Coronary microvascular dysfunction and heart failure with preserved ejection fraction: what are the mechanistic links?

Purpose of reviewHeart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort.There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically.CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.Papers of particular interest, published within the annual period of review, have been highlighted as:Up to 50% of patients with angina have nonobstructive coronary arteries (ANOCA) [1]. ANOCA is an umbrella term comprising several distinct pathophysiological entities, the most common one being coronary microvascular dysfunction (CMD). Coronary microvascular dysfunction is defined as an inability of the coronary vasculature to augment coronary blood flow (CBF), in response to a physiological stressor, in the absence of obstructive epicardial coronary artery disease (CAD). An impaired coronary flow reserve (CFR), which is the ratio of maximal achievable flow and resting flow in response to adenosine-mediated vasodilatation, is the hallmark of CMD [2]. Heart failure can be dichotomized into reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). HFpEF is a heterogenous syndrome comprising several distinct underlying causes. It has a dismal prognosis, which is partly because of our incomplete understanding of its pathophysiology that in turn has led to a paucity in the therapeutic options available for these patients. Recent evidence has suggested a strong link between CMD and HFpEF, with up to 75% of patients with HFpEF having underlying CMD [3]. However, whether this link is causal or simply associative is currently not well understood and is the focus of several ongoing studies. This review article focuses on the pathophysiological links between CMD and HFpEF. no caption availableCoronary microvascular dysfunction can result from altered function of endothelial cells, leading to attenuated nitric oxide (NO) production (endothelium-dependent microvascular dysfunction), or it can be because of the inability of the vascular smooth muscle (VSM) cells to vasodilate in response to NO (endothelium-independent microvascular dysfunction) [4]. In clinical practice, the former is characterized by an inability to augment CBF by at least 50% in response to acetylcholine infusion, and the latter is characterized as CFR less than 2.5 [5] in response to adenosine-mediated vasodilatation. Indeed, both of these entities can, and frequently do, co-exist. Furthermore, a majority of patients who have endothelium-independent microvascular dysfunction also have endothelium-dependent microvascular dysfunction, suggesting that the latter may be a precursor to the former [4]. Common cardiovascular risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia and cigarette smoking, are thought to lead to a systemic inflammatory state, which in turn leads to impaired endothelial and VSM cellular function. Up until recently, it was thought that endothelium-independent microvascular dysfunction was solely due to the inability to augment CBF during stress, that is, attenuation of hyperaemic flow. This was purported to be due to architectural changes, such as capillary rarefaction and vessel fibrosis. However, we have recently demonstrated that CMD may itself be a heterogenous condition comprising two distinct endotypes; functional and structural CMD [6]. Both endotypes are characterized by an impaired CFR and have similar degrees of coronary perfusion inefficiency during exercise and stress hypoperfusion on cardiac magnetic resonance (CMR) imaging; however, the underlying pathobiology appears to be distinct [6]. Patients with functional CMD have a normal minimal microvascular resistance and high resting CBF, whereas those with structural CMD have heightened minimal microvascular resistance and attenuated hyperaemic CBF [6]. Impairment of the NO pathway has been implicated in the pathophysiology of both these endotypes. The heightened resting CBF in functional CMD is purported to be due to elevated neuronal nitric oxide synthase (nNOS) levels, as nNOS regulates basal CBF [7], and the attenuated hyperaemic CBF in patients with structural CMD is purported to be due to impairment of the endothelial NOS (eNOS), as eNOS regulates CBF during stress [7]. These hypotheses are being investigated in ongoing studies. Therapeutic trials in patients with ANOCA have largely yielded equivocal results but whether endotype-directed therapy leads to better outcomes is currently not known.Purpose of reviewHeart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort.There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically.CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.Papers of particular interest, published within the annual period of review, have been highlighted as:Up to 50% of patients with angina have nonobstructive coronary arteries (ANOCA) [1]. ANOCA is an umbrella term comprising several distinct pathophysiological entities, the most common one being coronary microvascular dysfunction (CMD). Coronary microvascular dysfunction is defined as an inability of the coronary vasculature to augment coronary blood flow (CBF), in response to a physiological stressor, in the absence of obstructive epicardial coronary artery disease (CAD). An impaired coronary flow reserve (CFR), which is the ratio of maximal achievable flow and resting flow in response to adenosine-mediated vasodilatation, is the hallmark of CMD [2]. Heart failure can be dichotomized into reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). HFpEF is a heterogenous syndrome comprising several distinct underlying causes. It has a dismal prognosis, which is partly because of our incomplete understanding of its pathophysiology that in turn has led to a paucity in the therapeutic options available for these patients. Recent evidence has suggested a strong link between CMD and HFpEF, with up to 75% of patients with HFpEF having underlying CMD [3]. However, whether this link is causal or simply associative is currently not well understood and is the focus of several ongoing studies. This review article focuses on the pathophysiological links between CMD and HFpEF. no caption availableCoronary microvascular dysfunction can result from altered function of endothelial cells, leading to attenuated nitric oxide (NO) production (endothelium-dependent microvascular dysfunction), or it can be because of the inability of the vascular smooth muscle (VSM) cells to vasodilate in response to NO (endothelium-independent microvascular dysfunction) [4]. In clinical practice, the former is characterized by an inability to augment CBF by at least 50% in response to acetylcholine infusion, and the latter is characterized as CFR less than 2.5 [5] in response to adenosine-mediated vasodilatation. Indeed, both of these entities can, and frequently do, co-exist. Furthermore, a majority of patients who have endothelium-independent microvascular dysfunction also have endothelium-dependent microvascular dysfunction, suggesting that the latter may be a precursor to the former [4]. Common cardiovascular risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia and cigarette smoking, are thought to lead to a systemic inflammatory state, which in turn leads to impaired endothelial and VSM cellular function. Up until recently, it was thought that endothelium-independent microvascular dysfunction was solely due to the inability to augment CBF during stress, that is, attenuation of hyperaemic flow. This was purported to be due to architectural changes, such as capillary rarefaction and vessel fibrosis. However, we have recently demonstrated that CMD may itself be a heterogenous condition comprising two distinct endotypes; functional and structural CMD [6]. Both endotypes are characterized by an impaired CFR and have similar degrees of coronary perfusion inefficiency during exercise and stress hypoperfusion on cardiac magnetic resonance (CMR) imaging; however, the underlying pathobiology appears to be distinct [6]. Patients with functional CMD have a normal minimal microvascular resistance and high resting CBF, whereas those with structural CMD have heightened minimal microvascular resistance and attenuated hyperaemic CBF [6]. Impairment of the NO pathway has been implicated in the pathophysiology of both these endotypes. The heightened resting CBF in functional CMD is purported to be due to elevated neuronal nitric oxide synthase (nNOS) levels, as nNOS regulates basal CBF [7], and the attenuated hyperaemic CBF in patients with structural CMD is purported to be due to impairment of the endothelial NOS (eNOS), as eNOS regulates CBF during stress [7]. These hypotheses are being investigated in ongoing studies. Therapeutic trials in patients with ANOCA have largely yielded equivocal results but whether endotype-directed therapy leads to better outcomes is currently not known.Purpose of reviewHeart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort.There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically.CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question. Papers of particular interest, published within the annual period of review, have been highlighted as:Up to 50% of patients with angina have nonobstructive coronary arteries (ANOCA) [1]. ANOCA is an umbrella term comprising several distinct pathophysiological entities, the most common one being coronary microvascular dysfunction (CMD). Coronary microvascular dysfunction is defined as an inability of the coronary vasculature to augment coronary blood flow (CBF), in response to a physiological stressor, in the absence of obstructive epicardial coronary artery disease (CAD). An impaired coronary flow reserve (CFR), which is the ratio of maximal achievable flow and resting flow in response to adenosine-mediated vasodilatation, is the hallmark of CMD [2]. Heart failure can be dichotomized into reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). HFpEF is a heterogenous syndrome comprising several distinct underlying causes. It has a dismal prognosis, which is partly because of our incomplete understanding of its pathophysiology that in turn has led to a paucity in the therapeutic options available for these patients. Recent evidence has suggested a strong link between CMD and HFpEF, with up to 75% of patients with HFpEF having underlying CMD [3]. However, whether this link is causal or simply associative is currently not well understood and is the focus of several ongoing studies. This review article focuses on the pathophysiological links between CMD and HFpEF. no caption availableCoronary microvascular dysfunction can result from altered function of endothelial cells, leading to attenuated nitric oxide (NO) production (endothelium-dependent microvascular dysfunction), or it can be because of the inability of the vascular smooth muscle (VSM) cells to vasodilate in response to NO (endothelium-independent microvascular dysfunction) [4]. In clinical practice, the former is characterized by an inability to augment CBF by at least 50% in response to acetylcholine infusion, and the latter is characterized as CFR less than 2.5 [5] in response to adenosine-mediated vasodilatation. Indeed, both of these entities can, and frequently do, co-exist. Furthermore, a majority of patients who have endothelium-independent microvascular dysfunction also have endothelium-dependent microvascular dysfunction, suggesting that the latter may be a precursor to the former [4]. Common cardiovascular risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia and cigarette smoking, are thought to lead to a systemic inflammatory state, which in turn leads to impaired endothelial and VSM cellular function. Up until recently, it was thought that endothelium-independent microvascular dysfunction was solely due to the inability to augment CBF during stress, that is, attenuation of hyperaemic flow. This was purported to be due to architectural changes, such as capillary rarefaction and vessel fibrosis. However, we have recently demonstrated that CMD may itself be a heterogenous condition comprising two distinct endotypes; functional and structural CMD [6]. Both endotypes are characterized by an impaired CFR and have similar degrees of coronary perfusion inefficiency during exercise and stress hypoperfusion on cardiac magnetic resonance (CMR) imaging; however, the underlying pathobiology appears to be distinct [6]. Patients with functional CMD have a normal minimal microvascular resistance and high resting CBF, whereas those with structural CMD have heightened minimal microvascular resistance and attenuated hyperaemic CBF [6]. Impairment of the NO pathway has been implicated in the pathophysiology of both these endotypes. The heightened resting CBF in functional CMD is purported to be due to elevated neuronal nitric oxide synthase (nNOS) levels, as nNOS regulates basal CBF [7], and the attenuated hyperaemic CBF in patients with structural CMD is purported to be due to impairment of the endothelial NOS (eNOS), as eNOS regulates CBF during stress [7]. These hypotheses are being investigated in ongoing studies. Therapeutic trials in patients with ANOCA have largely yielded equivocal results but whether endotype-directed therapy leads to better outcomes is currently not known.Purpose of reviewHeart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort.There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically.CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.Papers of particular interest, published within the annual period of review, have been highlighted as:Up to 50% of patients with angina have nonobstructive coronary arteries (ANOCA) [1]. ANOCA is an umbrella term comprising several distinct pathophysiological entities, the most common one being coronary microvascular dysfunction (CMD). Coronary microvascular dysfunction is defined as an inability of the coronary vasculature to augment coronary blood flow (CBF), in response to a physiological stressor, in the absence of obstructive epicardial coronary artery disease (CAD). An impaired coronary flow reserve (CFR), which is the ratio of maximal achievable flow and resting flow in response to adenosine-mediated vasodilatation, is the hallmark of CMD [2]. Heart failure can be dichotomized into reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). HFpEF is a heterogenous syndrome comprising several distinct underlying causes. It has a dismal prognosis, which is partly because of our incomplete understanding of its pathophysiology that in turn has led to a paucity in the therapeutic options available for these patients. Recent evidence has suggested a strong link between CMD and HFpEF, with up to 75% of patients with HFpEF having underlying CMD [3]. However, whether this link is causal or simply associative is currently not well understood and is the focus of several ongoing studies. This review article focuses on the pathophysiological links between CMD and HFpEF. no caption availableCoronary microvascular dysfunction can result from altered function of endothelial cells, leading to attenuated nitric oxide (NO) production (endothelium-dependent microvascular dysfunction), or it can be because of the inability of the vascular smooth muscle (VSM) cells to vasodilate in response to NO (endothelium-independent microvascular dysfunction) [4]. In clinical practice, the former is characterized by an inability to augment CBF by at least 50% in response to acetylcholine infusion, and the latter is characterized as CFR less than 2.5 [5] in response to adenosine-mediated vasodilatation. Indeed, both of these entities can, and frequently do, co-exist. Furthermore, a majority of patients who have endothelium-independent microvascular dysfunction also have endothelium-dependent microvascular dysfunction, suggesting that the latter may be a precursor to the former [4]. Common cardiovascular risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia and cigarette smoking, are thought to lead to a systemic inflammatory state, which in turn leads to impaired endothelial and VSM cellular function. Up until recently, it was thought that endothelium-independent microvascular dysfunction was solely due to the inability to augment CBF during stress, that is, attenuation of hyperaemic flow. This was purported to be due to architectural changes, such as capillary rarefaction and vessel fibrosis. However, we have recently demonstrated that CMD may itself be a heterogenous condition comprising two distinct endotypes; functional and structural CMD [6]. Both endotypes are characterized by an impaired CFR and have similar degrees of coronary perfusion inefficiency during exercise and stress hypoperfusion on cardiac magnetic resonance (CMR) imaging; however, the underlying pathobiology appears to be distinct [6]. Patients with functional CMD have a normal minimal microvascular resistance and high resting CBF, whereas those with structural CMD have heightened minimal microvascular resistance and attenuated hyperaemic CBF [6]. Impairment of the NO pathway has been implicated in the pathophysiology of both these endotypes. The heightened resting CBF in functional CMD is purported to be due to elevated neuronal nitric oxide synthase (nNOS) levels, as nNOS regulates basal CBF [7], and the attenuated hyperaemic CBF in patients with structural CMD is purported to be due to impairment of the endothelial NOS (eNOS), as eNOS regulates CBF during stress [7]. These hypotheses are being investigated in ongoing studies. Therapeutic trials in patients with ANOCA have largely yielded equivocal results but whether endotype-directed therapy leads to better outcomes is currently not known.Purpose of reviewHeart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort.There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically.CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.Papers of particular interest, published within the annual period of review, have been highlighted as:Up to 50% of patients with angina have nonobstructive coronary arteries (ANOCA) [1]. ANOCA is an umbrella term comprising several distinct pathophysiological entities, the most common one being coronary microvascular dysfunction (CMD). Coronary microvascular dysfunction is defined as an inability of the coronary vasculature to augment coronary blood flow (CBF), in response to a physiological stressor, in the absence of obstructive epicardial coronary artery disease (CAD). An impaired coronary flow reserve (CFR), which is the ratio of maximal achievable flow and resting flow in response to adenosine-mediated vasodilatation, is the hallmark of CMD [2]. Heart failure can be dichotomized into reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). HFpEF is a heterogenous syndrome comprising several distinct underlying causes. It has a dismal prognosis, which is partly because of our incomplete understanding of its pathophysiology that in turn has led to a paucity in the therapeutic options available for these patients. Recent evidence has suggested a strong link between CMD and HFpEF, with up to 75% of patients with HFpEF having underlying CMD [3]. However, whether this link is causal or simply associative is currently not well understood and is the focus of several ongoing studies. This review article focuses on the pathophysiological links between CMD and HFpEF. no caption availableCoronary microvascular dysfunction can result from altered function of endothelial cells, leading to attenuated nitric oxide (NO) production (endothelium-dependent microvascular dysfunction), or it can be because of the inability of the vascular smooth muscle (VSM) cells to vasodilate in response to NO (endothelium-independent microvascular dysfunction) [4]. In clinical practice, the former is characterized by an inability to augment CBF by at least 50% in response to acetylcholine infusion, and the latter is characterized as CFR less than 2. 5 [5] in response to adenosine-mediated vasodilatation. Indeed, both of these entities can, and frequently do, co-exist. Furthermore, a majority of patients who have endothelium-independent microvascular dysfunction also have endothelium-dependent microvascular dysfunction, suggesting that the latter may be a precursor to the former [4]. Common cardiovascular risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia and cigarette smoking, are thought to lead to a systemic inflammatory state, which in turn leads to impaired endothelial and VSM cellular function. Up until recently, it was thought that endothelium-independent microvascular dysfunction was solely due to the inability to augment CBF during stress, that is, attenuation of hyperaemic flow. This was purported to be due to architectural changes, such as capillary rarefaction and vessel fibrosis. However, we have recently demonstrated that CMD may itself be a heterogenous condition comprising two distinct endotypes; functional and structural CMD [6]. Both endotypes are characterized by an impaired CFR and have similar degrees of coronary perfusion inefficiency during exercise and stress hypoperfusion on cardiac magnetic resonance (CMR) imaging; however, the underlying pathobiology appears to be distinct [6]. Patients with functional CMD have a normal minimal microvascular resistance and high resting CBF, whereas those with structural CMD have heightened minimal microvascular resistance and attenuated hyperaemic CBF [6]. Impairment of the NO pathway has been implicated in the pathophysiology of both these endotypes. The heightened resting CBF in functional CMD is purported to be due to elevated neuronal nitric oxide synthase (nNOS) levels, as nNOS regulates basal CBF [7], and the attenuated hyperaemic CBF in patients with structural CMD is purported to be due to impairment of the endothelial NOS (eNOS), as eNOS regulates CBF during stress [7]. These hypotheses are being investigated in ongoing studies. Therapeutic trials in patients with ANOCA have largely yielded equivocal results but whether endotype-directed therapy leads to better outcomes is currently not known.Purpose of reviewHeart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort.There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically. CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.Papers of particular interest, published within the annual period of review, have been highlighted as:Up to 50% of patients with angina have nonobstructive coronary arteries (ANOCA) [1]. ANOCA is an umbrella term comprising several distinct pathophysiological entities, the most common one being coronary microvascular dysfunction (CMD). Coronary microvascular dysfunction is defined as an inability of the coronary vasculature to augment coronary blood flow (CBF), in response to a physiological stressor, in the absence of obstructive epicardial coronary artery disease (CAD). An impaired coronary flow reserve (CFR), which is the ratio of maximal achievable flow and resting flow in response to adenosine-mediated vasodilatation, is the hallmark of CMD [2]. Heart failure can be dichotomized into reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). HFpEF is a heterogenous syndrome comprising several distinct underlying causes. It has a dismal prognosis, which is partly because of our incomplete understanding of its pathophysiology that in turn has led to a paucity in the therapeutic options available for these patients. Recent evidence has suggested a strong link between CMD and HFpEF, with up to 75% of patients with HFpEF having underlying CMD [3]. However, whether this link is causal or simply associative is currently not well understood and is the focus of several ongoing studies. This review article focuses on the pathophysiological links between CMD and HFpEF. no caption availableCoronary microvascular dysfunction can result from altered function of endothelial cells, leading to attenuated nitric oxide (NO) production (endothelium-dependent microvascular dysfunction), or it can be because of the inability of the vascular smooth muscle (VSM) cells to vasodilate in response to NO (endothelium-independent microvascular dysfunction) [4]. In clinical practice, the former is characterized by an inability to augment CBF by at least 50% in response to acetylcholine infusion, and the latter is characterized as CFR less than 2.5 [5] in response to adenosine-mediated vasodilatation. Indeed, both of these entities can, and frequently do, co-exist. Furthermore, a majority of patients who have endothelium-independent microvascular dysfunction also have endothelium-dependent microvascular dysfunction, suggesting that the latter may be a precursor to the former [4]. Common cardiovascular risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia and cigarette smoking, are thought to lead to a systemic inflammatory state, which in turn leads to impaired endothelial and VSM cellular function. Up until recently, it was thought that endothelium-independent microvascular dysfunction was solely due to the inability to augment CBF during stress, that is, attenuation of hyperaemic flow. This was purported to be due to architectural changes, such as capillary rarefaction and vessel fibrosis. However, we have recently demonstrated that CMD may itself be a heterogenous condition comprising two distinct endotypes; functional and structural CMD [6]. Both endotypes are characterized by an impaired CFR and have similar degrees of coronary perfusion inefficiency during exercise and stress hypoperfusion on cardiac magnetic resonance (CMR) imaging; however, the underlying pathobiology appears to be distinct [6]. Patients with functional CMD have a normal minimal microvascular resistance and high resting CBF, whereas those with structural CMD have heightened minimal microvascular resistance and attenuated hyperaemic CBF [6]. Impairment of the NO pathway has been implicated in the pathophysiology of both these endotypes. The heightened resting CBF in functional CMD is purported to be due to elevated neuronal nitric oxide synthase (nNOS) levels, as nNOS regulates basal CBF [7], and the attenuated hyperaemic CBF in patients with structural CMD is purported to be due to impairment of the endothelial NOS (eNOS), as eNOS regulates CBF during stress [7]. These hypotheses are being investigated in ongoing studies. Therapeutic trials in patients with ANOCA have largely yielded equivocal results but whether endotype-directed therapy leads to better outcomes is currently not known.Purpose of reviewHeart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort.There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically.CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.Papers of particular interest, published within the annual period of review, have been highlighted as:Up to 50% of patients with angina have nonobstructive coronary arteries (ANOCA) [1]. ANOCA is an umbrella term comprising several distinct pathophysiological entities, the most common one being coronary microvascular dysfunction (CMD). Coronary microvascular dysfunction is defined as an inability of the coronary vasculature to augment coronary blood flow (CBF), in response to a physiological stressor, in the absence of obstructive epicardial coronary artery disease (CAD). An impaired coronary flow reserve (CFR), which is the ratio of maximal achievable flow and resting flow in response to adenosine-mediated vasodilatation, is the hallmark of CMD [2]. Heart failure can be dichotomized into reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). HFpEF is a heterogenous syndrome comprising several distinct underlying causes. It has a dismal prognosis, which is partly because of our incomplete understanding of its pathophysiology that in turn has led to a paucity in the therapeutic options available for these patients. Recent evidence has suggested a strong link between CMD and HFpEF, with up to 75% of patients with HFpEF having underlying CMD [3]. However, whether this link is causal or simply associative is currently not well understood and is the focus of several ongoing studies. This review article focuses on the pathophysiological links between CMD and HFpEF. no caption availableCoronary microvascular dysfunction can result from altered function of endothelial cells, leading to attenuated nitric oxide (NO) production (endothelium-dependent microvascular dysfunction), or it can be because of the inability of the vascular smooth muscle (VSM) cells to vasodilate in response to NO (endothelium-independent microvascular dysfunction) [4]. In clinical practice, the former is characterized by an inability to augment CBF by at least 50% in response to acetylcholine infusion, and the latter is characterized as CFR less than 2.5 [5] in response to adenosine-mediated vasodilatation. Indeed, both of these entities can, and frequently do, co-exist. Furthermore, a majority of patients who have endothelium-independent microvascular dysfunction also have endothelium-dependent microvascular dysfunction, suggesting that the latter may be a precursor to the former [4]. Common cardiovascular risk factors, such as hypertension, diabetes mellitus, hyperlipidaemia and cigarette smoking, are thought to lead to a systemic inflammatory state, which in turn leads to impaired endothelial and VSM cellular function. Up until recently, it was thought that endothelium-independent microvascular dysfunction was solely due to the inability to augment CBF during stress, that is, attenuation of hyperaemic flow. This was purported to be due to architectural changes, such as capillary rarefaction and vessel fibrosis. However, we have recently demonstrated that CMD may itself be a heterogenous condition comprising two distinct endotypes; functional and structural CMD [6]. Both endotypes are characterized by an impaired CFR and have similar degrees of coronary perfusion inefficiency during exercise and stress hypoperfusion on cardiac magnetic resonance (CMR) imaging; however, the underlying pathobiology appears to be distinct [6]. Patients with functional CMD have a normal minimal microvascular resistance and high resting CBF, whereas those with structural CMD have heightened minimal microvascular resistance and attenuated hyperaemic CBF [6]. Impairment of the NO pathway has been implicated in the pathophysiology of both these endotypes. The heightened resting CBF in functional CMD is purported to be due to elevated neuronal nitric oxide synthase (nNOS) levels, as nNOS regulates basal CBF [7], and the attenuated hyperaemic CBF in patients with structural CMD is purported to be due to impairment of the endothelial NOS (eNOS), as eNOS regulates CBF during stress [7]. These hypotheses are being investigated in ongoing studies. Therapeutic trials in patients with ANOCA have largely yielded equivocal results but whether endotype-directed therapy leads to better outcomes is currently not known.