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Heart Failure With Preserved Ejection Fraction: Is Ischemia Due to Coronary Microvascular Dysfunction a Mechanistic Factor?
REVIEW
Heart Failure With Preserved Ejection Fraction: Is Ischemia Due to Coronary Microvascular Dysfunction a Mechanistic Factor? Islam Y. Elgendy, MD, Carl J. Pepine, MD Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville.
ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence and has no guidelinerecommended therapy, related in part to a lack of mechanism. Traditionally, HFpEF was thought to be secondary to afterload overload due to systemic hypertension; however, accumulating evidence suggests that HFpEF continues to worsen despite adequate control of blood pressure. Emerging data support the suggestion that myocardial ischemia secondary to coronary microvascular dysfunction could be the new paradigm pathophysiology. Several prospective, observational cohort studies indicate that the outcomes of patients with microvascular dysfunction, after an interval of several years, are dominated by HFpEF hospitalizations. Further, the most prevalent clinical phenotype (eg older women with multiple comorbidities) of patients with HFpEF resembles those with coronary microvascular dysfunction, albeit older. In this review, we provide in-depth insight about this emerging HFpEF paradigm, discuss potential therapeutic implications of this pathophysiology, and summarize some important knowledge gaps. Ó 2019 Elsevier Inc. All rights reserved. The American Journal of Medicine (2019) 132:692−697 KEYWORDS: Coronary artery disease; Heart failure; Ischemia; Microvascular dysfunction; Preserved ejection fraction
CORONARY MICROVASCULAR DYSFUNCTION AND NONOBSTRUCTIVE CORONARY ARTERY DISEASE Approximately 50% of patients with symptoms or signs of ischemia referred for elective coronary angiography are found to have nonobstructive coronary artery disease.1 Compared with those with “apparently normal” coronary arteries, their counterparts with nonobstructive coronary artery disease have worse outcomes. In a study of Funding: CJP receives support from the National Institutes of Health (NIH), National Heart, Lung and Blood Institute HL087366; HL033610, HL132448, HL130163; the United States Department of Defense PR161603; the Gatorade Trust through funds distributed by the University of Florida Department of Medicine; NIH NCATS—University of Florida Clinical and Translational Science UL1TR001427; and PCORnet-OneFlorida Clinical Research Consortium CDRN-1501-26692. Conflicts of Interest: None. Authorship: Both authors had access to the data and a role in writing this manuscript. Requests for reprints should be addressed to Carl J. Pepine, MD, Division of Cardiovascular Medicine, University of Florida, 1600 SW Archer Rd., PO Box 100277, Gainesville, FL, 32610. E-mail address: [email protected]
0002-9343/© 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjmed.2018.12.038
approximately 38,000 US veterans, the presence of nonobstructive coronary artery disease on elective coronary angiogram was associated with a higher mortality at 1 year, compared with those with “normal” coronary arteries.2 In a Danish registry of about 11,000 subjects with angina undergoing “a first” coronary angiogram, nonobstructive coronary artery disease was associated with a higher risk of adverse outcomes at 7.5 years median follow-up. This outcome was driven mostly by heart failure hospitalizations and cardiovascular mortality.3 These findings were further supported by a meta-analysis of »64,000 patients referred for either computed tomography coronary angiography or invasive coronary angiography, in which those with nonobstructive coronary artery disease, compared with those with normal angiograms, had >3-fold higher risk of major adverse cardiac events at 27 months median follow-up.4 Multiple reports document that symptomatic patients with nonobstructive coronary artery disease incur health care costs and disabilities similar to those with obstructive coronary artery disease, mostly because of repeated hospitalizations for heart failure and angina.5 In an economic
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analysis, women with nonobstructive coronary artery disstiffness as typically observed in patients with HFpEF. ease had substantially high, symptom-driven costs of care, Interestingly, the systemic inflammatory state generated mostly resulting from hospitalizations for angina and heart secondary to these comorbidities appears predictive of failure.5 incident HFpEF but not of incident heart failure with An important consideration is that patients with nonobreduced ejection fraction (HFrEF).9 Second, patients who structive coronary artery disease are likely to have preare obese tend to have more salt retention through served left ventricular ejection fraction. Despite that, these enhanced renal tubular sodium reabsorption.10 High salt patients are more prone to hosintake in patients with salt-sensipitalizations as a result of heart CLINICAL SIGNIFICANCE tive hypertension leads to sysfailure. In an analysis of 1218 temic oxidative stress as a result Traditionally, heart failure with preserved of renal production of proinflampatients referred for perfusion imaging for suspected myocarejection fraction (HFpEF) was thought to matory cytokines.11 Further, dial ischemia, those with be secondary to afterload overload due to individuals who are obese are impaired coronary flow reserve more likely to be inactive and systemic hypertension. (<2.0) had a higher incidence of have poor functional capacity, Emerging data support the suggestion that which has been linked to hospicardiac events, mainly due to myocardial ischemia secondary to coronary talizations for heart failure in the hospitalizations for heart failmicrovascular dysfunction could be the new population with coronary microure, at a median follow-up of only 1.3 years.6 These findings vascular dysfunction.12 With paradigm pathophysiology. strongly suggest a possible link expanding plasma volume, the This review provides in-depth insight about heart would normally react by between nonobstructive corothis emerging HFpEF paradigm, discusses chamber dilation; however, due nary artery disease/coronary the potential therapeutic implications of to underlying myocardial fibrosis microvascular dysfunction and this pathophysiology, and summarizes some and increased diastolic stiffness heart failure with preserved ejection fraction (HFpEF). In from the fibrosis, systemic important knowledge gaps. other words, nonobstructive inflammation, and underlying coronary artery disease with ischemia (see below) during coronary microvascular dysfunction appears to represent a daily life,7 the dilation is limited. In turn, this sequence of “pre-HFpEF” syndrome or condition.7 events increases cardiac filling pressures and leads to heart failure without impairment of systolic function. This is the “paradigm” shift for HFpEF pathophysiology described COMORBIDITIES IN PATIENTS WITH HFPEF by Paulus et al.13 COMPARED TO PATIENTS WITH CORONARY Another important observation is that patients with coronary microvascular dysfunction have an increased prevaMICROVASCULAR DYSFUNCTION lence of chronic kidney disease, which might be secondary Symptomatic patients with coronary microvascular dysto other comorbidities like hypertension and diabetes or function and nonobstructive coronary artery disease are independent by increasing superoxide and reducing nitric typically women ages 40-65 years old with multiple comoroxide, which results in endothelial dysfunction.14 In more bidities (eg hypertension, obesity, hypercholesteremia, diaadvanced stages of chronic kidney disease, retention of urebetes, inactivity, and even chronic kidney disease). They mic toxins further increases oxidative stress to amplify often exhibit diastolic left ventricular dysfunction on carmicrovascular dysfunction.15 Whether renal dysfunction is diac imaging and central aortic stiffening. Those with a predisposing factor in the pathogenesis of HFpEF or both HFpEF have a similar clinical phenotype except that they diseases are a consequence of microvascular dysfunction are likely to be older (>60 years). Thus, these findings supremains an important knowledge gap. port the suggestion that the “clinical phenotype” associated Patients with heart failure (both HFpEF and HFrEF) with HFpEF is remarkably similar to that of older patients have altered structure and function of the gastrointestinal with coronary microvascular dysfunction. So, is there a mucosa as a consequence of microcirculatory disturbanmechanistic link between these syndromes? ces.16 A leaky intestinal barrier, with an augmented bacteObesity could contribute to development of HFpEF rial biofilm, may contribute to chronic inflammation and through at least 2 important mechanisms. First, obesity malnutrition. Lack of mucosal integrity, with local and systriggers systemic inflammation. Adipose tissue, particutemic inflammation and dysfunction of transport proteins, larly visceral fat, is infiltrated with macrophages, which may worsen chronic heart failure and associated symprelease pro-inflammatory cytokines that stimulate myocartoms.17 It remains unclear whether the increase of adherent dial fibrosis and endothelial dysfunction within coronary 8 bacteria in patients with chronic heart failure is a primary microvasculature. The heightened systemic inflammatory or secondary event and whether this might contribute to state is linked with left ventricular hypertrophy, myocarsystemic inflammation. dial remodeling, fibrosis, and increased conduit vessel
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THE CORONARY MICROVASCULAR DYSFUNCTION/DISEASE PARADIGM This coronary microvascular dysfunction paradigm is increasing recognized as a potential pathophysiological mechanism of HFpEF, unlike myocardial overload secondary to hypertension that has been considered as the traditional mechanism.18 This was suggested previously by hypertensive animal models that demonstrated progression of concentric left ventricular remodeling to maladaptive eccentric remodeling, thus resulting in end-stage HFrEF.19 These findings were disputed in a recent study in which senescence-accelerated mice (ie cellular growth arrest linked with aging and inflammation) treated with Western high-salt, high-fat diet developed HFpEF as a result of endothelial dysfunction.20 In an echocardiographic study that longitudinally followed patients with HFpEF over 5 years, there was minimal reduction in ejection fraction (1%/year), and this decline was mostly concentrated among older patients and those with coronary artery disease.21 In a similar echocardiographic study over 4 years, subjects with increased left ventricular diastolic stiffness had weight gain associated with an increase in left ventricular diastolic stiffness, even after adjustment for changes in afterload.22 Extended follow-up of Health ABC (11 years) suggested that arterial stiffness (as carotid-femoral pulse wave velocity) was not associated with incident HFpEF, after adjustment for traditional cardiovascular risk factors (ie age, sex, body mass index, and diabetes or kidney disease).23 Additionally, multiple randomized trials have not found afterload reducing agents (eg nitrates, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers) beneficial in patients with HFpEF.24,25 Considerable evidence has found that myocardial contraction is modulated by molecules such as nitric oxide and prostaglandins from endothelium. In one study,26 nitric oxide released from endothelium lowered left ventricular systolic pressure and increased diastolic dispensability. Thus, endothelial dysfunction, as expected with ischemia as a result of coronary microvascular dysfunction, would likely result in decreased left ventricular dispensability. Collectively, these findings suggest that left ventricular afterload is not the only key underlying mechanism for HFpEF as once believed and that this coronary microvascular dysfunction-ischemia paradigm potentially plays an important role (Figure 1). Although these observations suggest that hypertension alone is not the underlying mechanism for HFpEF, this does not dismiss the role of proper control of blood pressure in patients with HFpEF. A secondary analysis of the Systolic Blood Pressure Intervention Trial that included patients with hypertension without diabetes found intensive systolic blood-pressure treatment (ie <120 mm Hg) was associated with reduced risk of hospitalizations due to heart failure compared to standard systolic blood-pressure treatment (ie <140 mm Hg).27 Important observations from other studies provide some insights highlighting the potential coronary microvascular
Figure 1 Pathogenic processes in HFpEF: Central role for microvascular ischemia. CMD = coronary microvascular disease; HFpEF = heart failure with preserved ejection fraction; VSM = vascular smooth muscle
dysfunction-ischemia paradigm as underlying HFpEF. For example, in 1 analysis, body mass index, rather than arterial blood pressure per se, predicted future HFpEF occurrence.28 In another study, abnormal exercise hemodynamics in patients with HFpEF with reduced transmyocardial oxygen gradient suggested impaired myocardial oxygen delivery as a key mechanism responsible for abnormal diastolic flow reserve.29 Others have found myocardial flow reserve (MFR, Rb-82 positron emission tomography) is reduced in patients with HFpEF.30 In this study, 378 patients with ejection fraction ≥50% and no history of obstructive coronary artery disease were divided based on a confirmed heart failure diagnosis (n=78) compared with those with no heart failure (n=298), and further stratified by presence (n=186) or absence (n=112) of systemic hypertension. HFpEF was associated with reduced global MFR (2.16 § 0.69) compared with hypertensive controls (2.54 § 0.80, p<0.02) as well as normotensive controls (2.89 § 0.70, p<0.001); both control groups had no heart failure. A HFpEF diagnosis was associated with 2.6-fold greater risk of having low global MFR (<2.0) and remained a significant predictor of reduced global MFR after adjusting for comorbidities.30 The hypothesis that coronary microvascular dysfunction could be the precursor of HFpEF was investigated in a prospective study of 201 consecutive patients without overt coronary artery disease: 108 patients had impaired MPR (<2.0), and impaired MPR was independently associated with diastolic dysfunction and hospitalizations for HFpEF during 4.1 years median follow-up.31 Interestingly, parvovirus B19 had been implicated in unexplained HFpEF; however, this virus did not affect cardiomyocytes but was present in coronary endothelium.32 In further support of this notion, autopsy studies have shown that patients with HFpEF had reduced coronary microvascular density, and indirect effects of left ventricular
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overload on myocardial vascularization appeared absent.33 Although the coronary microvascular dysfunction-ischemia paradigm appears to be an important emerging mechanistic factor for HFpEF, other phenotypes might be associated with coronary microvascular dysfunction and HFpEF. For example, cardiac amyloidosis, particularly transthyretin amyloidosis, often presents in the same older age group as coronary microvascular dysfunction with hemodynamic findings of HFpEF. Transthyretin amyloidosis is found in approximately 13% of patients with HFpEF.34 Incorporating advanced imaging techniques and genetic testing could help identify this subset of patients who would benefit from new transthyretin-modifying therapies. Angina, cardiac troponin elevation, and coronary microvascular dysfunction are found in cardiac amyloidosis with a HFpEF presentation, but the specific mechanisms are unclear.35 Knowledge gaps exist related to the usefulness of a more personalized approach with modern imaging techniques plus genetic and other biomarkers to further subclassify HFpEF into separate pathogenic subgroups and assess potential benefit from transthyretin-modifying management.
THERAPEUTIC IMPLICATIONS AND APPROACHES TO ADDRESS SOME OF THE KNOWLEDGE GAPS As we have highlighted, there is considerable emerging evidence to support the mechanistic role of this novel coronary microvascular dysfunction-ischemia-HFpEF paradigm,
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which has potentially important therapeutic implications. Future management strategies in patients with HFpEF should not only focus on systemic blood-pressure control, which has important mortality benefits in those with coronary artery disease as well,36 but treatment should also focus of coronary microvascular dysfunction and, in particular, endothelial dysfunction. As noted previously, there appears to be a time window from the onset of symptoms and signs of coronary microvascular ischemia and HFpEF development (Figure 2). Moreover, not all patients who exhibit coronary microvascular ischemia will develop HFpEF in the future. This provides an important opportunity to direct therapy to this time window and perhaps even prevent overt HFpEF. Limited efforts have targeted inflammatory pathways and anti-inflammatory agents such as immune-modulatory cytokines have shown encouraging results in animal models.37 Anakinra, an interleukin-1 receptor antagonist available for patients with rheumatoid arthritis, failed to improve peak oxygen consumption in a randomized-placebo controlled trial of 28 patients with HFpEF, but there was improvement in exercise time and quality of life.38 Some suggest that statin therapy could be of benefit in this HFpEF paradigm19 because statins exert an antiinflammatory effect, independent of low-density lipoprotein reduction, that reduces superoxide anion production and improves nitric oxide bioavailability.39 However, an analysis of the GISSI-HF trial showed no benefit with
Figure 2 Variable clinical course in coronary microvascular disease and heart failure with preserved function. Patients with multiple comorbidities, such as obesity and hypertension, develop progressive loss of coronary microvascular reserve secondary to the release of pro-inflammatory markers, which gradually worsens with years, until this reaches the threshold for ischemia, and then there will be gradual loss of the left ventricular diastolic reserve, which manifests later on with overt heart failure with preserved ejection fraction. HF = heart failure; IHD = ischemic heart disease; LV = left ventricular.
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rosuvastatin in patients with heart failure with ejection fraction >40%.40 These divergent findings for antiinflammatory agents represent an important knowledge gap for future investigations. Although phosphodiesterase-5 inhibitors such as sildenafil have been proposed to improve diastolic dysfunction in patients with HFpEF, a multicenter randomized trial found no improvement in exercise capacity or clinical status at 24 weeks compared with placebo.41 Phosphodiesterase-5 inhibitors exert a pulmonary vasodilatory effect that might improve symptoms related to pulmonary hypertension. Two small randomized trials evaluated the sildenafil in patients with HFpEF with pulmonary hypertension and found contradictory findings.42,43 There are data suggesting that pulmonary hypertension associated with HFpEF is not only due to postcapillary hypertension (ie elevation of left ventricular filling pressure), but a subset of these patients also develop combined post- and precapillary pulmonary hypertension.44 This latter category was not the group of interest in prior trials of sildenafil and represents important knowledge for future investigations. Although trials with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have failed to demonstrate benefit in patients with HFpEF,24,45 neprilysin inhibitors prevent the breakdown of many vasoactive natriuretic peptides. The angiotensin receptor neprilysin inhibitor sacubitril/valsartan has shown promising findings in a Phase II trial.46 The fully recruited PARAGON-HF Trial will shed the light on the potential therapeutic benefit of sacubitril/valsartan in patients with HFpEF.47 Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors might reduce the risk of hospitalizations for heart failure in subjects with type 2 diabetes and coronary microvascular dysfunction because HFpEF is prevalent in patients with diabetes. In a multicenter randomized trial of 7020 patients with diabetes at high risk for cardiovascular events, empagliflozin, a SGLT-2 inhibitor, reduced hospitalizations for heart failure within a brief follow-up period.48 This effect could not be attributed only to glucose lowering because the early change in hemoglobin A1C was minimal. Another trial of >10,000 patients with diabetes, two-thirds with a history of atherosclerotic vascular disease, found reduction in risk of hospitalizations due to heart failure with canagliflozin at 3.6 years.49 It is hypothesized that SGLT-2 inhibitors induce osmotic diuresis, reducing volume overload without significant impact on tissue perfusion, as well as reducing cardiac oxygen demands.50 Although data regarding ejection fraction were not provided in these trials, it is plausible to assume that these patients with diabetes hospitalized with heart failure likely had HFpEF and coronary microvascular dysfunction. It would be of interest to investigate whether initiation of SGLT-2 inhibitors early in the course of patients with diabetes and microvascular disease reduces hospitalizations for heart failure. Clinical trials addressing this question (ie NCT03057951 and NCT03030235) are underway.
SUMMARY Accumulating evidence suggests that the traditional or afterload overload concept of the pathophysiology of HFpEF is likely not the only culprit and that coronary microvascular dysfunction secondary to multiple co-morbidities is an important pathogenetic mechanism. This is further supported by the fact that many patients with angina without obstructive coronary artery disease have coronary microvascular dysfunction, and their outcomes are dominated by HFpEF. Thus, a functional relevance of ischemia due to a coronary microvascular dysfunction as an early disease marker for the onset of HFpEF seems reasonable. Clearly, the pathophysiology of HFpEF is complex and multifactorial, and knowledge gaps exist related to a more personalized approach with modern imaging techniques plus biomarkers to subclassify HFpEF into the separate pathogenic subgroups.
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Heart Failure With Preserved Ejection Fraction: Is Ischemia Due to Coronary Microvascular Dysfunction a Mechanistic Factor? Islam Y. Elgendy, MD, Carl J. Pepine, MD Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville.
ABSTRACT Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence and has no guidelinerecommended therapy, related in part to a lack of mechanism. Traditionally, HFpEF was thought to be secondary to afterload overload due to systemic hypertension; however, accumulating evidence suggests that HFpEF continues to worsen despite adequate control of blood pressure. Emerging data support the suggestion that myocardial ischemia secondary to coronary microvascular dysfunction could be the new paradigm pathophysiology. Several prospective, observational cohort studies indicate that the outcomes of patients with microvascular dysfunction, after an interval of several years, are dominated by HFpEF hospitalizations. Further, the most prevalent clinical phenotype (eg older women with multiple comorbidities) of patients with HFpEF resembles those with coronary microvascular dysfunction, albeit older. In this review, we provide in-depth insight about this emerging HFpEF paradigm, discuss potential therapeutic implications of this pathophysiology, and summarize some important knowledge gaps. Ó 2019 Elsevier Inc. All rights reserved. The American Journal of Medicine (2019) 132:692−697 KEYWORDS: Coronary artery disease; Heart failure; Ischemia; Microvascular dysfunction; Preserved ejection fraction
CORONARY MICROVASCULAR DYSFUNCTION AND NONOBSTRUCTIVE CORONARY ARTERY DISEASE Approximately 50% of patients with symptoms or signs of ischemia referred for elective coronary angiography are found to have nonobstructive coronary artery disease.1 Compared with those with “apparently normal” coronary arteries, their counterparts with nonobstructive coronary artery disease have worse outcomes. In a study of Funding: CJP receives support from the National Institutes of Health (NIH), National Heart, Lung and Blood Institute HL087366; HL033610, HL132448, HL130163; the United States Department of Defense PR161603; the Gatorade Trust through funds distributed by the University of Florida Department of Medicine; NIH NCATS—University of Florida Clinical and Translational Science UL1TR001427; and PCORnet-OneFlorida Clinical Research Consortium CDRN-1501-26692. Conflicts of Interest: None. Authorship: Both authors had access to the data and a role in writing this manuscript. Requests for reprints should be addressed to Carl J. Pepine, MD, Division of Cardiovascular Medicine, University of Florida, 1600 SW Archer Rd., PO Box 100277, Gainesville, FL, 32610. E-mail address: [email protected]
0002-9343/© 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjmed.2018.12.038
approximately 38,000 US veterans, the presence of nonobstructive coronary artery disease on elective coronary angiogram was associated with a higher mortality at 1 year, compared with those with “normal” coronary arteries.2 In a Danish registry of about 11,000 subjects with angina undergoing “a first” coronary angiogram, nonobstructive coronary artery disease was associated with a higher risk of adverse outcomes at 7.5 years median follow-up. This outcome was driven mostly by heart failure hospitalizations and cardiovascular mortality.3 These findings were further supported by a meta-analysis of »64,000 patients referred for either computed tomography coronary angiography or invasive coronary angiography, in which those with nonobstructive coronary artery disease, compared with those with normal angiograms, had >3-fold higher risk of major adverse cardiac events at 27 months median follow-up.4 Multiple reports document that symptomatic patients with nonobstructive coronary artery disease incur health care costs and disabilities similar to those with obstructive coronary artery disease, mostly because of repeated hospitalizations for heart failure and angina.5 In an economic
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analysis, women with nonobstructive coronary artery disstiffness as typically observed in patients with HFpEF. ease had substantially high, symptom-driven costs of care, Interestingly, the systemic inflammatory state generated mostly resulting from hospitalizations for angina and heart secondary to these comorbidities appears predictive of failure.5 incident HFpEF but not of incident heart failure with An important consideration is that patients with nonobreduced ejection fraction (HFrEF).9 Second, patients who structive coronary artery disease are likely to have preare obese tend to have more salt retention through served left ventricular ejection fraction. Despite that, these enhanced renal tubular sodium reabsorption.10 High salt patients are more prone to hosintake in patients with salt-sensipitalizations as a result of heart CLINICAL SIGNIFICANCE tive hypertension leads to sysfailure. In an analysis of 1218 temic oxidative stress as a result Traditionally, heart failure with preserved of renal production of proinflampatients referred for perfusion imaging for suspected myocarejection fraction (HFpEF) was thought to matory cytokines.11 Further, dial ischemia, those with be secondary to afterload overload due to individuals who are obese are impaired coronary flow reserve more likely to be inactive and systemic hypertension. (<2.0) had a higher incidence of have poor functional capacity, Emerging data support the suggestion that which has been linked to hospicardiac events, mainly due to myocardial ischemia secondary to coronary talizations for heart failure in the hospitalizations for heart failmicrovascular dysfunction could be the new population with coronary microure, at a median follow-up of only 1.3 years.6 These findings vascular dysfunction.12 With paradigm pathophysiology. strongly suggest a possible link expanding plasma volume, the This review provides in-depth insight about heart would normally react by between nonobstructive corothis emerging HFpEF paradigm, discusses chamber dilation; however, due nary artery disease/coronary the potential therapeutic implications of to underlying myocardial fibrosis microvascular dysfunction and this pathophysiology, and summarizes some and increased diastolic stiffness heart failure with preserved ejection fraction (HFpEF). In from the fibrosis, systemic important knowledge gaps. other words, nonobstructive inflammation, and underlying coronary artery disease with ischemia (see below) during coronary microvascular dysfunction appears to represent a daily life,7 the dilation is limited. In turn, this sequence of “pre-HFpEF” syndrome or condition.7 events increases cardiac filling pressures and leads to heart failure without impairment of systolic function. This is the “paradigm” shift for HFpEF pathophysiology described COMORBIDITIES IN PATIENTS WITH HFPEF by Paulus et al.13 COMPARED TO PATIENTS WITH CORONARY Another important observation is that patients with coronary microvascular dysfunction have an increased prevaMICROVASCULAR DYSFUNCTION lence of chronic kidney disease, which might be secondary Symptomatic patients with coronary microvascular dysto other comorbidities like hypertension and diabetes or function and nonobstructive coronary artery disease are independent by increasing superoxide and reducing nitric typically women ages 40-65 years old with multiple comoroxide, which results in endothelial dysfunction.14 In more bidities (eg hypertension, obesity, hypercholesteremia, diaadvanced stages of chronic kidney disease, retention of urebetes, inactivity, and even chronic kidney disease). They mic toxins further increases oxidative stress to amplify often exhibit diastolic left ventricular dysfunction on carmicrovascular dysfunction.15 Whether renal dysfunction is diac imaging and central aortic stiffening. Those with a predisposing factor in the pathogenesis of HFpEF or both HFpEF have a similar clinical phenotype except that they diseases are a consequence of microvascular dysfunction are likely to be older (>60 years). Thus, these findings supremains an important knowledge gap. port the suggestion that the “clinical phenotype” associated Patients with heart failure (both HFpEF and HFrEF) with HFpEF is remarkably similar to that of older patients have altered structure and function of the gastrointestinal with coronary microvascular dysfunction. So, is there a mucosa as a consequence of microcirculatory disturbanmechanistic link between these syndromes? ces.16 A leaky intestinal barrier, with an augmented bacteObesity could contribute to development of HFpEF rial biofilm, may contribute to chronic inflammation and through at least 2 important mechanisms. First, obesity malnutrition. Lack of mucosal integrity, with local and systriggers systemic inflammation. Adipose tissue, particutemic inflammation and dysfunction of transport proteins, larly visceral fat, is infiltrated with macrophages, which may worsen chronic heart failure and associated symprelease pro-inflammatory cytokines that stimulate myocartoms.17 It remains unclear whether the increase of adherent dial fibrosis and endothelial dysfunction within coronary 8 bacteria in patients with chronic heart failure is a primary microvasculature. The heightened systemic inflammatory or secondary event and whether this might contribute to state is linked with left ventricular hypertrophy, myocarsystemic inflammation. dial remodeling, fibrosis, and increased conduit vessel
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THE CORONARY MICROVASCULAR DYSFUNCTION/DISEASE PARADIGM This coronary microvascular dysfunction paradigm is increasing recognized as a potential pathophysiological mechanism of HFpEF, unlike myocardial overload secondary to hypertension that has been considered as the traditional mechanism.18 This was suggested previously by hypertensive animal models that demonstrated progression of concentric left ventricular remodeling to maladaptive eccentric remodeling, thus resulting in end-stage HFrEF.19 These findings were disputed in a recent study in which senescence-accelerated mice (ie cellular growth arrest linked with aging and inflammation) treated with Western high-salt, high-fat diet developed HFpEF as a result of endothelial dysfunction.20 In an echocardiographic study that longitudinally followed patients with HFpEF over 5 years, there was minimal reduction in ejection fraction (1%/year), and this decline was mostly concentrated among older patients and those with coronary artery disease.21 In a similar echocardiographic study over 4 years, subjects with increased left ventricular diastolic stiffness had weight gain associated with an increase in left ventricular diastolic stiffness, even after adjustment for changes in afterload.22 Extended follow-up of Health ABC (11 years) suggested that arterial stiffness (as carotid-femoral pulse wave velocity) was not associated with incident HFpEF, after adjustment for traditional cardiovascular risk factors (ie age, sex, body mass index, and diabetes or kidney disease).23 Additionally, multiple randomized trials have not found afterload reducing agents (eg nitrates, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers) beneficial in patients with HFpEF.24,25 Considerable evidence has found that myocardial contraction is modulated by molecules such as nitric oxide and prostaglandins from endothelium. In one study,26 nitric oxide released from endothelium lowered left ventricular systolic pressure and increased diastolic dispensability. Thus, endothelial dysfunction, as expected with ischemia as a result of coronary microvascular dysfunction, would likely result in decreased left ventricular dispensability. Collectively, these findings suggest that left ventricular afterload is not the only key underlying mechanism for HFpEF as once believed and that this coronary microvascular dysfunction-ischemia paradigm potentially plays an important role (Figure 1). Although these observations suggest that hypertension alone is not the underlying mechanism for HFpEF, this does not dismiss the role of proper control of blood pressure in patients with HFpEF. A secondary analysis of the Systolic Blood Pressure Intervention Trial that included patients with hypertension without diabetes found intensive systolic blood-pressure treatment (ie <120 mm Hg) was associated with reduced risk of hospitalizations due to heart failure compared to standard systolic blood-pressure treatment (ie <140 mm Hg).27 Important observations from other studies provide some insights highlighting the potential coronary microvascular
Figure 1 Pathogenic processes in HFpEF: Central role for microvascular ischemia. CMD = coronary microvascular disease; HFpEF = heart failure with preserved ejection fraction; VSM = vascular smooth muscle
dysfunction-ischemia paradigm as underlying HFpEF. For example, in 1 analysis, body mass index, rather than arterial blood pressure per se, predicted future HFpEF occurrence.28 In another study, abnormal exercise hemodynamics in patients with HFpEF with reduced transmyocardial oxygen gradient suggested impaired myocardial oxygen delivery as a key mechanism responsible for abnormal diastolic flow reserve.29 Others have found myocardial flow reserve (MFR, Rb-82 positron emission tomography) is reduced in patients with HFpEF.30 In this study, 378 patients with ejection fraction ≥50% and no history of obstructive coronary artery disease were divided based on a confirmed heart failure diagnosis (n=78) compared with those with no heart failure (n=298), and further stratified by presence (n=186) or absence (n=112) of systemic hypertension. HFpEF was associated with reduced global MFR (2.16 § 0.69) compared with hypertensive controls (2.54 § 0.80, p<0.02) as well as normotensive controls (2.89 § 0.70, p<0.001); both control groups had no heart failure. A HFpEF diagnosis was associated with 2.6-fold greater risk of having low global MFR (<2.0) and remained a significant predictor of reduced global MFR after adjusting for comorbidities.30 The hypothesis that coronary microvascular dysfunction could be the precursor of HFpEF was investigated in a prospective study of 201 consecutive patients without overt coronary artery disease: 108 patients had impaired MPR (<2.0), and impaired MPR was independently associated with diastolic dysfunction and hospitalizations for HFpEF during 4.1 years median follow-up.31 Interestingly, parvovirus B19 had been implicated in unexplained HFpEF; however, this virus did not affect cardiomyocytes but was present in coronary endothelium.32 In further support of this notion, autopsy studies have shown that patients with HFpEF had reduced coronary microvascular density, and indirect effects of left ventricular
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overload on myocardial vascularization appeared absent.33 Although the coronary microvascular dysfunction-ischemia paradigm appears to be an important emerging mechanistic factor for HFpEF, other phenotypes might be associated with coronary microvascular dysfunction and HFpEF. For example, cardiac amyloidosis, particularly transthyretin amyloidosis, often presents in the same older age group as coronary microvascular dysfunction with hemodynamic findings of HFpEF. Transthyretin amyloidosis is found in approximately 13% of patients with HFpEF.34 Incorporating advanced imaging techniques and genetic testing could help identify this subset of patients who would benefit from new transthyretin-modifying therapies. Angina, cardiac troponin elevation, and coronary microvascular dysfunction are found in cardiac amyloidosis with a HFpEF presentation, but the specific mechanisms are unclear.35 Knowledge gaps exist related to the usefulness of a more personalized approach with modern imaging techniques plus genetic and other biomarkers to further subclassify HFpEF into separate pathogenic subgroups and assess potential benefit from transthyretin-modifying management.
THERAPEUTIC IMPLICATIONS AND APPROACHES TO ADDRESS SOME OF THE KNOWLEDGE GAPS As we have highlighted, there is considerable emerging evidence to support the mechanistic role of this novel coronary microvascular dysfunction-ischemia-HFpEF paradigm,
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which has potentially important therapeutic implications. Future management strategies in patients with HFpEF should not only focus on systemic blood-pressure control, which has important mortality benefits in those with coronary artery disease as well,36 but treatment should also focus of coronary microvascular dysfunction and, in particular, endothelial dysfunction. As noted previously, there appears to be a time window from the onset of symptoms and signs of coronary microvascular ischemia and HFpEF development (Figure 2). Moreover, not all patients who exhibit coronary microvascular ischemia will develop HFpEF in the future. This provides an important opportunity to direct therapy to this time window and perhaps even prevent overt HFpEF. Limited efforts have targeted inflammatory pathways and anti-inflammatory agents such as immune-modulatory cytokines have shown encouraging results in animal models.37 Anakinra, an interleukin-1 receptor antagonist available for patients with rheumatoid arthritis, failed to improve peak oxygen consumption in a randomized-placebo controlled trial of 28 patients with HFpEF, but there was improvement in exercise time and quality of life.38 Some suggest that statin therapy could be of benefit in this HFpEF paradigm19 because statins exert an antiinflammatory effect, independent of low-density lipoprotein reduction, that reduces superoxide anion production and improves nitric oxide bioavailability.39 However, an analysis of the GISSI-HF trial showed no benefit with
Figure 2 Variable clinical course in coronary microvascular disease and heart failure with preserved function. Patients with multiple comorbidities, such as obesity and hypertension, develop progressive loss of coronary microvascular reserve secondary to the release of pro-inflammatory markers, which gradually worsens with years, until this reaches the threshold for ischemia, and then there will be gradual loss of the left ventricular diastolic reserve, which manifests later on with overt heart failure with preserved ejection fraction. HF = heart failure; IHD = ischemic heart disease; LV = left ventricular.
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rosuvastatin in patients with heart failure with ejection fraction >40%.40 These divergent findings for antiinflammatory agents represent an important knowledge gap for future investigations. Although phosphodiesterase-5 inhibitors such as sildenafil have been proposed to improve diastolic dysfunction in patients with HFpEF, a multicenter randomized trial found no improvement in exercise capacity or clinical status at 24 weeks compared with placebo.41 Phosphodiesterase-5 inhibitors exert a pulmonary vasodilatory effect that might improve symptoms related to pulmonary hypertension. Two small randomized trials evaluated the sildenafil in patients with HFpEF with pulmonary hypertension and found contradictory findings.42,43 There are data suggesting that pulmonary hypertension associated with HFpEF is not only due to postcapillary hypertension (ie elevation of left ventricular filling pressure), but a subset of these patients also develop combined post- and precapillary pulmonary hypertension.44 This latter category was not the group of interest in prior trials of sildenafil and represents important knowledge for future investigations. Although trials with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have failed to demonstrate benefit in patients with HFpEF,24,45 neprilysin inhibitors prevent the breakdown of many vasoactive natriuretic peptides. The angiotensin receptor neprilysin inhibitor sacubitril/valsartan has shown promising findings in a Phase II trial.46 The fully recruited PARAGON-HF Trial will shed the light on the potential therapeutic benefit of sacubitril/valsartan in patients with HFpEF.47 Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors might reduce the risk of hospitalizations for heart failure in subjects with type 2 diabetes and coronary microvascular dysfunction because HFpEF is prevalent in patients with diabetes. In a multicenter randomized trial of 7020 patients with diabetes at high risk for cardiovascular events, empagliflozin, a SGLT-2 inhibitor, reduced hospitalizations for heart failure within a brief follow-up period.48 This effect could not be attributed only to glucose lowering because the early change in hemoglobin A1C was minimal. Another trial of >10,000 patients with diabetes, two-thirds with a history of atherosclerotic vascular disease, found reduction in risk of hospitalizations due to heart failure with canagliflozin at 3.6 years.49 It is hypothesized that SGLT-2 inhibitors induce osmotic diuresis, reducing volume overload without significant impact on tissue perfusion, as well as reducing cardiac oxygen demands.50 Although data regarding ejection fraction were not provided in these trials, it is plausible to assume that these patients with diabetes hospitalized with heart failure likely had HFpEF and coronary microvascular dysfunction. It would be of interest to investigate whether initiation of SGLT-2 inhibitors early in the course of patients with diabetes and microvascular disease reduces hospitalizations for heart failure. Clinical trials addressing this question (ie NCT03057951 and NCT03030235) are underway.
SUMMARY Accumulating evidence suggests that the traditional or afterload overload concept of the pathophysiology of HFpEF is likely not the only culprit and that coronary microvascular dysfunction secondary to multiple co-morbidities is an important pathogenetic mechanism. This is further supported by the fact that many patients with angina without obstructive coronary artery disease have coronary microvascular dysfunction, and their outcomes are dominated by HFpEF. Thus, a functional relevance of ischemia due to a coronary microvascular dysfunction as an early disease marker for the onset of HFpEF seems reasonable. Clearly, the pathophysiology of HFpEF is complex and multifactorial, and knowledge gaps exist related to a more personalized approach with modern imaging techniques plus biomarkers to subclassify HFpEF into the separate pathogenic subgroups.
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