Introduction
COPD, asthma, and HF frequently coexist, creating a high-risk clinical triad with overlapping symptoms and pathophysiological mechanisms.1,2 COPD-asthma-HF overlap refers to the concurrent presence of these conditions in a single patient, complicating diagnosis and treatment due to shared features such as dyspnea, wheezing, and exercise intolerance.3 While COPD and asthma are both obstructive airway diseases, HF contributes to respiratory symptoms through pulmonary congestion and reduced cardiac output, further exacerbating airflow limitation.4–6 Epidemiologically, this overlap is increasingly recognized, particularly in older adults with long-standing respiratory disease and cardiovascular risk factors. Studies suggest that up to 30% of COPD patients have concomitant HF, while 20–25% of HF patients exhibit undiagnosed COPD or asthma.7–9 Asthma-COPD overlap affects 15–20% of obstructive airway disease patients, many of whom also develop HF due to chronic hypoxia, systemic inflammation, or shared risk factors like smoking and hypertension.10 In a study, it was stated that 14.5% was died who diagnosed COPD with right and left heart failure. The right heart failure is an individual and primary risk factor for mortality in COPD. In the patients, 86.3% had COPD alone, 8.1% had COPD and HF, 3.9%, Ischemic heart disease (IHD) 1.7%.11 It was found that mortality was increased in the patient with higher cardiovascular risk. The interplay between COPD, asthma, and HF is driven by overlapping pathophysiological mechanisms, including chronic inflammation, airway obstruction, and cardiac dysfunction, which collectively worsen disease progression and clinical outcomes.12,13 Persistent low-grade inflammation is a hallmark of all three conditions. In COPD and asthma, airway inflammation involves neutrophils, eosinophils, and pro-inflammatory cytokines (eg, IL-6, TNF-α), contributing to bronchoconstriction and remodeling.14,15 This inflammatory milieu extends beyond the lungs, promoting endothelial dysfunction and atherosclerosis, which exacerbate HF progression. Conversely, HF itself induces systemic inflammation due to reduced cardiac output and tissue hypoxia, further aggravating pulmonary inflammation and airway hyperresponsiveness.16 Both COPD (fixed obstruction) and asthma (reversible obstruction) impair airflow, increasing work of breathing and oxygen demand.17,18 In HF, pulmonary congestion from left ventricular dysfunction leads to interstitial edema and reduced lung compliance, mimicking or worsening obstructive symptoms.19,20 Additionally, chronic hypoxia in advanced COPD or asthma can induce pulmonary hypertension, increasing right ventricular afterload and accelerating HF development.21–23 HF exacerbates respiratory disease through fluid overload and reduced perfusion, while chronic lung disease strains the heart via hypoxia-induced vasoconstriction and hyperinflation-related impaired ventricular filling (eg, “cardiopulmonary coupling”).5,24,25 Beta-agonist overuse in obstructive lung disease may also precipitate arrhythmias or worsen myocardial demand in HF.26–28
In COPD and asthma, persistent airway inflammation driven by neutrophils, eosinophils, and cytokines like IL-6 and TNF-α triggers bronchoconstriction, remodeling, and oxidative stress.29,30 This inflammatory cascade extends beyond the lungs, promoting endothelial dysfunction and atherosclerosis, which exacerbate HF.31,32 Conversely, HF amplifies pulmonary inflammation through reduced cardiac output, tissue hypoxia, and venous congestion, further worsening airway obstruction.22,33 Additionally, mechanical interactions between the heart and lungs play a critical role: pulmonary hypertension from chronic hypoxia in COPD or asthma increases right ventricular afterload, while left ventricular dysfunction in HF induces pulmonary edema, impairing gas exchange and lung compliance.34,35 These intertwined processes blur the lines between cardiac and respiratory symptoms, complicating clinical management. Pollen-induced allergic asthma contributes to cardiovascular disease pathogenesis via dual inflammatory and hypoxic mechanisms. IgE-mediated mast cell/eosinophil activation releases pro-inflammatory cytokines (IL-4, IL-6, IFN-γ), driving persistent pulmonary inflammation and hypoxia in asthmatic lungs29,36 (Figure 1).
 |
Figure 1 Pollen-induced allergic asthma promotes cardiovascular disease through inflammatory and hypoxic pathways. When exposed to pollen, IgE-mediated responses stimulate mast cells and eosinophils, leading to the release of cytokines like IL-4, IL-6, and IFN-γ. Unlike healthy lungs, asthmatic lungs experience persistent inflammation and hypoxia. This systemic inflammation, driven by circulating inflammatory factors, increases the risk of cardiovascular disease (CVD). Additionally, hypoxia worsens both asthma and CVD, establishing a connection between pollen-induced allergic asthma and cardiovascular disease through immune and vascular pathways.
|
In COPD and asthma, fixed or reversible airflow limitation increases the work of breathing and oxygen demand, straining an already compromised cardiovascular system.37 HF exacerbates this burden by reducing perfusion to respiratory muscles and promoting fluid retention, which narrows airways and mimics obstructive symptoms.20,38 Meanwhile, therapies for one condition may inadvertently harm another, for instance, beta-agonists for asthma/COPD can precipitate tachycardia or arrhythmias in HF, while diuretics for HF may exacerbate COPD-related mucus viscosity.39,40 The resulting therapeutic dilemma underscores the need for a nuanced approach that balances bronchodilation, anti-inflammatory effects, and cardiac support (Table 1).
 |
Table 1 Diagnostic Challenges in COPD-Asthma-HF Overlap
|
Diagnostic Challenges and Phenotyping in Overlapping Presentations
The clinical diagnosis of COPD-asthma-HF overlap is notoriously challenging due to the significant symptom overlap between these conditions, particularly dyspnea, wheezing, and reduced exercise tolerance.55 Dyspnea, the most common presenting symptom, occurs in all three disorders but arises from distinct mechanisms: airflow limitation in COPD and asthma versus pulmonary congestion and reduced cardiac output in HF.55 This makes it difficult to attribute breathlessness to a single cause without comprehensive testing. Wheezing, traditionally associated with asthma and COPD, can also manifest in HF due to bronchial compression from pulmonary edema or increased airway resistance from interstitial fluid, leading to potential misdiagnosis.2,4 Similarly, reduced exercise tolerance may reflect skeletal muscle deconditioning in COPD, bronchoconstriction in asthma, or impaired cardiac function in HF, further complicating clinical assessment.56,57 Cigarette smoke induces a pathogenic cascade linking airway disease (asthma/COPD) to cardiovascular complications through synergistic inflammatory and hypoxic pathways. By triggering airway obstruction, inflammatory cell infiltration, and ROS generation, smoking establishes chronic hypoxia58–60 (Figure 2).
 |
Figure 2 Mechanistic links between smoking-induced airway disease (asthma/COPD) and cardiovascular complications. Cigarette smoke causes airway blockage, attracts inflammatory cells, and generates reactive oxygen species (ROS), resulting in chronic hypoxia. In asthma and COPD, ongoing inflammation exacerbates impaired vascular function. Systemic oxidative stress and hypoxia further promote atherosclerosis, establishing a connection between smoking-induced lung disease and cardiovascular risk via common inflammatory and hypoxic pathways.
|
The diagnostic dilemma is compounded by the limitations of traditional diagnostic tools. Spirometry, while essential for identifying obstructive lung disease, cannot differentiate between COPD and asthma in the context of HF, where bronchodilator responsiveness may be blunted due to cardiac-related airflow limitation.61–63 Biomarkers such as B-type natriuretic peptide (BNP) may be elevated in HF but can also be influenced by acute exacerbations of lung disease.64,65 Imaging studies like chest X-rays or echocardiograms may reveal cardiogenic pulmonary edema or structural heart disease but often fail to distinguish between chronic lung pathologies.66 Consequently, clinicians must rely on a combination of detailed history-taking, multimodal testing, and therapeutic trials to disentangle these overlapping conditions, emphasizing the need for an integrated diagnostic approach in this high-risk population.
Phenotyping these patients requires a multimodal approach that integrates clinical history, biomarkers, and imaging. Eosinophilia may indicate an asthma-predominant phenotype but can also occur in COPD or even HF with eosinophilic inflammation.67,68 Provocative testing, such as cardiopulmonary exercise testing, may further clarify whether exercise limitation stems primarily from ventilatory impairment or cardiac insufficiency. Ultimately, accurate phenotyping is critical for guiding therapy, as misclassification risks inappropriate treatment such as excessive beta-agonist use in HF or underutilization of guideline-directed HF therapies in patients mistakenly attributed solely to pulmonary disease. A structured diagnostic algorithm incorporating these elements is essential for optimizing care in this complex overlap population.
The Impact of Asthma and COPD Pathophysiology on Cardiac Function
The interplay between chronic airway inflammation and cardiac dysfunction forms a critical pathophysiological axis in the COPD-asthma-HF overlap syndrome. In both asthma and COPD, persistent pulmonary inflammation initiates a cascade of systemic effects that directly and indirectly impair cardiac function.69 Asthma, typically characterized by eosinophilic airway inflammation driven by type 2 cytokines (IL-4, IL-5, IL-13), and COPD, dominated by neutrophilic inflammation with elevated IL-6, IL-8, and TNF-α, share the common feature of creating a pro-inflammatory milieu that extends beyond the lungs.70,71 These circulating inflammatory mediators promote endothelial dysfunction, accelerate atherosclerosis, and contribute to myocardial remodeling key processes in the development and progression of HF.72,73 The impact of chronic airway inflammation on the cardiovascular system occurs through multiple mechanisms.74 First, systemic hypoxia resulting from impaired gas exchange in COPD and severe asthma triggers compensatory polycythemia and pulmonary vasoconstriction, increasing right ventricular afterload and potentially leading to cor pulmonale.75,76 Second, the oxidative stress associated with chronic lung diseases promotes the release of reactive oxygen species that directly damage cardiomyocytes and impair cardiac contractility.77,78 Third, the increased mechanical load on the heart from pulmonary hypertension (common in advanced COPD) combines with systemic inflammation to promote left ventricular diastolic dysfunction, a precursor to HF with preserved ejection fraction (HFpEF).79 This is particularly relevant in elderly patients with long-standing lung disease, where the cumulative burden of inflammation and hypoxia manifests as concurrent cardiac dysfunction.
Clinically, these interactions create diagnostic and therapeutic challenges. Patients may present with worsening dyspnea that could equally reflect an asthma/COPD exacerbation or acute HF decompensation.42,80 The inflammatory state of chronic lung disease also alters the cardiovascular response to therapy, for instance, beta-agonists used for bronchoconstriction may have reduced efficacy in the setting of myocardial inflammation while simultaneously increasing arrhythmia risk.40,81 Furthermore, corticosteroids, though effective for controlling airway inflammation, can exacerbate fluid retention and hypertension, potentially worsening cardiac function.82,83 Understanding these complex interactions is essential for managing the overlap syndrome. Biomarkers such as C-reactive protein (CRP) and NT-proBNP may help differentiate the relative contributions of inflammation versus cardiac strain, while imaging techniques like cardiac MRI can detect early myocardial fibrosis.84 Therapeutic strategies must balance anti-inflammatory control of lung disease with cardioprotective approaches, potentially including targeted biologics for eosinophilic asthma or pulmonary vasodilators in COPD-associated pulmonary hypertension.85 The recognition that chronic airway inflammation serves as both a driver and amplifier of cardiac dysfunction underscores the need for integrated care pathways in this high-risk population. Episodic asthma or chronic COPD, often with specific triggers (allergens, infections) and may improve with bronchodilators. Whilst, acute HF exerts exertional, orthopnea, paroxysmal nocturnal dyspnea (PND). HF has poor response to bronchodilator alone and improve with diuresis.
Effects of Pulmonary Hypertension and Right Heart Strain in COPD-HF Overlap
The development of pulmonary hypertension (PH) and subsequent right heart strain represents a critical pathway through which COPD exacerbates HF, creating a distinct phenotype within the overlap syndrome.21,86 In COPD, chronic alveolar hypoxia triggers hypoxic pulmonary vasoconstriction, which, when sustained, leads to vascular remodeling and increased pulmonary vascular resistance.87,88 This afterload elevation imposes significant strain on the right ventricle (RV), initially causing adaptive hypertrophy but eventually progressing to RV dilation and dysfunction – a condition termed cor pulmonale. The presence of concurrent HF further compounds this pathophysiology through multiple mechanisms: left ventricular diastolic dysfunction increases pulmonary venous pressures (post-capillary PH), while chronic systemic inflammation from COPD accelerates pulmonary vascular remodeling (pre-capillary PH).89,90
Clinically, this manifests as worsening exertional dyspnea disproportionate to spirometric findings, peripheral edema, and elevated jugular venous pressure – symptoms that overlap substantially with both COPD exacerbations and HF decompensation.91,92 The diagnostic challenge is heightened because traditional echocardiographic measures of RV function may be unreliable in COPD patients due to hyperinflation, while NT-proBNP levels can be elevated from either RV strain or left-sided HF.93,94 Therapeutic implications are profound: bronchodilators, while essential for COPD management, must be carefully titrated to avoid further increases in pulmonary artery pressures.95 Supplemental oxygen becomes crucial to break the cycle of hypoxic vasoconstriction, particularly in patients demonstrating nocturnal desaturation.96,97 Emerging evidence suggests a potential role for targeted PH therapies in select patients, though their use requires careful consideration of the underlying hemodynamics. This complex interplay underscores the need for comprehensive hemodynamic assessment in COPD-HF overlap patients presenting with disproportionate respiratory symptoms or exercise limitation.
Bronchoconstriction and Airway Remodeling in Asthma Exacerbating HF Symptoms
The interplay between asthma-related airway pathology and heart failure creates a particularly challenging clinical scenario within the overlap syndrome.10,98 In asthma patients with concomitant HF, bronchoconstriction and chronic airway remodeling impose significant additional burdens on an already compromised cardiovascular system through several distinct mechanisms.12,99 The acute bronchoconstriction characteristic of asthma exacerbations dramatically increases intrathoracic pressure fluctuations, which in turn elevate left ventricular afterload and reduce cardiac output.100 This effect is particularly pronounced in HF patients with reduced ejection fraction, where the heart operates on the steep portion of the Frank-Starling curve.101–103 Chronic airway remodeling in long-standing asthma further compounds these effects through persistent airflow limitation and dynamic hyperinflation.103,104 The resulting increased work of breathing raises myocardial oxygen demand while simultaneously reducing diastolic filling time due to tachycardia – a dangerous combination for patients with existing coronary artery disease or ventricular dysfunction.105,106 Additionally, the inflammatory milieu of poorly controlled asthma (particularly eosinophilic inflammation) may directly contribute to myocardial inflammation and fibrosis, potentially accelerating HF progression.107
These pathophysiological interactions create a vicious cycle where asthma exacerbations precipitate HF decompensation, and vice versa.108,109 The clinical presentation often manifests as refractory dyspnea that responds poorly to conventional bronchodilator therapy, with physical findings that may include both wheezing and pulmonary crackles.110 This overlap poses significant diagnostic challenges, as traditional markers like BNP may be elevated in both acute asthma exacerbations and HF decompensation.64 Therapeutic approaches must therefore address both the bronchoconstrictive component and its cardiovascular consequences, requiring careful balancing of beta-agonist therapy (with its potential arrhythmogenic effects) against the need for adequate bronchodilation.27,111 Distinct inflammatory profiles in COPD (neutrophilic; IL-8/TNF-α) and asthma (eosinophilic; IL-4/5/13) converge to drive systemic hypoxia, endothelial dysfunction, and cor pulmonale, creating a self-amplifying cardiopulmonary syndrome that requires targeted anti-inflammatory and bronchodilator interventions112 (Figure 3).
 |
Figure 3 Inflammatory and cardiopulmonary interactions in COPD-asthma-heart failure overlap. COPD (neutrophil-driven, involving IL-8 and TNF-α) and asthma (eosinophil-driven, involving IL-4, IL-5, and IL-13) contribute to lung inflammation, systemic hypoxia, and airway blockage (causing dyspnea and wheezing), which worsen endothelial dysfunction and atherosclerosis. Systemic inflammation (mediated by IL-6) further aggravates cardiovascular disease (CVD) and heart failure, while cor pulmonale (indicated by elevated BNP) signals right heart stress. This disease triad accelerates progression through shared pathways, highlighting the need for optimized bronchodilators and ICS to reduce inflammation, hypoxia, and cardiopulmonary impairment.
|
Identifying Treatable Traits: Eosinophilic Inflammation, Fluid Overload, and Bronchospasm
Within the COPD-asthma-HF overlap syndrome, a precision medicine approach focusing on identifiable and modifiable “treatable traits” offers a strategic framework for personalized management. Eosinophilic inflammation represents a particularly actionable target, as elevated blood or sputum eosinophil counts may predict responsiveness to inhaled corticosteroids (ICS) in asthma-COPD overlap while also indicating potential cardiac involvement, since eosinophilic myocarditis can worsen HF outcomes.113 However, distinguishing true Type 2 inflammation from HF-related eosinophilia requires correlation with clinical context and additional biomarkers like fractional exhaled nitric oxide (FeNO).48,114
Fluid overload, a cardinal feature of HF, frequently complicates respiratory symptoms in overlap patients.115,116 Careful assessment of jugular venous pressure, peripheral edema, and lung ultrasound B-lines helps differentiate cardiac from pulmonary causes of dyspnea.117,118 Notably, overzealous diuresis may worsen COPD by increasing mucus viscosity, while under-treatment perpetuates bronchial wall edema that mimics refractory asthma.119 Dynamic weight monitoring and natriuretic peptide trends provide objective measures to guide therapy. Bronchospasm, common to both asthma and COPD, requires nuanced management in HF patients.50 Reversible airflow obstruction on spirometry supports bronchodilator use, but the choice of agent matters long-acting muscarinic antagonists may be preferable to beta-agonists in HF due to lower arrhythmogenic potential.120,121 Treatment response should be assessed with both pulmonary function and cardiac parameters, as bronchodilation may unexpectedly improve ventricular filling in patients with hyperinflation-related diastolic dysfunction.122,123 By systematically evaluating these treatable traits, clinicians can develop targeted interventions that address the multifactorial pathophysiology of this high-risk overlap population.
Pharmacological Management Strategies: Bronchodilators in the Triad
The use of bronchodilators in the COPD-asthma-HF overlap requires careful balancing of pulmonary benefits against cardiovascular risks, necessitating an individualized approach based on dominant phenotypes.124 For patients with asthma-COPD predominance, long-acting β2-agonists (LABAs) remain foundational, but their cardiovascular effects demand particular caution in HF.125,126 Studies demonstrate that while selective β2-agonists improve FEV1 by 12–15% in overlap patients, they may increase heart rate by 8–10 bpm and potentially exacerbate arrhythmias in vulnerable individuals.81,127 This has led to preferential use of long-acting muscarinic antagonists (LAMAs) in HF-associated cases, which show comparable bronchodilation with superior cardiac safety profiles. Emerging evidence suggests tiotropium may reduce HF exacerbations in COPD patients by 21% compared to LABAs, possibly through reduced dynamic hyperinflation and improved cardiac filling.50
Dual bronchodilation (LAMA/LABA) presents a therapeutic dilemma – while highly effective for airflow limitation, the combination may compound risks in severe HF.128,129 Current guidelines recommend a stepwise approach: initiating LAMA monotherapy in high-risk cardiac patients, then cautiously adding LABAs while monitoring for tachycardia or arrhythmias.130 Ultra-LABAs like indacaterol, with faster onset and lower peak serum concentrations, may offer improved safety margins. Importantly, bronchodilator response should be assessed not just by spirometry, but through comprehensive evaluation including dyspnea scores, exercise tolerance, and cardiac biomarkers, as pulmonary decompression may unexpectedly improve ventricular function in some patients with significant hyperinflation. This nuanced approach underscores the need for close cardiopulmonary monitoring when optimizing bronchodilator therapy in this complex triad.
Role of LABAs/LAMAs in COPD-Asthma Overlap with HF
The therapeutic application of long-acting bronchodilators in patients with COPD-asthma-heart failure overlap requires careful consideration of both pulmonary efficacy and cardiovascular safety.131 LAMAs (eg, tiotropium, glycopyrronium) have emerged as preferred first-line agents due to their neutral cardiac profile, demonstrating comparable bronchodilation to LABAs without significant effects on heart rate or arrhythmia risk. Importantly, LAMAs may improve ventricular filling in HF patients by reducing dynamic hyperinflation, with studies showing a 15–20% improvement in cardiac output in responders.132,133
For LABA therapy (eg, salmeterol, formoterol), current evidence suggests cautious use in HF, particularly in patients with pre-existing arrhythmias or ischemic cardiomyopathy.134 While LABAs provide superior symptom relief in asthma-predominant overlap, their β2-adrenergic activity may increase myocardial oxygen demand and potentially worsen outcomes in advanced HF.135 Recent pharmacokinetic studies indicate that the newer ultra-LABAs (eg, indacaterol, olodaterol) with faster receptor dissociation may offer improved cardiac safety profiles.136
Risks of Beta-Agonists in HF and ICS Benefits in Eosinophilic Inflammation
The use of beta-agonists in HF requires careful risk stratification due to their potential to exacerbate cardiovascular instability.26 By stimulating β2-adrenergic receptors, these agents can induce tachycardia (increasing heart rate by 10–15 bpm) and lower serum potassium levels, thereby predisposing patients to atrial and ventricular arrhythmias particularly dangerous in those with pre-existing ischemic cardiomyopathy or reduced ejection fraction.137 Observational data suggest that frequent SABA use is associated with a 27% increased risk of HF hospitalization, while LABAs may elevate the relative risk of cardiovascular events by 1.3-fold in vulnerable populations. Key precautions include: (1) preferential use of cardioselective beta-agonists (eg, salmeterol over formoterol), (2) continuous cardiac monitoring during exacerbations, and (3) avoidance in decompensated HF (NYHA Class IV).50,138
Conversely, ICS demonstrate particular value in asthma-COPD overlap patients with eosinophilic inflammation (blood eosinophils ≥ 300 cells/μL), where they reduce exacerbation frequency by 30–40%.139 ICS mitigate airway inflammation through NF-κB inhibition, which may also beneficially modulate systemic inflammation contributing to HF progression.140 However, their use requires careful patient selection: ICS should be avoided in non-eosinophilic COPD phenotypes due to increased pneumonia risk, and in HF patients with fluid retention tendencies, as corticosteroids may worsen edema.141 Practical strategies include: (1) confirming eosinophilic inflammation via CBC or sputum analysis, (2) using the lowest effective ICS dose (eg, fluticasone 100 mcg BID), and (3) combining ICS with LAMAs rather than LABAs in HF patients to minimize β-adrenergic stimulation.142,143 Regular reassessment of both respiratory control and cardiac status ensures optimal benefit-risk balance in this complex triad. While LAMA/LABA combinations effectively alleviate airflow obstruction and hyperinflation in COPD-asthma-heart failure overlap, their cardiovascular safety profile necessitates individualized use, particularly avoiding LABAs in arrhythmia-prone patients to optimize cardiopulmonary outcomes3,144 (Figure 4).
 |
Figure 4 Cardiopulmonary Effects of LAMA/LABA Therapy in COPD-Asthma-Heart Failure Overlap. LAMAs exhibit cardiovascular neutrality, offering safe bronchodilation while enhancing ventricular filling and cardiac output in heart failure patients. Their combination with LABAs improves symptom control in asthma/COPD, though requires careful use in patients with arrhythmias or ischemic cardiomyopathy due to potential tachycardia risks. While reducing dynamic hyperinflation may improve cardiac function, LABAs necessitate vigilance for arrhythmic effects. Effective bronchodilator therapy in this high-risk patient group requires careful selection to optimize airway benefits (alleviating obstruction and hypoxia) while maintaining cardiac safety, underscoring the need for personalized treatment to prevent cardiovascular complications stemming from systemic hypoxia.
|
Potential Risks of Pneumonia and Fluid Retention in HF Patients
The use of ICS in COPD-asthma-HF overlap patients introduces two critical safety considerations that require vigilant monitoring: pneumonia risk and fluid retention.124 ICS therapy increases the relative risk of pneumonia by 1.5- to 2-fold in COPD patients, with this risk being particularly pronounced in those with concurrent HF due to pre-existing immune dysfunction and pulmonary congestion.145,146 Mechanistically, ICS impair alveolar macrophage function and mucociliary clearance, creating a permissive environment for bacterial colonization.147 This risk is further amplified in HF patients who frequently exhibit compromised respiratory defenses secondary to chronic pulmonary edema. Clinically, this necessitates careful screening for recurrent pneumonia (≥2 episodes/year) as a potential indication for ICS dose reduction or discontinuation, particularly in non-eosinophilic patients.148
Fluid retention represents another ICS-associated complication that may destabilize HF management. Corticosteroids enhance renal sodium reabsorption and potentiate mineralocorticoid effects, which can precipitate peripheral edema and worsen pulmonary congestion even at moderate doses.82 This effect is particularly problematic in patients with pre-existing right heart failure or renal impairment. Monitoring parameters should include daily weight measurements (alert threshold: >2 kg gain in 3 days), regular assessment of jugular venous pressure, and periodic BNP monitoring.149 Mitigation strategies include: (1) preferential use of ciclesonide (which has lower systemic bioavailability), (2) co-administration with diuretics, and (3) strict sodium restriction (<2 g/day).150 These precautions are especially crucial during acute exacerbations when systemic steroid bursts are required, as even short courses (eg, prednisone 40 mg × 5 days) can significantly worsen fluid balance in decompensated HF patients.151
Diuretics and Cardiac Medications: Loop Diuretics for HF with Pulmonary Congestion
In patients with the COPD-asthma-HF triad, loop diuretics play a pivotal yet nuanced role in managing pulmonary congestion while requiring careful titration to avoid exacerbating respiratory symptoms. These agents (eg, furosemide, torsemide) effectively reduce pulmonary vascular congestion by inhibiting the Na-K-2Cl transporter in the loop of Henle, thereby decreasing pulmonary capillary wedge pressure and improving gas exchange.152,153 However, their use in this overlap population presents unique challenges: over-aggressive diuresis may lead to excessive bronchial mucus dehydration, increasing sputum viscosity and exacerbating airflow obstruction in COPD, while electrolyte imbalances (particularly hypokalemia and hypomagnesemia) can lower the threshold for ventricular arrhythmias when combined with beta-agonist therapy.154,155 Optimal management requires a balanced approach, initiating with low-to-moderate doses (eg, furosemide 20–40 mg IV or equivalent oral dosing) and titrating based on both cardiac (eg, jugular venous pressure, daily weights) and respiratory (eg, sputum characteristics, oxygen saturation) parameters. Combination therapy with thiazide diuretics may be considered in refractory cases, though this necessitates close monitoring of renal function and electrolytes.156 Importantly, clinicians must remain vigilant for drug interactions – beta-agonists may counteract diuretic efficacy by promoting sodium retention, while corticosteroids can exacerbate fluid retention through mineralocorticoid effects. Emerging strategies such as lung ultrasound-guided diuresis, which allows real-time assessment of pulmonary edema resolution through B-line quantification, may help strike the crucial balance between alleviating cardiac congestion and maintaining adequate bronchial hydration in these complex patients5,157 (Table 2).
 |
Table 2 Pharmacological Management Strategies for the Triad
|
Non-Pharmacological Interventions
Non-pharmacological approaches are vital and complement pharmacological approaches. Higher improvements of these strategies have been found to enhance quality of life and reduce the risk of disease initiation. The primary and secondary non-pharmacological strategies are pulmonary rehabilitation, long-term oxygen therapy, non-invasive ventilation, smoking cessation, and patient education.168 Long-term oxygen therapy contributes to alleviate hypoxia, vasoconstriction, ventricular afterload, and pulmonary hypertension. Non-invasive ventilation provides massive support through unloading respiratory muscles, improving gas exchange, and reducing ventricular afterload.168 Therefore, risk of concomitant cardiac failure can be avoided in patients. Cigarette smoke initiates lung injury by enhancing airway inflammation, chronic hypoxia, and oxidative stress. Thereby, these series of events drive bronchial obstruction and endothelial dysfunction. Therefore, smoking cessation is highly effective to prevent further pulmonary damage and mitigate disease progression. Furthermore, patient education is a vital self-management which includes regular self-checkup, promoting smoking cessation, and mitigating exacerbations. Precisely, non-pharmacological interventions are promising alternatives to develop quality of life, mitigate disease progression, and to reduce hospitalizations.169
Conclusion
The COPD-asthma-HF overlap represents a high-risk clinical triad with shared pathophysiology, including chronic inflammation, airway obstruction, and cardiac dysfunction, leading to worsened outcomes. Diagnosis is challenging due to overlapping symptoms (dyspnea, wheezing, exercise intolerance) and limitations of conventional tests, necessitating a multimodal approach. Phenotyping patients based on treatable traits such as eosinophilic inflammation, fluid overload, or bronchospasm enables precision medicine strategies. Early diagnosis of HF is suggested for COPD patients to avoid recurrent exacerbation. NT-proBNP test is recommended in routine blood test for patients having HF symptoms. Patients with higher NT-proBNP are referred for further monitoring for suspected HF. Pharmacological management requires careful balancing: LAMAs are preferred in HF for their cardiac safety, while beta-agonists pose arrhythmia risks. ICS benefit eosinophilic inflammation but increase pneumonia and fluid retention risks in HF. Diuretics must be titrated carefully to avoid exacerbating COPD. Emerging strategies, including lung ultrasound-guided therapy and targeted pulmonary hypertension treatments, show promise. A multidisciplinary, patient-centered approach is essential to optimize care. Future research should refine diagnostic algorithms, explore novel biomarkers, and develop therapies that simultaneously target pulmonary and cardiovascular pathways. Improved recognition and tailored management of this complex overlap syndrome are crucial for reducing hospitalizations and mortality.
Funding
There is no funding to report.
Disclosure
The authors report no conflicts of interest in this work.
References
1. Khalid K, Padda J, Komissarov A, et al. The coexistence of chronic obstructive pulmonary disease and heart failure. Cureus. 2021;13(8):e17387. doi:10.7759/cureus.17387
2. Ingebrigtsen TS, Marott JL, Vestbo J, Nordestgaard BG, Lange P. Coronary heart disease and heart failure in asthma, COPD and asthma-COPD overlap. BMJ Open Resp Res. 2020;7(1):e000470. doi:10.1136/bmjresp-2019-000470
3. Long T. Chronic obstructive pulmonary disease (COPD 231).
4. Nakawah MO, Hawkins C, Barbandi F. Asthma, chronic obstructive pulmonary disease (COPD), and the overlap syndrome. J Am Board Fam Med. 2013;26(4):470–477. doi:10.3122/jabfm.2013.04.120256
5. Figueroa MS, Peters JI. Congestive heart failure: diagnosis, pathophysiology, therapy, and implications for respiratory care. Resp Care. 2006;51(4):403–412.
6. Dubé B-P, Agostoni P, Laveneziana P. Exertional dyspnoea in chronic heart failure: the role of the lung and respiratory mechanical factors. Eur Respir Rev. 2016;25(141):317–332. doi:10.1183/16000617.0048-2016
7. de Miguel Díez J, Morgan JC, García RJ. The association between COPD and heart failure risk: a review. Int J Chronic Obstr. 2013;305–312. doi:10.2147/COPD.S31236
8. Van Schayck C, Chavannes N. Detection of asthma and chronic obstructive pulmonary disease in primary care. Eur Respir J. 2003;21(39 suppl):16s–22s. doi:10.1183/09031936.03.00040403
9. Richie RC. Morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). J Insurance Med. 2023;49(4):230–243. doi:10.17849/insm-49-04-230-243.1
10. Leung JM, Sin DD. Asthma-COPD overlap syndrome: pathogenesis, clinical features, and therapeutic targets. BMJ. 2017;2017:358.
11. Brea TP, Lado-Baleato Ó, Elena Toubes Navarro M, Ferreiro Fernández L, Valdés L. Prognostic influence of cardiac comorbidities in chronic obstructive pulmonary disease. Respir Med. 2025;2025:108554.
12. Ahmad S, Isbatan A, Chen S, Dudek SM, Minshall RD, Chen J. The interplay of heart failure and lung disease: clinical correlations, mechanisms, and therapeutic implications. J Resp Biol Transl Med. 2024;1(4):10020. doi:10.70322/jrbtm.2024.10020
13. Triposkiadis F, Xanthopoulos A, Parissis J, Butler J, Farmakis D. Pathogenesis of chronic heart failure: cardiovascular aging, risk factors, comorbidities, and disease modifiers. Heart Fail Rev. 2022;27(1):337–344. doi:10.1007/s10741-020-09987-z
14. Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016;138(1):16–27. doi:10.1016/j.jaci.2016.05.011
15. Holgate ST. Airway inflammation and remodeling in asthma: current concepts. Mol Biotechnol. 2002;22(2):179–189. doi:10.1385/MB:22:2:179
16. Hasper D, Hummel M, Kleber F, Reindl I, Volk H-D. Systemic inflammation in patients with heart failure. Eur Heart J. 1998;19(5):761–765. doi:10.1053/euhj.1997.0858
17. Rogliani P, Ora J, Puxeddu E, Cazzola M. Airflow obstruction: is it asthma or is it COPD? Int J Chronic Obstr. 2016;Volume 11:3007–3013. doi:10.2147/COPD.S54927
18. Bakakos A, Vogli S, Dimakou K, Hillas G. Asthma with fixed airflow obstruction: from fixed to personalized approach. J Personalized Med. 2022;12(3):333. doi:10.3390/jpm12030333
19. Kee K, Naughton MT. Heart failure and the lung. Circ J. 2010;74(12):2507–2516. doi:10.1253/circj.CJ-10-0869
20. Tanai E, Frantz S. Pathophysiology of heart failure. Compr Physiol. 2016;6(1):187–214. doi:10.1002/j.2040-4603.2016.tb00669.x
21. Zangiabadi A, De Pasquale CG, Sajkov D. Pulmonary hypertension and right heart dysfunction in chronic lung disease. Biomed Res Int. 2014;2014(1):739674. doi:10.1155/2014/739674
22. Rosenkranz S, Howard LS, Gomberg-Maitland M, Hoeper MM. Systemic consequences of pulmonary hypertension and right-sided heart failure. Circulation. 2020;141(8):678–693. doi:10.1161/CIRCULATIONAHA.116.022362
23. Cassady SJ, Ramani GV. Right heart failure in pulmonary hypertension. Cardiol Clin. 2020;38(2):243–255. doi:10.1016/j.ccl.2020.02.001
24. Cotter G, Metra M, Milo‐Cotter O, Dittrich HC, Gheorghiade M. Fluid overload in acute heart failure—re‐distribution and other mechanisms beyond fluid accumulation. Eur J Heart Failure. 2008;10(2):165–169. doi:10.1016/j.ejheart.2008.01.007
25. Miller WL. Fluid volume overload and congestion in heart failure: time to reconsider pathophysiology and how volume is assessed. Circulation. 2016;9(8):e002922. doi:10.1161/CIRCHEARTFAILURE.115.002922
26. Hawkins NM, Petrie MC, MacDonald MR, et al. Heart failure and chronic obstructive pulmonary disease: the quandary of beta-blockers and beta-agonists. J Ame College Cardiol. 2011;57(21):2127–2138. doi:10.1016/j.jacc.2011.02.020
27. Miguel R, Siddharth C, Timothy V. The role of beta-agonist therapy for chronic obstructive airway disease in pa-tients with coexistent atrial fibrillation: literature review. J Clin Images Med Case Rep. 2021;2(6):1416. doi:10.52768/2766-7820/1416
28. Rodriguez-Guerra M, Chinta S, Montes De Oca Manuel VT. The role of beta-agonist therapy for chronic obstructive airway disease in patients with coexistent atrial fibrillation.
29. Sethi GS, Dharwal V, Naura AS. Immunological basis of Oxidative stress-induced lung inflammation in asthma and COPD. In: Oxidative Stress in Lung Diseases. Vol. 1. Springer; 2019:195–223.
30. Albano GD, Gagliardo RP, Montalbano AM, Profita M. Overview of the mechanisms of oxidative stress: impact in inflammation of the airway diseases. Antioxidants. 2022;11(11):2237. doi:10.3390/antiox11112237
31. Theofilis P, Sagris M, Oikonomou E, et al. Inflammatory mechanisms contributing to endothelial dysfunction. Biomedicines. 2021;9(7):781. doi:10.3390/biomedicines9070781
32. Zuchi C, Tritto I, Carluccio E, Mattei C, Cattadori G, Ambrosio G. Role of endothelial dysfunction in heart failure. Heart Fail Rev. 2020;25(1):21–30. doi:10.1007/s10741-019-09881-3
33. Healy F, Hanna B, Zinman R. Pulmonary complications of congenital heart disease. Paediatric Resp Rev. 2012;13(1):10–15. doi:10.1016/j.prrv.2011.01.007
34. Fontecave Jallon J, Abdulhay E, Calabrese P, Baconnier P, Gumery P-Y. A model of mechanical interactions between heart and lungs. Philos Trans Royal Soc A. 2009;367(1908):4741–4757. doi:10.1098/rsta.2009.0137
35. Mahmood SS, Pinsky MR. Heart-lung interactions during mechanical ventilation: the basics. Ann Translat Med. 2018;6(18):349. doi:10.21037/atm.2018.04.29
36. Sampath V, Aguilera J, Prunicki M, Nadeau KC. Mechanisms of Climate Change and Related Air Pollution on the Immune System Leading to Allergic Disease and Asthma. Elsevier. 2023:101765.
37. Macleod I, Sawyer S. The respiratory system and associated disorders. Fundamentals of Applied Pathophysiology for Paramedics. 2024:199–218.
38. Mocan D, Jipa R, Jipa DA, et al. Unveiling the systemic impact of congestion in heart failure: a narrative review of multisystem pathophysiology and clinical implications. J Cardiovasc Dev Dis. 2025;12(4):124. doi:10.3390/jcdd12040124
39. Tanwar S, Dhingra G, Goyal S, Chaturvedi V, Tanwar K. Beta-2-agonists in the management of asthma and chronic obstructive pulmonary disease. J Pharmaceut Educ Res. 2022;11:4.
40. Baker JG, Wilcox RG. β-Blockers, heart disease and COPD: current controversies and uncertainties. Thorax. 2017;72(3):271–276. doi:10.1136/thoraxjnl-2016-208412
41. Wahls SA. Causes and evaluation of chronic dyspnea. Am Family Phys. 2012;86(2):173–180.
42. Berliner D, Schneider N, Welte T, Bauersachs J. The differential diagnosis of dyspnea. Dtsch Arztebl Int. 2016;113(49):834. doi:10.3238/arztebl.2016.0834
43. Karnani NG, Reisfield GM, Wilson GR. Evaluation of chronic dyspnea. Am Family Phys. 2005;71(8):1529–1537.
44. Johnson J, Abraham T, Sandhu M, Jhaveri D, Hostoffer R, Sher T. Differential Diagnosis of Asthma. Allergy and Asthma. Springer; 2019:383–400.
45. Kann K, Long B, Koyfman A. Clinical mimics: an emergency medicine–focused review of asthma mimics. J Emergency Med. 2017;53(2):195–201. doi:10.1016/j.jemermed.2017.01.005
46. Güder G, Rutten FH. Comorbidity of heart failure and chronic obstructive pulmonary disease: more than coincidence. Current Heart Failure Rep. 2014;11(3):337–346. doi:10.1007/s11897-014-0212-x
47. Bottnera PC, Fernándeza TC, Valenzuelab ML, Romeroa PC. Miocardiopatía dilatada e insuficiencia cardíaca grave. Puesta al día para el médico pediatra. de Pediatría. 2018;413: e421–8.
48. Golino M. Interleukin-1 and eosinophils in heart failure. 2023.
49. Dharmage SC, Bui DS, Walters EH, et al. Lifetime spirometry patterns of obstruction and restriction, and their risk factors and outcomes: a prospective cohort study. Lancet Respir Med. 2023;11(3):273–282. doi:10.1016/S2213-2600(22)00364-2
50. Canepa M, Franssen FM, Olschewski H, et al. Diagnostic and therapeutic gaps in patients with heart failure and chronic obstructive pulmonary disease. JACC Heart Fail. 2019;7(10):823–833. doi:10.1016/j.jchf.2019.05.009
51. Stern EJ, Frank MS. CT of the lung in patients with pulmonary emphysema: diagnosis, quantification, and correlation with pathologic and physiologic findings. AJR. 1994;162(4):791–798. doi:10.2214/ajr.162.4.8140992
52. Alkhanfar D. Phenotyping Pulmonary Hypertension with CT and MR Imaging: Pulmonary Vessel and Right Ventricular Analysis. University of Sheffield; 2023.
53. Loukeri AA, Kampolis CF, Tatsis I, Loukeri PS, Tzagaraki A, Kythreotis P. Inhaled beta2-agonists and beta-blockers in patients with chronic obstructive pulmonary disease and cardiovascular comorbidities: therapeutic dilemmas, myths and realities. Pneumon. 2013;26(1):1.
54. Moon MA. Beta-Blockers: too Little in COPD, Too Soon in MI. J Med. 2012;367:904–912.
55. Öcal S, Durusu Tanrıöver M, Öcal A, et al. The coexistence of heart and lung diseases in patients with chronic dyspnoea that is unexplained by clinical evaluation. J Clin Pract Res. 2013;35(2):63.
56. Wagner PD. Skeletal muscles in chronic obstructive pulmonary disease: deconditioning, or myopathy? Respirology. 2006;11(6):681–686. doi:10.1111/j.1440-1843.2006.00939.x
57. Silva K, Marrara K, Marino D, Di Lorenzo V, Jamami M. Skeletal muscle weakness and exercise intolerance in patients with chronic obstructive pulmonary disease. Braz J Phys Ther. 2008;12:169–175.
58. Strzelak A, Ratajczak A, Adamiec A, Feleszko W. Tobacco smoke induces and alters immune responses in the lung triggering inflammation, allergy, asthma and other lung diseases: a mechanistic review. Int J Environ Res Public Health. 2018;15(5):1033. doi:10.3390/ijerph15051033
59. Mehta M, Dhanjal DS, Paudel KR, et al. Cellular signalling pathways mediating the pathogenesis of chronic inflammatory respiratory diseases: an update. Inflammopharmacology. 2020;28(4):795–817. doi:10.1007/s10787-020-00698-3
60. Bartlett LG. Defining the Pathophysiological Impact of Cigarette Smoke Extract in Mice as a Model for Chronic Obstructive Pulmonary Disease (COPD). University of Nottingham; 2024.
61. D’Urzo AD, Price D, Kardos P, Maleki-Yazdi MR. Importance of distinguishing between asthma and chronic obstructive pulmonary disease in primary care. Can Family Phys. 2021;67(9):661–667. doi:10.46747/cfp.6709661
62. Bouwens JD, Bischoff EW, in’t Veen JC, Schermer TR. Diagnostic differentiation between asthma and COPD in primary care using lung function testing. NPJ Primary Care Resp Med. 2022;32(1):32. doi:10.1038/s41533-022-00298-4
63. Balady GJ, Arena R, Sietsema K, et al. Clinician’s guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation. 2010;122(2):191–225. doi:10.1161/CIR.0b013e3181e52e69
64. Castiglione V, Aimo A, Vergaro G, Saccaro L, Passino C, Emdin M. Biomarkers for the diagnosis and management of heart failure. Heart Fail Rev. 2022;27(2):625–643. doi:10.1007/s10741-021-10105-w
65. McKie PM, Burnett JC. B-Type Natriuretic Peptide as a Biomarker Beyond Heart Failure: Speculations and Opportunities. Elsevier. 2005:1029–1036.
66. Tárnoki DL, Karlinger K, Ridge CA, et al. Lung imaging methods: indications, strengths and limitations. Breathe. 2024;20(3):230127. doi:10.1183/20734735.0127-2023
67. Vatrella A, Maglio A, Pelaia C, Ciampo L, Pelaia G, Vitale C. Eosinophilic inflammation: an appealing target for pharmacologic treatments in severe asthma. Biomedicines. 2022;10(9):2181. doi:10.3390/biomedicines10092181
68. Ramakrishnan RK, Mahboub B, Hamid Q. Asthma-chronic obstructive pulmonary disease overlap: a distinct pathophysiological and clinical entity. In: Asthma, COPD, and Overlap. CRC Press; 2018:41–52.
69. Wouters EF, Reynaert NL, Dentener MA, Vernooy JH. Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection? Proc Am Thorac Soc. 2009;6(8):638–647. doi:10.1513/pats.200907-073DP
70. Pelaia G, Vatrella A, Busceti MT, et al. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma. Mediators Inflamm. 2015;2015(1):879783. doi:10.1155/2015/879783
71. Lambrecht BN, Hammad H, Fahy JV. The cytokines of asthma. Immunity. 2019;50(4):975–991. doi:10.1016/j.immuni.2019.03.018
72. Glezeva N, Baugh J. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Fail Rev. 2014;19(5):681–694. doi:10.1007/s10741-013-9405-8
73. Anzai T. Inflammatory mechanisms of cardiovascular remodeling. Circ J. 2018;82(3):629–635. doi:10.1253/circj.CJ-18-0063
74. Aghasafari P, George U, Pidaparti R. A review of inflammatory mechanism in airway diseases. Inflammation Res. 2019;68(1):59–74. doi:10.1007/s00011-018-1191-2
75. Rodriguez-Roisin R. Acute severe asthma: pathophysiology and pathobiology of gas exchange abnormalities. Eur Respir J. 1997;10(6):1359–1371. doi:10.1183/09031936.97.10061359
76. Arrigo M, Price S, Harjola V-P, et al. Diagnosis and treatment of right ventricular failure secondary to acutely increased right ventricular afterload (acute cor pulmonale): a clinical consensus statement of the Association for Acute CardioVascular Care of the European Society of Cardiology. Eur Heart J Acute Cardiovasc Care. 2024;13(3):304–312. doi:10.1093/ehjacc/zuad157
77. Kubin A-M, Skoumal R, Tavi P, et al. Role of reactive oxygen species in the regulation of cardiac contractility. J Mol Cell Cardiol. 2011;50(5):884–893. doi:10.1016/j.yjmcc.2011.02.005
78. Zhang D, Li Y, Heims-Waldron D, et al. Mitochondrial cardiomyopathy caused by elevated reactive oxygen species and impaired cardiomyocyte proliferation. Circul Res. 2018;122(1):74–87. doi:10.1161/CIRCRESAHA.117.311349
79. Gulen ST, Eryilmaz U, Yilmaz M, Karadag F. Left ventricular dysfunction in relation with systemic inflammation in chronic obstructive pulmonary disease patients. Kor J Internal Med. 2018;34(3):569. doi:10.3904/kjim.2017.366
80. Celli BR, Fabbri LM, Aaron SD, et al. Differential diagnosis of suspected chronic obstructive pulmonary disease exacerbations in the acute care setting: best practice. Am J Respir Crit Care Med. 2023;207(9):1134–1144. doi:10.1164/rccm.202209-1795CI
81. Petta V, Perlikos F, Loukides S, et al. Therapeutic effects of the combination of inhaled beta2-agonists and beta-blockers in COPD patients with cardiovascular disease. Heart Fail Rev. 2017;22(6):753–763. doi:10.1007/s10741-017-9646-z
82. Janahi IA, Rehman A, Baloch NU-A. Corticosteroids and their use in respiratory disorders. In: Corticosteroids. London, UK: InTech Open; 2018:47–57.
83. Mokra D, Mikolka P, Kosutova P, Mokry J. Corticosteroids in acute lung injury: the dilemma continues. Int J Mol Sci. 2019;20(19):4765. doi:10.3390/ijms20194765
84. Wang Q, An Y, Wang H, Zhang N, Deng S. The clinical significance of changes in cTnT, CRP and NT-proBNP levels in patients with heart failure. Am J Transl Res. 2021;13(4):2947.
85. Victoni T, Barreto E, Lagente V, Carvalho VF. Oxidative imbalance as a crucial factor in inflammatory lung diseases: could antioxidant treatment constitute a new therapeutic strategy? Oxid Med Cell Longev. 2021;2021(1):6646923. doi:10.1155/2021/6646923
86. Guazzi M, Naeije R. Pulmonary hypertension in heart failure: pathophysiology, pathobiology, and emerging clinical perspectives. J Ame College Cardiol. 2017;69(13):1718–1734. doi:10.1016/j.jacc.2017.01.051
87. Sylvester J, Shimoda LA, Aaronson PI, Ward JP. Hypoxic pulmonary vasoconstriction. Physiol Rev. 2012;92(1):367–520. doi:10.1152/physrev.00041.2010
88. Simmons DH, Linde LM, Miller JH, O’reilly RJ. Relation between lung volume and pulmonary vascular resistance. Circul Res. 1961;9(2):465–471. doi:10.1161/01.RES.9.2.465
89. Riccardi M, Pagnesi M, Sciatti E, et al. Combined pre-and post-capillary pulmonary hypertension in left heart disease. Heart Fail Rev. 2023;28(1):137–148. doi:10.1007/s10741-022-10251-9
90. Karnati S, Seimetz M, Kleefeldt F, et al. Chronic obstructive pulmonary disease and the cardiovascular system: vascular repair and regeneration as a therapeutic target. Front Cardiovasc Med. 2021;8:649512. doi:10.3389/fcvm.2021.649512
91. Neder JA, Phillips DB, O’Donnell DE, Dempsey JA. Excess ventilation and exertional dyspnoea in heart failure and pulmonary hypertension. Eur Respir J. 2022;60(5):2200144. doi:10.1183/13993003.00144-2022
92. James MD, Phillips DB, Domnik NJ, Neder JA. Pathophysiological mechanisms of exertional dyspnea in people with cardiopulmonary disease: recent advances. Respir Physiol Neurobiol. 2025;336:104423. doi:10.1016/j.resp.2025.104423
93. Alter P, Watz H, Kahnert K, et al. Effects of airway obstruction and hyperinflation on electrocardiographic axes in COPD. Respir Res. 2019;20(1):61. doi:10.1186/s12931-019-1025-y
94. Porpáczy A, Nógrádi Á, Vértes V, et al. Left atrial stiffness is superior to volume and strain parameters in predicting elevated NT-proBNP levels in systemic sclerosis patients. Int J Cardiovasc Imaging. 2019;35(10):1795–1802. doi:10.1007/s10554-019-01621-w
95. Nardini S, Camiciottoli G, Locicero S, et al. COPD: maximization of bronchodilation. Multidiscip Resp Med. 2014;9(1):50. doi:10.1186/2049-6958-9-50
96. Owens RL, Derom E, Ambrosino N. Supplemental oxygen and noninvasive ventilation. Eur Respir Rev. 2023;32(167):220159. doi:10.1183/16000617.0159-2022
97. Ulrich S, Schneider SR, Bloch KE. Effect of hypoxia and hyperoxia on exercise performance in healthy individuals and in patients with pulmonary hypertension: a systematic review. J Appl Physiol. 2017;123(6):1657–1670. doi:10.1152/japplphysiol.00186.2017
98. Cazzola M, Page CP, Hanania NA, Calzetta L, Matera MG, Rogliani P. Asthma and cardiovascular diseases: navigating mutual pharmacological interferences. Drugs. 2024;84(10):1251–1273. doi:10.1007/s40265-024-02086-5
99. Forfia PR, Vaidya A, Wiegers SE. Pulmonary heart disease: the heart-lung interaction and its impact on patient phenotypes. Pulmonary Circul. 2013;3(1):5–19. doi:10.4103/2045-8932.109910
100. Papiris S, Kotanidou A, Malagari K, Roussos C. Clinical review: severe asthma. Critical Care. 2001;6(1):30. doi:10.1186/cc1451
101. Jacob R, Dierberger B, Kissling G. Functional significance of the Frank-Starling mechanism under physiological and pathophysiological conditions. Eur Heart J. 1992;13(suppl_E):7–14. doi:10.1093/eurheartj/13.suppl_E.7
102. Solaro RJ. Mechanisms of the Frank-Starling law of the heart: the beat goes on. Biophys J. 2007;93(12):4095–4096. doi:10.1529/biophysj.107.117200
103. Konhilas JP, Irving TC, de Tombe PP. Frank-Starling law of the heart and the cellular mechanisms of length-dependent activation. Pflügers Archiv. 2002;445(3):305–310. doi:10.1007/s00424-002-0902-1
104. Huang Y, Qiu C. Research advances in airway remodeling in asthma: a narrative review. Ann Translat Med. 2022;10(18):1023. doi:10.21037/atm-22-2835
105. GANz W, Donoso R, Marcus H, Swan H. Coronary hemodynamics and myocardial oxygen metabolism during oxygen breathing in patients with and without coronary artery disease. Circulation. 1972;45(4):763–768. doi:10.1161/01.CIR.45.4.763
106. Gutierrez C, Blanchard DG. Diastolic heart failure: challenges of diagnosis and treatment. Am Family Phys. 2004;69(11):2609–2617.
107. Roman-Pepine D, Serban AM, Capras R-D, Cismaru CM, Filip AG. A comprehensive review: unraveling the role of inflammation in the etiology of heart failure. Heart Failure Rev. 2025;2025:1–24.
108. Mann DL, Chakinala M. Heart failure: pathophysiology and diagnosis. Harrison, s Principles Internal Med. 2015;20:4383–4402.
109. Neder JA, Rocha A, Berton DC, O’Donnell DE. Clinical and physiologic implications of negative cardiopulmonary interactions in coexisting chronic obstructive pulmonary disease-heart failure. Clinics Chest Med. 2019;40(2):421–438. doi:10.1016/j.ccm.2019.02.006
110. Seifm Schreuder, Schreuder IM, Jiandani MP. Management of respiratory. Tidy’s Physiotherapy, South Asia Edition-E-Book. 2024:399.
111. Gosens R, Grainge C. Bronchoconstriction and airway biology: potential impact and therapeutic opportunities. Chest. 2015;147(3):798–803. doi:10.1378/chest.14-1142
112. Mathis BJ, Kusumoto M, Zaboronok A, Hiramatsu Y. Packaging and delivery of asthma therapeutics. Pharmaceutics. 2021;14(1):92. doi:10.3390/pharmaceutics14010092
113. Singh D. Blood eosinophil counts in chronic obstructive pulmonary disease: a biomarker of inhaled corticosteroid effects. Tubercul Resp Dis. 2020;83(3):185. doi:10.4046/trd.2020.0026
114. Lachowicz JI, Gać P. Short-term and long-term effects of inhaled ultrafine particles on blood markers of cardiovascular diseases: a systematic review and meta-analysis. J Clin Med. 2025;14(8):2846. doi:10.3390/jcm14082846
115. Tuy T, Peacock IVWF. Fluid Overload Assessment and Management in Heart Failure Patients. Elsevier. 2012. 112–120
116. Palazzuoli A, Evangelista I, Nuti R. Congestion occurrence and evaluation in acute heart failure scenario: time to reconsider different pathways of volume overload. Heart Fail Rev. 2020;25(1):119–131. doi:10.1007/s10741-019-09868-0
117. Srinivasan S. Lung and pleural pathology II: pulmonary edema, lung ultrasound.
118. Blay CM. The Use of Chest Ultrasound in Differential Diagnosis of Acute Dyspnea. Lithuanian University of Health Sciences (Lithuania); 2019.
119. Lin VY, Kaza N, Birket SE, et al. Excess mucus viscosity and airway dehydration impact COPD airway clearance. Eur Respir J. 2020;55(1):1900419. doi:10.1183/13993003.00419-2019
120. Smith HR, Iroin CG, Cherniack RM. The utility of spirometry in the diagnosis of reversible airways obstruction. Chest. 1992;101(6):1577–1581. doi:10.1378/chest.101.6.1577
121. Rebordosa C, Plana E, Rubino A, et al. Risk assessment of acute myocardial infarction and stroke associated with long-acting muscarinic antagonists, alone or in combination, versus long-acting beta2-agonists. Int J Chronic Obstr. 2022;Volume 17:1715–1733. doi:10.2147/COPD.S363997
122. Langer D, Ciavaglia CE, Neder JA, Webb KA, O’Donnell DE. Lung hyperinflation in chronic obstructive pulmonary disease: mechanisms, clinical implications and treatment. Expert Rev Resp Med. 2014;8(6):731–749. doi:10.1586/17476348.2014.949676
123. Aaron CP, Hoffman EA, Lima JA, et al. Pulmonary vascular volume, impaired left ventricular filling and dyspnea: the Mesa Lung Study. PLoS One. 2017;12(4):e0176180. doi:10.1371/journal.pone.0176180
124. Aljaroof M. Evaluation of Acute Cardiorespiratory Disease: Integrating Metabolite-Wide Analysis and Lung Mechanics Pathophysiology. University of Leicester; 2024.
125. Amegadzie JE. Pharmaco-Epidemiological Study of Cardiorespiratory Safety of Β2-Agonists for the Treatment and Management of Asthma, Chronic Obstructive Pulmonary Disease (DOPD) and Asthma-COPD Overlap. Memorial University of Newfoundland; 2021.
126. Xing G, Woo AY-H, Pan L, Lin B, Cheng M-S. Recent advances in β2-agonists for treatment of chronic respiratory diseases and heart failure. J Med Chem. 2020;63(24):15218–15242. doi:10.1021/acs.jmedchem.0c01195
127. Sima CA. Resting Heart Rate and Arterial Stiffness Relationship in Patients with Chronic Obstructive Pulmonary Disease. University of British Columbia; 2017.
128. Matera MG, Rogliani P, Calzetta L, Cazzola M. Safety considerations with dual bronchodilator therapy in COPD: an update. Drug Safety. 2016;39(6):501–508. doi:10.1007/s40264-016-0402-4
129. Cazzola M, Page C, Rogliani P, Calzetta L, Matera MG. Dual bronchodilation for the treatment of COPD: from bench to bedside. Br J Clin Pharmacol. 2022;88(8):3657–3673. doi:10.1111/bcp.15390
130. Mammen MJ, Pai V, Aaron SD, Nici L, Alhazzani W, Alexander PE. Dual LABA/LAMA therapy versus LABA or LAMA monotherapy for chronic obstructive pulmonary disease. A systematic review and meta-analysis in support of the American Thoracic Society clinical practice guideline. Ann Am Thoracic Soc. 2020;17(9):1133–1143. doi:10.1513/AnnalsATS.201912-915OC
131. Huang W-C, Fox GJ, Pham NY, et al. A syndromic approach to assess diagnosis and management of patients presenting with respiratory symptoms to healthcare facilities in Vietnam. ERJ Open Res. 2021;7(1):00572–2020. doi:10.1183/23120541.00572-2020
132. Jardim JR. Current Optimized Medical Treatment and the Impact on Dynamic Hyperinflation. In: Severe Pulmonary Emphysema. CRC Press; 2024:77–83.
133. Zhang C, Zhang M, Wang Y, et al. Efficacy and cardiovascular safety of LAMA in patients with COPD: a systematic review and meta-analysis. J Investig Med. 2021;69(8):1391–1398. doi:10.1136/jim-2021-001931
134. Lahousse L, Verhamme KM, Stricker BH, Brusselle GG. Cardiac effects of current treatments of chronic obstructive pulmonary disease. Lancet Respir Med. 2016;4(2):149–164. doi:10.1016/S2213-2600(15)00518-4
135. Packer M. β-Adrenergic blockade in chronic heart failure: principles, progress, and practice. Prog Cardiovasc Dis. 1998;41(1):39–52. doi:10.1016/S0033-0620(98)80030-3
136. Cazzola M, Rogliani P, Matera MG. Ultra-LABAs for the treatment of asthma. Respir Med. 2019;156:47–52. doi:10.1016/j.rmed.2019.08.005
137. Motiejunaite J, Amar L, Vidal-Petiot E. Adrenergic Receptors and Cardiovascular Effects of Catecholamines. Elsevier.2021: 193–197
138. Amegadzie JE, Gamble J-M, Farrell J, Gao Z. Association between inhaled β2-agonists initiation and risk of major adverse cardiovascular events: a population-based nested case-control study. Int J Chronic Obstr. 2022;Volume 17:1205–1217. doi:10.2147/COPD.S358927
139. Albertson TE, Chenoweth JA, Pearson SJ, Murin S. The pharmacological management of asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS). Exp Opinion Pharmacother. 2020;21(2):213–231. doi:10.1080/14656566.2019.1701656
140. Schuliga M. NF-kappaB signaling in chronic inflammatory airway disease. Biomolecules. 2015;5(3):1266–1283. doi:10.3390/biom5031266
141. Kostakou E, Kaniaris E, Filiou E, et al. Acute severe asthma in adolescent and adult patients: current perspectives on assessment and management. J Clin Med. 2019;8(9):1283. doi:10.3390/jcm8091283
142. Olschewski H, Canepa M, Kovacs G. Pulmonary and cardiac drugs: clinically relevant interactions. Herz. 2019;44(6):517–521. doi:10.1007/s00059-019-4834-3
143. Fuso L, Mores N, Valente S, Malerba M, Montuschi P. Long-acting beta-agonists and their association with inhaled corticosteroids in COPD. Curr Med Chem. 2013;20(12):1477–1495. doi:10.2174/0929867311320120003
144. Huang W-C. Complex Interventions to Address Chronic Respiratory Diseases and Tobacco Smoking in a Lower-Middle Income Setting. University of New South Wales (Australia); 2021.
145. Sibila O, Anzueto A, Restrepo MI. The paradoxical effect on pneumonia of chronic inhaled corticosteroids. Clin Pulm Med. 2013;20(1):6–10. doi:10.1097/CPM.0b013e31827a2a60
146. Corneanu LE, Sîngeap MS, Mutruc V, et al. The complex relationship between heart failure and chronic obstructive pulmonary disease: a comprehensive review. J Clin Med. 2025;14(13):4774. doi:10.3390/jcm14134774
147. Rodriguez-Rodriguez L, Gillet L, Machiels B. Shaping of the alveolar landscape by respiratory infections and long-term consequences for lung immunity. Front Immunol. 2023;14:1149015. doi:10.3389/fimmu.2023.1149015
148. MacLeod M, Papi A, Contoli M, et al. Chronic obstructive pulmonary disease exacerbation fundamentals: diagnosis, treatment, prevention and disease impact. Respirology. 2021;26(6):532–551. doi:10.1111/resp.14041
149. Javed F, Farrugia S, Colefax M, Schindhelm K. Early warning of acute decompensation in heart failure patients using a noncontact measure of stability index. IEEE Trans Biomed Eng. 2015;63(2):438–448. doi:10.1109/TBME.2015.2463283
150. Triposkiadis F, Xanthopoulos A, Skoularigis J. Targeting sodium in heart failure. J Personalized Med. 2024;14(10):1064. doi:10.3390/jpm14101064
151. Singh J, Palda V, Stanbrook M, Chapman K. Corticosteroid therapy for patients with acute exacerbations of chronic obstructive pulmonary disease: a systematic review. Arch Internal Med. 2002;162(22):2527–2536. doi:10.1001/archinte.162.22.2527
152. Shankar SS, Brater DC. Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol. 2003;284(1):F11–F21. doi:10.1152/ajprenal.00119.2002
153. Ferrari F, Zanza C, Tesauro M, et al. Clinical pharmacology of loop diuretics in critical care: f. Clin Pharmacokinet. 2025;2025:1–11.
154. Datta PK, Chowdhury SR, Aravindan A, Saha S, Rapaka S. Medical and surgical care of critical burn patients: a comprehensive review of current evidence and practice. Cureus. 2022;14(11):1.
155. Bardari S, D’Agata B, Sinagra G. Acute Management of Patients with Arrhythmias and Non-cardiac Diseases: metabolite Disorders and Ion Disturbances. In: The Arrhythmic Patient in the Emergency Department: A Practical Guide for Cardiologists and Emergency Physicians. Springer; 2015:129–150.
156. Gogikar A, Nanda A, Janga LSN, et al. Combination diuretic therapy with thiazides: a systematic review on the beneficial approach to overcome refractory fluid overload in heart failure. Cureus. 2023;15(9):1.
157. Mhanna M, Beran A, Nazir S, et al. Lung ultrasound–guided management to reduce hospitalization in chronic heart failure: a systematic review and meta-analysis. Heart Fail Rev. 2022;27(3):821–826. doi:10.1007/s10741-021-10085-x
158. Anzueto A, Miravitlles M. Tiotropium in chronic obstructive pulmonary disease–A review of clinical development. Respir Res. 2020;21(1):199. doi:10.1186/s12931-020-01407-y
159. Cuthbert JJ, Pellicori P, Clark AL. Optimal management of heart failure and chronic obstructive pulmonary disease: clinical challenges. Int J Gene Med. 2022;15:7961. doi:10.2147/IJGM.S295467
160. Garzon-Siatoya WT, Carrillo-Martin I, Chiarella SE, Gonzalez-Estrada A. State-of-the-art beta-adrenoreceptor agonists for the treatment of asthma. Exp Opinion Pharmacother. 2022;23(2):243–254. doi:10.1080/14656566.2021.1988074
161. Brzozowski T, Aguilar MEH, Abreu GEA. Topics in Autonomic Nervous System. BoD–Books on Demand; 2023.
162. Lee HW. Pharmacologic therapies for preventing chronic obstructive pulmonary disease exacerbations: a comprehensive review. Tubercul Resp Dis. 2025;88(2):216. doi:10.4046/trd.2024.0170
163. Habraken C. Inhaled Corticosteroids in the Treatment of COPD: The Risk of Developing Pneumonia. Faculty of Science and Engineering; 2015.
164. Arumugham V, Shahin M. Therapeutic uses of diuretic agents. StatPearls. 2023.
165. Suri SS, Pamboukian SV. Optimal diuretic strategies in heart failure. Ann Translat Med. 2021;9(6):517. doi:10.21037/atm-20-4600
166. Corrao S, Brunori G, Lupo U, Perticone F. Effectiveness and safety of concurrent beta-blockers and inhaled bronchodilators in COPD with cardiovascular comorbidities. Eur Respir Rev. 2017;26(145):160123. doi:10.1183/16000617.0123-2016
167. Malerba M, Montuschi P, Radaeli A, Pirisi M. Role of beta-blockers in patients with COPD: current perspective. Drug Discovery Today. 2015;20(1):129–135. doi:10.1016/j.drudis.2014.09.005
168. Janssens W, Verleden GM. Nonpharmacological interventions in COPD. Eur Respir Rev. 2023;32(167):230028. doi:10.1183/16000617.0028-2023
169. Bourbeau J, Marciniuk J. Non-pharmacological treatments of asthma chronic obstructive pulmonary disease overlap and rehabilitation programs. Immunol Allergy Clin North Am. 2022;42(3s):e1–e12. doi:10.1016/j.iac.2023.05.002