CARDIAC AND BLOOD PRESSURE EFFECTS OF LEAD EXPOSURE

Abstract

Objective: To construct a review on cardiac effects and blood pressure of lead exposure. Method: This is a structured narrative review in three distinct phases: 1) elaboration of the guiding question: “What are the cardiac and blood pressure effects of lead exposure?”; 2) Sampling in the literature and selection of studies; 3) Critical analysis of selected studies. Results: several aspects related to cardiac effects and blood pressure of lead exposure were obtained, among them: arterial hypertension, autonomic dysregulation, dysregulation of myocardial contractility, increase in ventricular overload, increase in afterload and of the pulse pressure. Furthermore, the evidence is suggestive of an association between exposure to lead and mortality from cardiovascular causes, particularly related to ischemic heart disease. Conclusion: researchers on the subject warn that exposure to lead is reasoned as a cardiovascular risk factor.transplantation will be used.

Introduction

Lead is a toxic metal and an environmental pollutant used in the manufacture of batteries, paints, ceramics, crystals, cables, ammunition and high-tech products, such as nuclear reactor protectors and thin plates of electronic components.¹

Although several countries adopt measures to reduce the emission of lead, environmental contamination by this metal still remains a public health problem.² The World Health Organization (WHO) estimates that 140,000 people die every year, due to contamination by this metal, in addition to causing 600,000 cases of intellectual loss in children.²

Several studies have documented the adverse effects of lead exposure in the adult population and in children.^3-5 Young children are particularly vulnerable to the toxic and, in some cases, permanent effects of lead, especially by affecting the nervous system.⁶ Studies indicate an association between blood lead concentration                 and development of hypertension, gastrointestinal disorders, as well as renal and cardiovascular dysfunctions.^1,6

Considering the toxic potential of lead, this article seeks to compile information from the scientific literature and to support the construction of a reference on cardiac toxicity and the effects on blood pressure on exposure to this metal.

Method

This is a narrative review related to cardiac toxicity and the effects on blood pressure of lead exposure. We chose this type of literature review that allows the incorporation of evidence for convenience, for an expertise in the theme, in order to build a body of knowledge about a certain topic of scientific relevance.

The review process was systematized in three distinct phases, the first of which was the elaboration of the guiding question: “What are the cardiac effects and blood pressure of lead exposure?”. The second phase corresponded to sampling in the literature, which sought to include the largest possible variety of identified products and ensure the variety and breadth of results.

In this sense, electronic selection was performed in the databases of LILACS (Latin American and Caribbean Literature) and MEDLINE (National Library of Medicine, USA). The electronic search was performed through the following combinations of Descriptors in Health Sciences (DeCS): “lead; toxicity; heart; Arterial pressure” and was based on the adoption of the following inclusion criteria: the indexing of studies in the respective databases in Portuguese, English and Spanish. Exclusion criteria were defined as: productions without availability of text in full or with a central theme of the study, unrelated to the topic of cardiac toxicity and effects on blood pressure in lead exposure.

The third phase of this review consisted of a critical analysis of the selected studies. The decision to include or reject the studies was based on the reading of the titles of the selected studies, followed by the critical analysis of the abstracts, and the studies with a central theme unrelated to the theme proposed for the review were rejected. In a second analysis, we verified the content in its entirety, which was guided by the thematic analysis technique to identify the central ideas presented.

Results / Discussion

In order to inform and contribute to analyzes and debates about the effects of exposure to lead, heart and blood pressure, the contents that make up the review were stratified in the following categories.

– Exposure to lead and hypertension

Population studies of the cardiovascular effects of lead are focused on the development of arterial hypertension while studies with experimental animals seek to elucidate the mechanisms involved in cardiovascular changes.^4,7-12

Several clinical and epidemiological studies point to an association between exposure to lead and high blood pressure. However, only recently has it been shown that blood lead concentration below the limits considered safe for human health,^13,14 or exposure to a single dose of metal,¹⁵ are able to raise the systolic blood pressure of experimental animals.

It is believed that the pathogenesis of lead toxicity in the development of hypertension is multifactorial, as: alter calcium homeostasis,^9,14,16 promote sympathetic hyperactivity,^14,17 induce increased renin-angiotensin system activity^15,18 to depress the antioxidant reserves of the organism and/or increase the production of reactive oxygen species (ROS), resulting in oxidative stress,^7,19,20 alter the vascular response to vasoactive agents,^13,21 promote endothelial damage, reduce bioavailability of nitric oxide and increase endothelin levels^11,22 besides inducing renal damage.²³

– Exposure to lead and autonomic deregulation

Autonomic imbalance, characterized by hyperactivity of the sympathetic system and hypoactivity of the parasympathetic system, is associated with several pathological conditions that may favor the                     onset or aggravate cardiovascular diseases.^24-28 Some clinical and animal studies have focused on the Sympathetic system as a possible mediator of hypertension and cardiovascular diseases induced by lead exposure.

GUMP et al,²⁵ studied the cardiovascular response to acute stress in children exposed to low prenatal concentrations of lead and to low concentrations of this metal during childhood. These authors showed that the highest blood concentrations of lead are associated with higher systolic pressures and increased peripheral vascular resistance and, consequently, increased cardiac overload. Moreover, the blood concentration of lead was associated with a reduction in systolic volume and cardiac output, which were associated with a reduction in cardiac autonomic dysregulation.²⁶

In adults, PARK and co-workers have shown that chronically exposed people may be more susceptible to cardiac autonomic dysfunction.^27,28 In experimental animals, sympathetic hyperactivity and its inotropic and chronotropic consequences in lead exposure are well documented.^9,14,17 Elevation of plasma norepinephrine and reduction of β-adrenergic receptor density are the two best mechanisms reported in interference in the autonomic regulation of lead exposure.

– Exposure to lead and elevation of pulse pressure

Chronic exposure to lead is associated with increased pulse pressure, a marker of arterial stiffness, and an indicator of cardiovascular disease. ZANGH et al.²⁹ studied 619 participants of the Normative Aging Study in the United States of America and demonstrated that H63D gene polymorphism of hemochromatosis (which may alter lead deposition and hence its cardiotoxic effect) increases susceptibility to deleterious effects of Lead in the pulse pressure. The increase of the pulse pressure is attributed to progressive arterial stiffness and consequent alteration in vascular structure and function with degradation of elastin, increase of collagen, calcification and atherosclerosis. These effects are made possible by pro-oxidative or pro-inflammatory mechanisms that occur in lead exposure, since lead induces oxidative stress and this can promote direct damage in different organs and systems, including the heart itself.³⁰ The mechanisms by which Lead induces oxidative stress include lipid peroxidation in membranes, damage to the DNA and antioxidant system of the organism resulting in greater generation and/or availability of free radicals.^7,21,31

– Exposure to lead and disturbances in myocardial contractility

Vassallo et al.³² studied isolated right ventricle strips submitted to acute lead exposure and recorded reduction of isometric strength and indicated lead as a risk factor capable of altering cardiac function. Later, Fioresi et al.⁹ investigated the acute effects of lead in the isometric contraction of isolated papillary muscles of the left ventricle of rats and demonstrated that the increase in ventricular pressure induced by acute exposure to lead has, besides vascular involvement, direct changes in myocardial contractility.

Fioresi et al.¹⁴ showed that a blood concentration of lead, below the limits considered safe, results in an increase in blood pressure, HR and left ventricular inotropism, in addition to promoting changes in the calcium cycle of the cardiomyocyte, which may contribute to the deleterious effects of this metal on the heart.

Figure 1 shows the mechanisms by which lead, in the treatment model used by Fioresi et al,¹⁴ alters the calcium cycle in the cardiomyocyte: there is a greater influx of transarcolemal calcium, but this higher influx does not result in positive inotropism, since the sarcoplasmic reticulum calcium pump (SERCA 2) is desensitized and the sodium-calcium exchanger (NCX) promotes the extrusion of these ions from the cell.

Figure 1: Mechanism proposed by which exposure to lead changes the calcium cycle in the cardiomyocyte. 1: Lead promotes greater influx of transarcolemal calcium; 2: There is an increase in [Ca] i; 3: There is desensitisation of SERCA 2 and less calcium reuptake; 4: Consequently, the increase in [Ca]i activates NCX to remove cytosolic calcium; 5: Increased NCX activity results in an increase in [Na]i, which in turn activates NKA.

– Exposure to lead and cardiovascular mortality

Several studies associate the blood concentration of lead to mortality. Weisskopf et al,³³ studied 868 men participating in the Normative Aging Study in the United States of America and found an association between lead bone content and cardiovascular mortality in the chronically exposed population at low blood concentrations of this metal. This association between lead exposure and mortality due to cardiovascular causes is particularly related to ischemic heart disease.³⁴ Although cardiac ischemic disease is multifactorial, exposure to lead may represent a risk factor that contributes to this outcome.³⁴

There are several deleterious cardiovascular effects triggered by exposure to lead which, in combination, may lead to increased cardiovascular mortality.⁴ Among these effects are: interference in cardiac contractility;^9,14,32 increase in vascular tone and peripheral resistance;¹⁹ stimulation of the renin-angiotensin system;^15,18 reduction in the availability of nitric oxide and increased oxidative stress;^13,35 interference in the cardiac autonomic control.³⁶

Conclusion

Lead has toxic effects on the heart and exposure to this metal may be considered a cardiovascular risk factor, since several studies point to a causal relationship between this exposure and the development of hypertension.

There is sufficient evidence that chronic exposure to lead has deleterious cardiac effects by affecting autonomic regulation and promoting ventricular overload, by increasing pressure afterload and pulse pressure. Furthermore, the evidence is suggestive of an association between exposure to lead and mortality from cardiovascular causes, particularly related to ischemic heart disease.

Although there is a need for further research, especially clinical and epidemiological studies, to clarify the effects and mechanisms involved in lead cardiotoxicity, it is essential for the responsible public agencies to reevaluate the safe exposure values and that the investigation of exposure to this metal to be routinely included in the cardiovascular research, mainly in workers occupationally exposed to lead.

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Authors

Mirian Fioresi¹; Maylla Ronacher Simões²; Karolini Zuqui Nunes³; Jonaína Fiorim⁴; Edna Aparecida Silveira⁵

¹ Department of Nursing, Federal University of Espírito Santo, Vitoria, ES, Brazil

^2,3 Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, ES, Brazil.

^4,5 Physiotherapists at the Hospital Universitário Cassiano Antônio Moraes, HUCAM.