial dysfunction, which may contribute to atherothrombotic events. An increase in the activity of the enzyme xanthine oxidase, which regulates the synthesis of UA and which uses molecular oxygen as an electron acceptor for its function, determines the formation of reactive oxygen species (ROS) [66]. ROS are responsible for the lipid oxidation and the reduction of the nitric oxide concentration, which causes the loss of the physiological vasodilating effect of the endothelium and determines a prothrombotic phenotype. UA also favors an increase in the deposition of low-density lipoproteins at the endothelial level and their uptake by macrophages, which are transformed into foam cells, thus starting the process of atherosclerosis [67]. More recently, it has been highlighted how endothelial cells (ECs) may acquire a prothrombotic phenotype by expressing functional tissue factor (TF) once exposed to increasing doses of UA that can be reversed by the preincubation with an uricosuric agent [68]. Moreover, the endothelial dysfunction induced by hyperuricemia also favors the expression on the cell surface of the adhesion molecules (CAMs) involved in the initiation of the atherosclerosis process. This mechanism appears to be regulated by a modulation of the NF-kappaB pathway, leading to the upregulation of TF on cell surface and downregulation of its natural inhibitor, the Tissue Factor Pathway inhibitor (TFPI) [69]. Furthermore, the inflammasome [70] seems also to be involved with an increase in caspase-1 function, which would promote a particular type of endothelial cell apoptosis, known as pyroptosis, and the release of TNF-alpha [71]. A summary of the possible mechanisms by which UA is involved in CVD is provided in Figure 2.
Figure 2. Major pathways UA related involved in pathogenesis of CVD.
These basic findings have been corroborated by a more recent clinical evaluation on patients with acute coronary syndrome (ACS) [72] by reporting that higher UA levels are associated with higher C-reactive protein (CRP) and troponin values. Additionally, ACS patients with high UA levels showed an angiographic picture of multivessel coronary artery disease and complex atherosclerosis according to the Ellis classification [72]. As regards the relationship between hyperuricemia and systemic arterial hypertension, several studies have shown an increase in blood pressure in patients with increased uric acid. A meta-analysis that studied 55,607 patients showed that for each 1 mg/dL increase in uric acid, the incidence of arterial hypertension increases by approximately 13% [73]. At the basis of this relationship, there would be the lower release of nitric acid and the activation of the renin–angiotensin–aldosterone system promoted by uric acid, which determine vasoconstriction and consequent increase in blood pressure. A relationship between hyperuricemia and increased onset of atrial fibrillation (AF) has been highlighted by the ARIC study, which shows a 1.16-fold increase in the risk of AF in subjects, mostly female and of African origin, with high UA values [74]. Atrial remodeling induced by the inflammatory effects and oxidative stress related to UA seems to be the underlying mechanism [75]. In light of the relationship between hyperuricemia and increased cardiovascular risk, the current therapeutic options mainly are represented by allopurinol and febuxostat, which inhibit the enzyme xanthine oxidase, and therefore, the UA production could have a role in reducing the incidence of cardiovascular events.
2.3. Vitamin D: Light and Shadow in Cardiovascular Prevention
Vitamin D, commonly known as the “sunshine vitamin”, is an essential nutrient that plays a critical role in the absorption and regulation of calcium and phosphorus, essential minerals necessary for strong bones, teeth, and overall skeletal health [76]. Unlike other vitamins, the human body can produce vitamin D through exposure to sunlight [77]. The precursor form of vitamin D, indeed known as 7-dehydrocholesterol, is naturally present in the skin [78]. Upon exposure to UVB radiation emitted by sunlight, a photochemical reaction takes place, leading to the transformation of 7-dehydrocholesterol into pre-vitamin D3 [78]. Subsequently, through heat-induced isomerization, pre-vitamin D3 is converted into cholecalciferol, also known as vitamin D3. Another form of vitamin D, the Vitamin D2, also known as ergocalciferol, is primarily derived from plant-based sources and is commonly utilized in fortified food products and some dietary supplements. Vitamin D2 and D3 are fully activated through two consecutive hydroxylation reactions catalyzed by specific P450 isoenzymes. The First hydroxylation, which occurs on the carbon in position 25, takes place in the liver by vitamin D 25-hydroxylase (CYP2R1) to form the pro-hormone 25-hydroxyvitamin D. Due its solubility and BPD binding properties, the level of this metabolite better reflects the body’s vitamin D status. The second hydroxylation occurs on the carbon in position 1 by 25-hydroxyvitamin D-1alpha-hydroxylase renal (CYP27B1) and is responsible for the synthesis of the biologically active metabolite, 1,25-dihydroxyvitamin D [78].
Beyond its well-known role in bone health, vitamin D has garnered increasing attention in relation to cardiovascular health. Numerous observational studies have investigated the link between vitamin D levels and CVDs. Although the results show some degree of variability, they consistently highlight an inverse association between vitamin D status and the risk of developing CVD [79,80,81]. The inverse correlation between vitamin D status and CVD seems to be particularly strong in older adults [82,83]. Meta-analyses of epidemiological studies support the inverse correlation between vitamin D levels and CVD [82,84]. The correlation between vitamin D levels and arterial hypertension holds significant importance. Blood pressure tends to exhibit geographical and racial disparities, whereby the risk of hypertension tends to rise from south to north in the Northern hemisphere. A suggested explanation for this latitude-based correlation is that sunlight exposure may offer protection, potentially due to the influence of ultraviolet B (UVB) radiation or vitamin D [85]. This association appears to be supported by animal studies. Mice that lack the vitamin D receptor (VDR) or have a genetic deficiency in the 1-alpha-hydroxylase gene, which is responsible for vitamin D activation, have been shown to develop high renin hypertension and cardiac hypertrophy [86,87]. In vitro studies highlight a favorable cardioprotective effect of 1,25-dihydroxyvitamin D. It has been reported that the pretreatment of ECs with vitamin D reduce the expression and activity of TF and CAMs induced by oxidized lipids [68] or interleukin-6 [88], possibly preserving endothelial function.
All the putative cardiovascular mechanisms associated with vitamin D are provided in Figure 3.
Figure 3. Putative cardiovascular pathways Vitamin D-related: see text for details.
While in vitro studies and epidemiological studies have provided promising insights into the potential cardioprotective effects of vitamin D, the results from randomized controlled trials (RCTs) in this field have been inconclusive to date. The majority of trials conducted so far have primarily focused on investigating the impact of vitamin D supplementation on bone health. In many cases, vitamin D supplementation has been administered alongside calcium supplementation. Meta-analyses of randomized controlled trials (RCTs) have demonstrated non-significant reductions in CVD events with vitamin D supplementation [89,90,91].
3. Non-Metabolic Risk Factors and Surrogates
3.1. Obstructive Sleep Apnea Syndrome: The Diving Board to CVDs
Obstructive sleep apnea (OSA) syndrome is a clinical condition characterized by cyclical episodes of total (apnea) or partial (hypopnea) collapse of the upper airways, occurring during sleep, with the persistence of thoracoabdominal movements. At the end of the events, arousal occurs with transient hypoxemia, autonomic alterations, and sleep fragmentation [137].
Apnea is defined as a reduction in airflow of at least 90% compared to the basal one, lasting at least 10 s while hypopnea is defined as a reduction in airflow of at least 30%, for no less than 10 s, associated with a reduction of at least 3% in oxygen saturation (SaO2) [138].
The severity of OSA is based on the number of events/hour, and it is defined as AHI index (apnea/hypopnea index). Specifically, <5 events/hour define a normal respiratory pattern, 5–14 events/hour a mild apnea, 15–29 events/hour a moderate apnea, and from 30 events/h a severe apnea [138]. The gold standard for the diagnosis of OSA is represented by polysomnography (PSG) [138].
A diagnosis of OSA is made based on nocturnal breathing disorders (snoring, breathing pauses in sleep, restless sleep, awakening choking) and/or daytime sleepiness symptoms associated with an AHI > 5; on the contrary, if the AHI index is greater than 15, OSA can be diagnosed in the absence of symptoms [139].
In general population, OSA prevalence is approximately 34% in men and 17% in women [137,140] while in CVD populations, it ranges from 40% to 60% [141,142].
During sleep, a failure of the neuromuscular reflex that preserves the patency of the airways occurs, resulting in hypoxemia and hypercapnia, determining an increase in the respiratory effort and an awakening of a few seconds, which restores patency of the upper airways, thanks to a series of reflex mechanisms. When sleep resumes, the cycle repeats [143].
OSA represents an independent risk factor for CVDs, such as HTN, AF and other arrhythmias, HF, CAD, stroke, pulmonary hypertension, metabolic syndrome, and diabetes as shown in Figure 4. The involved mechanisms are multiple and probably interconnected.
Figure 4. Pathophysiological pathways OSA related leading to CVD.
During the apneic phase, by stimulating peripheral and central chemoreceptors [144], hypoxia and hypercapnia determine the activation of the sympathetic nervous system with consequent peripheral vasoconstriction and an increase in vascular resistance and heart rate [145]. This results in an increase in left ventricular afterload and cardiac work. In addition, there is an overall increase in left ventricular transmural pressure (that is the difference between ventricular systolic pressure and intrathoracic pressure) with increased wall stress [146,147]. The cycle repeats many times every night; therefore, the cardiovascular system is chronically exposed to neuro-hormonal stress, and the hyperactivity of the autonomic nervous system also extends to the daytime hours over time [145,148].
Intermittent hypoxia is also responsible for an increase in oxidative stress [149]: during the hypoxic phase, the cells adapt to an environment with low oxygen content, and with the reoxygenation phase, there is a sudden increase of oxygen with ROS formation, leading to cellular damage in the ischemic tissue [150,151].
Furthermore, a reduction in the levels of circulating NO has also been highlighted during OSA [152], and this could be implicated in endothelial dysfunction [153].
OSA is present in up to 30–50% of HTN patients, and 80% of patients with resistant HTN have OSA [139,154], representing an independent risk factor [137]. In patients with OSA, due to the overactivity of the sympathetic nervous system, the physiological reduction in blood pressure during the night (which configures the “dipper” profile) does not occur [155,156]. Therefore, there seems to be a correlation between sleep apnea and the non-dipper profile of essential HTN [157,158]. Furthermore, several randomized trials and meta-analysis have shown a reduction in blood pressure in patients with sleep apnea treated with CPAP [137,159].
OSA is associated with heart rhythm disturbances and sudden death; pauses and bradycardia are common in patients with OSA [139].
OSA is also an independent risk factor for AF with several pathophysiological mechanisms implicated. In particular, sudden changes in intrathoracic pressure can cause atrial remodeling and atrial fibrosis with consequent electrophysiological alterations [160]. Moreover, the sudden increase in sympathetic activity during apneas can lead to the activation of catecholamine-sensitive atrial on channels, thus determining focal discharges from which AF can be originated [161]. OSA is also associated with an increase in systemic inflammation, which may contribute to the genesis of AF [162].
Sleep apnea also increases the risk of CAD by favoring atherosclerotic process via oxidative stress, endothelial dysfunction, inflammatory state, and autonomic dysfunction. It has been reported that in OSA patients, myocardial infarction occurs more frequently during the night hours [163], and a higher pro-inflammatory profile is present [164] with an effective reduction of the latter if CPAP therapy is used [164]. This study, therefore, suggests that OSA could activate vascular inflammation with non-traditional pathogenetic mechanisms.
OSA is also a risk factor for incident strokes, stroke recurrence [165], and functional and cognitive outcomes [166].
Pulmonary hypertension is closely related to OSA. Hypoxia and hypercapnia induce arteriolar vasoconstriction in the short term and vascular remodeling in the long term that could lead to an irreversible increase in pulmonary vascular resistance and the development of pulmonary hypertension [167].
Sleep apnea, mainly the central form (CSA), is highly prevalent in HF patients as well, ranging from 40% to 60% of symptomatic patients [168].
OSA is also linked to obesity and metabolic syndrome since chronic intermittent hypoxemia and sleep loss is associated to higher plasma leptin levels [169], glucose metabolism impairment, and insulin resistance [170].
At least, there is a reciprocal interaction between obesity and OSA where they both reinforce their progression and their severity in a vicious circle. It is believed that the deposition of fat in the upper airways and the functional alteration of the airways themselves are the mechanisms involved in the pathogenesis of OSA in the obese subjects [171]. On the other hand, daytime sleepiness and decreased physical activity together with hyperleptinemia are the mechanisms probably implicated in weight gain in OSA.
3.2. Air Pollution: Health Breath as Part of Prevention
Air pollution is the contamination of the environment, indoor or outdoor, by a mixture of chemical, physical, or biological agents that change the characteristics of the atmosphere and even at low concentrations cause damage to human health, other living organisms and the environment [172]. According to the Global Burden of Disease (GBD) report, air pollution was responsible for 6.7 million deaths in 2019 alone [172,173]. Globally, nearly 20% of CVD deaths are attributable to air pollution [173]. The main components of this mixture of pollutants are Total Suspended Particulate Matter (PM), gaseous compounds including ozone (O3), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and volatile organic compounds including benzene [172]. According to the World Health Organization, 99% of the world’s population breathes air that contains annual average levels of air pollutants that exceed guideline recommendations. Particularly high exposures have been documented in cities in Asia, western sub-Saharan Africa, and Latin America [172]. The most consistent evidence on health damage is attributed to PM, i.e., the set of airborne particles, ranging in diameter from 0.1 to 100 mm, capable of remaining in suspension in the air even for long periods [174,175]. Short- and long-term exposure to PM is associated with increased morbidity and mortality, impacting the progression of atherosclerosis [176], ischemic heart disease [177,178,179], stroke [180], and lung disease as well as the course of pregnancy and the health of newborns [181]. PM10 (particles between 2.5 and 10 mm in diameter) and, largely, PM2.5 (diameter < 2.5 mm), are the most linked to CVD and affecting global public health [182,183]. Lung inflammation and oxidative stress pathway is the primary response to air pollution exposure [184], contributing to the development of a systemic pro-inflammatory state and activation of secondary effector pathways that result in endothelial dysfunction, increased atherosclerotic plaque vulnerability, and the activation of a prothrombotic and proarrhythmic state [177,185,186]. Experimental animal models seem indeed to support this hypothesis [187]. Moreover, human exposure to pollutant nanoparticles causes their translocation into the systemic circulation through the alveolus-capillary membrane, interacting with the endothelium, accumulating at sites of vascular inflammation, thus favoring atherosclerotic process [188,189,190], with effects similar to those observed in the lungs [191] and thrombotic complications [192]. A relevant change in platelet function toward increased prothrombotic tendency has been confirmed in diabetic patients after recent (within two hours) exposure to PM [193]. In addition to these mechanisms, short-term PM2.5 exposure in animal models is associated with sympathetic nervous system activation and hypertension, probably mediated by neuroinflammation [194,195]. In a meta-analysis of 33 studies, short-term exposure to PM2.5 was associated with a significant decrease in heart rate variability (HRV) [196]. Decreased HRV is an index of autonomic system dysfunction and predicts an increased risk of cardiovascular morbidity and mortality in patients with heart disease [197]. Increased blood pressure and decreased HRV suggest an autonomic imbalance in favor of sympathetic tone and could further explain the rapid cardiovascular responses associated with air pollution, such as the initiation of fatal tachyarrhythmias and increased myocardial infarctions [177], as confirmed by the available literature [198]. High short-term exposure to PM2.5 is associated with an increased risk of acute coronary event, acutely destabilizing and rupturing atherosclerotic plaque, in patients with clinically significant pre-existing CAD but not in those with uninjured coronary arteries [199]. Moreover, short-term exposure to elevated levels of PM2.5 and PM10 is also associated with increased daily hospitalizations for STEMI and increased incidence of STEMI-related ventricular arrhythmias and cardiac death [200]. The effect of long-term exposure to major air pollutants was assessed by the ESCAPE study that have evaluated the incidence of acute coronary events in 11 European cohorts. At a mean follow-up of 11.5 years, exposure to annual mean levels of PM2.5 > 5 μg/m3 and PM10> 10 μg/m3 was associated with a 13% and 12% increase in the risk of nonfatal acute coronary events, respectively, with no evidence of heterogeneity between cohorts [201]. Other observational studies and meta-analyses have reported a positive correlation between long-term exposure to air pollution and the development and progression of subclinical atherosclerosis and calcium accumulation [202] as well as increased carotid intima-media thickness [203]. Based on the published data, no more doubts should exist on the role of air pollutants in CVD development. A schematic view of the relationship between air pollution and CVD is provided in Figure 5.
Figure 5. Molecular mechanisms linked air pollution to CVD.
3.3. Climate Change: The Impact of Temperature
Temperature and its extreme variation is now recognized as a cardiovascular risk factor [204,205,206]. A very recent analysis evaluating 32,000 cardiovascular deaths in 27 countries on 5 continents over 40 years support the role of extremely hot or cold temperatures in determining heart disease deaths [206]. Mortality and morbidity induced by climate change are not exclusively due to hypothermia or hyperthermia, but also to indirect causes, such as respiratory diseases and CVDs, which can be undetected when the human body tries to adapt to climate changes [207]. A relationship between mortality from CVD and temperature exists with a U-, V-, or J shaped curve [208,209,210]. While the correlation between temperature and CVD has been established, the role of diurnal temperature range (DTR), defined as the difference between the maximum and minimum temperatures recorded in one day, in determining CV events needs to be better evaluated. Extreme cold weather conditions associated to climate change contributes to an increase in temperature variability that might increase clinical cardiovascular events [205]. It is known that exposure to cold activates both the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), which interact with each other, leading to HTN and myocardial damage [211]. Skin blood flow (SBF) is reduced in response to cold due to vasoconstriction and increased urine output, thus inducing dehydration, hemoconcentration, and hyperviscosity [212]. Furthermore, eNOS and adiponectin inhibition contributes to endothelial dysfunction and lipid deposition, thus favoring atherosclerosis and plaque instability. Cold exposure also triggers mitochondrial dysfunction with myocardial damage, cardiac hypertrophy, and cardiac dysfunction. The increase in cardiac work and peripheral resistance contributes to an increase in oxygen consumption and a reduction in the ischemic threshold [211], which is clinically relevant, especially when the coronary circulation is already compromised.
On the contrary, exposure to heat leads to increased blood flow and sweating with loss of fluids and dehydration. The resulting hemoconcentration and hyperviscosity may cause thromboembolism, leading to increased risk of ischemic stroke [213]. In the presence of heat stroke, the increase in core temperature redistributes the flow on the skin to facilitate heat loss. Intestinal blood flow is reduced, and this could cause increased permeability of the intestinal epithelium, allowing bacteria, their toxic cell wall component LPS, or HMBG1 to move from the intestinal lumen into the circulation. TLR4 recognizes these molecules, stimulating innate and adaptive immune responses and causing systemic inflammatory response syndrome (SIRS). Along with this, hyperthermia induces the occlusion of arterioles and capillaries (microcirculatory thrombosis) or excessive bleeding (consumptive coagulation), leading to multiorgan dysfunction. The putative mechanisms linking climate changes and CVD is provided in Figure 6.
Figure 6. Correlation between climate changes and CVD: possible basic mechanisms. Several variables affect the response to temperature changes.
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11092353
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