A clinical approach to obstructive sleep apnea as a risk factor for cardiovascular disease

Figures & data

Table 1 Overview of the association between OSA and cardiovascular risk factors, surrogate markers of cardiovascular dysfunction, and cardiovascular diseases and the impact of treatment with CPAP

	Association with OSA	Beneficial effect of CPAP
Cardiovascular risk factors
Hypertension	++^Citation20^–^Citation23	++^Citation23^–^Citation25,Citation27,Citation28
Diabetes/insulin resistance	++^Citation31,Citation32	(+)^Citation32^–^Citation34
Markers of autonomic tone
Muscle sympathetic nerve activity	+^Citation43,Citation44	+^Citation45
Heart rate variability	+^Citation46,Citation47
Heart rate recovery	+^Citation50,Citation51	+^Citation52
Markers of vascular structure/function
Endothelial function	++^Citation53,Citation54	++^Citation53,Citation55,Citation56
Carotid intima–media thickness	+^Citation57	+^Citation58
Aortic size	(+)^Citation60,Citation62,Citation63
Cardiac structure and function (in patients without overt cardiac disease)
Left ventricular mass	++^Citation18,Citation64^–^Citation66	+^Citation67
Systolic mitral annular velocity (s‘)	++^Citation68	+^Citation68
Global longitudinal strain	++^Citation70,Citation71	+^Citation70
Left ventricular diastolic function	++^Citation68,Citation73,Citation75	++^Citation67,Citation68,Citation73
Left atrial size	++^Citation68,Citation75	++^Citation67,Citation68
Pulmonary pressure	+^Citation77	+^Citation77,Citation67
Right ventricular size	+^Citation78	+^Citation67,Citation78,Citation82
Right ventricular function	+^Citation78,Citation80	+^Citation78,Citation82
CAD
Prevalence	++^Citation98,Citation99,Citation101
Incidence	+^Citation100
Clinical events in patients with established CAD	+^Citation103,Citation105,Citation106	+^Citation111,Citation112
Arrhythmia
Prevalence/incidence of atrial fibrillation	++^Citation115,Citation116
Recurrence of atrial fibrillation after cardioversion	++^Citation117^–^Citation119	+^Citation119,Citation120
Sudden cardiac death	+^Citation124
QT interval	+^Citation126
Heart failure
Prevalence	+^Citation98
Incidence	+^Citation66,Citation100
Measures of autonomic dysfunction	++^Citation132	++^Citation133^–^Citation135
LVEF in patients with HFrEF		+^Citation137,Citation138
Mortality	+^Citation136
Cardiac biomarkers
BNP/NT-proBNP	(+)^Citation83^–^Citation88	(+)^Citation52,Citation67,Citation90
Cardiac troponin	+^Citation87,Citation93^–^Citation96	−^Citation67,Citation97

Notes: Symbols to semiquantitatively indicate the strength of evidence: ++, good evidence from several high-quality large studies or mechanistic studies; +, consistent evidence from one large study and/or several small studies; (+), inconsistent findings; −, negative/neutral study results.

Abbreviations: BNP, B-type natriuretic peptide; CAD, coronary artery disease; CPAP, continuous positive airway pressure; HFrEF, heart failure with reduced LVEF; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal-pro-B-type natriuretic peptide; OSA, obstructive sleep apnea.

Figure 1 Schematic representation of the OSA-related effects on cardiac structure and function.

Note: Red, effects on the left heart; blue, effects on the pulmonary circulation and right heart.
Abbreviations: LA, left atrium/atrial; LV, left ventricle/ventricular; OSA, obstructive sleep apnea; RA, right atrium/atrial; RV, right ventricle/ventricular.

Figure 2 Illustration of the possible interplay between classical cardiovascular risk factors and cardiac diseases, and the role of OSA.

Notes: The black arrows indicate the effects by OSA on risk factors/cardiac diseases. The gray arrows indicate the coexisting effects between risk factors/cardiac diseases, which together with the OSA-related effects may eventually lead to heart failure.
Abbreviations: AF, atrial fibrillation; CAD, coronary artery disease; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; OSA, obstructive sleep apnea.

Table 2 Key findings and future directions regarding the impact of OSA on different aspects of cardiovascular diseases

	Current concept/key findings	Future directions/key questions
Hypertension	Association between higher AHI and higher prevalence and incidence of hypertension Limited data on the role of CPAP in prevention of hypertension in patients with OSA Significant, but relatively weak antihypertensive effect of CPAP in patients with hypertension and OSA	To define the role of blood pressure reduction by CPAP in patients with difficult-to-treat/resistant hypertension and OSA; role of CPAP versus pharmacological therapy
Diabetes	Association between higher AHI and higher prevalence and incidence of diabetes Conflicting data on the role of CPAP in prevention and therapy of diabetes in patients with OSA	To define the impact of treatment of OSA by CPAP on the measures of insulin resistance and long-term glucose control as well as body weight and lipids; role of CPAP versus insulin/metformin
OSA as a cardiovascular risk factor	Increased mortality in patients with severe OSA; mechanisms unknown	To find out whether OSA per se is associated with increased mortality or whether OSA is a surrogate for a cardiac disease To identify the mechanisms by which severe OSA mediates poor outcomes
Markers of increased sympathetic tone	Association between presence of OSA and OSA severity with increased muscle sympathetic nerve activity and impaired heart rate variability and heart rate recovery	To find out whether these markers provide relevant information for the management of patients with OSA, in addition to traditional markers of OSA severity
Vessels	Association between AHI and markers of early atherosclerosis (carotid intima–media thickness) and endothelial dysfunction Improvement by CPAP Some evidence of association between OSA and progression of aortic aneurysms	To identify the role of CPAP in addition to lifestyle changes and pharmacological therapy to preserve “vascular health” in primary prevention To identify the effect of CPAP on aortic aneurysm progression in patients with concomitant significant OSA
Cardiac structure and function	Association between OSA and LV mass, LV diastolic and systolic function, as well as atrial size Improvement in these parameters in small, predominantly uncontrolled studies	To identify (in controlled studies) the long-term effects of OSA treatment on LV mass, LV function, and left atrial size and function in selected patient groups, for example, patients with features of hypertensive heart disease and concomitant severe OSA
Pulmonary hypertension	Association between OSA and noninvasively assessed pulmonary pressure Small reduction in pulmonary pressure following CPAP; no invasive data available	To identify the invasive hemodynamic profile of “pure” severe OSA To identify the effect of CPAP on pulmonary pressure in patients with OSA and pulmonary artery hypertension without obvious cause
Cardiac biomarkers	No association between OSA and natriuretic peptides Association between OSA severity and high-sensitivity cardiac troponin T and I Association between high-sensitivity cardiac troponin T and death in patients with OSA	To establish the mechanisms which lead to cardiac troponin elevation in OSA (silent CAD, LV dysfunction, hypertension?)
CAD	Association between presence of OSA and prevalence and incidence of CAD (at least in males <70 years) Worse outcome of patients with established CAD and concomitant OSA; CPAP seems to attenuate this risk	To identify the effect of CPAP on CAD progression (vascular level), LV remodeling after myocardial infarction, and clinical endpoints (reinfarction, repeat revascularization, death)
AF	Association between presence and severity of OSA and prevalence and incidence of AF Lower risk of AF recurrence in OSA patients treated with CPAP	To identify the effect of CPAP on recurrence of AF in patients with paroxysmal AF treated pharmacologically and in patients with AF undergoing catheter ablation
HFrEF	Improvement in LVEF in HFrEF patients with OSA treated with CPAP (NB: adverse effect of ventilation observed only in HFrEF patients with central sleep apnea treated with adaptive servo-ventilation)	To identify the effect of CPAP in HFrEF patients with concomitant OSA on LV remodeling, exercise capacity, biomarkers, and clinical endpoints
HFpEF	OSA suggested as a possible factor involved in the pathophysiology of HFpEF (obese, hypertensive phenotype), but virtually no data available	Mechanistic studies on the impact of CPAP on cardiac function (noninvasive, invasive) in well-selected patients with HFpEF

Abbreviations: AF, atrial fibrillation; AHI, apnea–hypopnea index; CAD, coronary artery disease; CPAP, continuous positive airway pressure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; LVEF, left ventricular ejection fraction; OSA, obstructive sleep apnea.

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