Heart Failure and Chronic Obstructive Pulmonary Disease
Heart Failure and Chronic Obstructive Pulmonary Disease
Cardiologists readily accept the 'cardiovascular disease continuum', the hypothesis that frames cardiovascular diseases as a chain of events initiated by risk factors and progressing through numerous physiological pathways to the development of end-stage heart disease and HF. Hopefully in coming years, the concept of a 'cardiopulmonary continuum', as a common ground of heart and lung disease, will be the basis for future achievements. Interest has grown in the association of chronic pulmonary and cardiac diseases; the observation that HF and COPD coexist more frequently than expected from their respective population prevalences being a major reason for this interest. These epidemiological observations encourage new pathophysiological interpretations to understand the connection between the pulmonary and cardiovascular continuum.
Apart from smoking as a common risk factor, patients with COPD share an additional determinant of cardiovascular disease: low-grade systemic inflammation. The risk of underlying ischaemic heart disease is greatest in patients with airflow obstruction and elevated C-reactive protein. Furthermore, almost 50% of patients with COPD present coexisting metabolic syndrome as well as increased levels of systemic inflammatory markers, independent of lung function impairment. Diabetes is likewise independently associated with reduced lung function, while obesity may further worsen ventilatory mechanics. Diabetes, metabolic syndrome (and its individual components), and physical inactivity are all major determinants of cardiovascular disease. The fact that each also acts through pro-inflammatory mechanisms strengthens the view that low-grade systemic inflammation is a common pathophysiological link between COPD and cardiovascular diseases.
This concept is substantiated by the observation that direct pro-inflammatory agents, namely cigarette smoking, air pollution, and occupational exposures, induce systemic cellular and humoral inflammation, oxidative stress, striking changes of vasomotor and endothelial function, and enhanced circulating concentrations of several procoagulant factors. Thus, 'cardiovascular' and 'pulmonary' risk factors create a 'cardiopulmonary continuum' through shared systemic inflammatory processes, inducing cascades of events which underpin chronic diseases including COPD, coronary disease, and HF. This pathophysiological relationship revolves around common inflammatory pathways (Figure 1). TNF-α plays a central role in chronic inflammatory processes of the pulmonary and cardiovascular system and is involved in the activation of secondary mediators including C-reactive protein and pro-inflammatory cytokines. These in turn mediate the phenotype of syndromes characterized by chronic comorbidities and peripheral abnormalities.
(Enlarge Image)
Figure 1.
Inflammatory pathways involved in the cardiopulmonary continuum. Patients with chronic obstructive pulmonary disease have peripheral lung inflammation. These patients have also increased circulating cytokines, including interleukin (IL)- 1b, IL-6, IL-18, and TNFa, as well as acute-phase proteins, such as C-reactive protein and serum amyloid A (SAA). This low grade chronic inflammation may represent the link with the increased propensity to cardiovascular, metabolic, bone, neurological diseases as well as the peripheral muscle abnormalities typical of the syndrome (From Boschetto et al., 2012).
A challenge for the future will be to understand the role of genetic factors, their genotype–phenotype correlations, and clinical implications. The recent availability of techniques such as genome-wide association studies has increased identification of susceptibility genes for both COPD and cardiovascular disease phenotypes including hypertension, dyslipidaemia, and coronary artery disease. A functional link between susceptibility genes has been elucidated only for certain risk factors, such as the low-density lipoprotein receptor defects and other hyperlipidaemia disorders. While the association among the most annotated genes and risk factors is defined, heritability and phenotype are less clear: for COPD, several genes are associated with disease susceptibility (e.g. CHRA3–5 or FAM13A9), but the population attributable risk is limited (approximately below 15%) and no functional link clearly established. Notably, no potential common candidate gene for both COPD and cardiovascular disease phenotypes has yet been identified. The interplay between the two common multigenic diseases remains elusive. Thus far, our understanding of the interaction between cardiovascular and pulmonary disease derives from registries and subgroup analyses. No prospective study has addressed the specific role of pulmonary comorbidity in the treatment and outcomes of cardiovascular disease patients. Nevertheless, in large, retrospective analyses statins and/or angiotensin-converting enzyme inhibitors improve both cardiac and pulmonary outcomes in patients with COPD, with the largest benefits obtained by combining therapies. Cardiovascular medicine has an armamentarium of survival enhancing therapies. These need to be systematically tested in large randomized controlled trials in patients with COPD, with and without overt cardiovascular disease.
From Shared Risk Factors to Pathophysiological Mechanisms
Cardiologists readily accept the 'cardiovascular disease continuum', the hypothesis that frames cardiovascular diseases as a chain of events initiated by risk factors and progressing through numerous physiological pathways to the development of end-stage heart disease and HF. Hopefully in coming years, the concept of a 'cardiopulmonary continuum', as a common ground of heart and lung disease, will be the basis for future achievements. Interest has grown in the association of chronic pulmonary and cardiac diseases; the observation that HF and COPD coexist more frequently than expected from their respective population prevalences being a major reason for this interest. These epidemiological observations encourage new pathophysiological interpretations to understand the connection between the pulmonary and cardiovascular continuum.
Apart from smoking as a common risk factor, patients with COPD share an additional determinant of cardiovascular disease: low-grade systemic inflammation. The risk of underlying ischaemic heart disease is greatest in patients with airflow obstruction and elevated C-reactive protein. Furthermore, almost 50% of patients with COPD present coexisting metabolic syndrome as well as increased levels of systemic inflammatory markers, independent of lung function impairment. Diabetes is likewise independently associated with reduced lung function, while obesity may further worsen ventilatory mechanics. Diabetes, metabolic syndrome (and its individual components), and physical inactivity are all major determinants of cardiovascular disease. The fact that each also acts through pro-inflammatory mechanisms strengthens the view that low-grade systemic inflammation is a common pathophysiological link between COPD and cardiovascular diseases.
This concept is substantiated by the observation that direct pro-inflammatory agents, namely cigarette smoking, air pollution, and occupational exposures, induce systemic cellular and humoral inflammation, oxidative stress, striking changes of vasomotor and endothelial function, and enhanced circulating concentrations of several procoagulant factors. Thus, 'cardiovascular' and 'pulmonary' risk factors create a 'cardiopulmonary continuum' through shared systemic inflammatory processes, inducing cascades of events which underpin chronic diseases including COPD, coronary disease, and HF. This pathophysiological relationship revolves around common inflammatory pathways (Figure 1). TNF-α plays a central role in chronic inflammatory processes of the pulmonary and cardiovascular system and is involved in the activation of secondary mediators including C-reactive protein and pro-inflammatory cytokines. These in turn mediate the phenotype of syndromes characterized by chronic comorbidities and peripheral abnormalities.
(Enlarge Image)
Figure 1.
Inflammatory pathways involved in the cardiopulmonary continuum. Patients with chronic obstructive pulmonary disease have peripheral lung inflammation. These patients have also increased circulating cytokines, including interleukin (IL)- 1b, IL-6, IL-18, and TNFa, as well as acute-phase proteins, such as C-reactive protein and serum amyloid A (SAA). This low grade chronic inflammation may represent the link with the increased propensity to cardiovascular, metabolic, bone, neurological diseases as well as the peripheral muscle abnormalities typical of the syndrome (From Boschetto et al., 2012).
A challenge for the future will be to understand the role of genetic factors, their genotype–phenotype correlations, and clinical implications. The recent availability of techniques such as genome-wide association studies has increased identification of susceptibility genes for both COPD and cardiovascular disease phenotypes including hypertension, dyslipidaemia, and coronary artery disease. A functional link between susceptibility genes has been elucidated only for certain risk factors, such as the low-density lipoprotein receptor defects and other hyperlipidaemia disorders. While the association among the most annotated genes and risk factors is defined, heritability and phenotype are less clear: for COPD, several genes are associated with disease susceptibility (e.g. CHRA3–5 or FAM13A9), but the population attributable risk is limited (approximately below 15%) and no functional link clearly established. Notably, no potential common candidate gene for both COPD and cardiovascular disease phenotypes has yet been identified. The interplay between the two common multigenic diseases remains elusive. Thus far, our understanding of the interaction between cardiovascular and pulmonary disease derives from registries and subgroup analyses. No prospective study has addressed the specific role of pulmonary comorbidity in the treatment and outcomes of cardiovascular disease patients. Nevertheless, in large, retrospective analyses statins and/or angiotensin-converting enzyme inhibitors improve both cardiac and pulmonary outcomes in patients with COPD, with the largest benefits obtained by combining therapies. Cardiovascular medicine has an armamentarium of survival enhancing therapies. These need to be systematically tested in large randomized controlled trials in patients with COPD, with and without overt cardiovascular disease.
