Author + information
- Javed Butler, MD, MPH, MBA∗ ( and )
- Hal Skopicki, MD, PhD
- ↵∗Address for correspondence:
Dr. Javed Butler, Stony Brook University Medical Center, Health Sciences Center, T-16, Room 080, 100 Nicolls Road, Stony Brook, New York 11794.
Diastolic function is a compendium of electrical permissiveness during repolarization, myocardial cell relaxation governed by the availability of mitochondria-derived adenosine triphosphate permitting calcium reuptake under the grace of coronary perfusion, and the interplay of myocardial cells with its surrounding matrix and senescent scar. It is no wonder that diastolic dysfunction is both heterogeneous and complex, with pathophysiological abnormalities affecting myocardial relaxation and compliance along a continuum that has in common the limitation in left ventricular filling. Inadequate left ventricular filling during the diastolic filling period of the cardiac cycle is ubiquitous and manifests throughout multiple forms of cardiac disease. For instance, although coronary ischemia may compromise adenosine triphosphate generation, with resulting early diastolic dysfunction, more pronounced ischemia (and inflammation) associated with myocardial cell death and scar formation can manifest with widely varying degrees of progressive diastolic dysfunction. Multiple disorders of the myocardium, myofibroblast, or myocardial matrix, both directly and indirectly, can impair myocardial diastole. Clinically, we sum all these into a disease state described only by heart failure symptoms coupled with a left ventricular ejection fraction of ≥50%, but lacking in clinically available diagnostic testing with adequate predictive characteristics to ensure the presence of this entity.
In this issue of the Journal, Reddy et al. (1) present their work linking arterial compliance or vascular resistance and arterial and reflected load with exercise to abnormal cardiac relaxation in patients with heart failure with preserved ejection fraction. Confronting a formidable body of published reports (2), the central role of vascular hemodynamics and the vasculature itself is championed (3). However, in both instances, causality has been difficult to demonstrate. In comparing central blood pressure or aortic compliance and wave reflection in patients with invasively proven heart failure with preserved ejection fraction with hypertensive control subjects, both at rest and during exercise, subjects with heart failure with preserved ejection fraction demonstrated similar indices in arterial compliance and vasodilatory reserve at baseline. For patients with heart failure with preserved ejection fraction compared with hypertensive control subjects, aortic pulse pressure and arterial elastance were higher, whereas arterial compliance was lower. Moreover, these abnormalities correlated with elevated left ventricular end-diastolic pressure and blunting of cardiac output. At a minimum, these sophisticated studies give us deep insights into exercise physiology in these patient populations. As in most studies, these data are not without their limitations. Hypertensive control subjects in the study were younger and had a lower mean body mass index. Both factors may have a role in arterial stiffening or central aortic stiffening and impaired arterial vasodilator reserve that may not have been adequately controlled for by regression analyses in a smaller sample size; these characteristics are not necessarily statistically controlled for.
However, what of the distinction between hypertensive heart disease and heart failure with preserved ejection fraction? Heart failure symptoms are usually the discriminator, despite their limitations resulting from overlapping coexisting comorbidities such as diabetes, obesity, and chronic kidney disease in both hypertensive heart disease and heart failure with preserved ejection fraction. Another problem with symptoms is not necessarily their presence but actually eliciting them. Do patients with hypertension, left ventricular hypertrophy, normal left ventricular ejection fraction, and diastolic filling abnormalities on Doppler echocardiography (a common phenotype) who do not complain much of symptoms but have very limited exercise capacity on formal exercise testing have hypertensive heart disease or heart failure with preserved ejection fraction? Does the same patient who complains of exercise intolerance but is obese or has anemia have hypertensive heart disease or heart failure with preserved ejection fraction? Are natriuretic peptide levels in patients with left ventricular hypertrophy and diastolic filling abnormalities the ideal discriminators between the 2 states, considering the high prevalence of chronic kidney disease or obesity in these patients?
While these questions are being debated, it is critical to consider whether the clinical manifestations such as exercise intolerance and their underpinnings, e.g., hemodynamic origins, should really be rooted in their underlying pathophysiology rather than in clinical diagnoses. Both hypertensive heart disease and heart failure with preserved ejection fraction are clinical manifestations of multiple cardiovascular structural and functional abnormalities and comorbid conditions. Thus, although the investigators show the average differences between the 2 groups, these differences likely lie across a spectrum in both conditions. If effective therapies are identified, earlier targeting of the underlying pathophysiological features, rather than awaiting an arbitrary clinical diagnosis, may have a more substantial clinical impact. These issues are true for both cardiac and vascular abnormalities (e.g., endothelial dysfunction, vascular fibrotic changes, and reactive cardiac fibrosis), all of which may manifest across the 2 conditions and symptom spectra. Further assessment of pulsed wave velocity, endothelial function, and extracellular volume fraction changes can better inform these concepts, and obviously the entire premise needs to be studied carefully.
Although specific therapies for heart failure with preserved ejection fraction to date have fallen short of expectations, it is not for lack of effort. Multiple studies have been undertaken in an attempt to identify a unifying neurohumoral paradigm of heart failure with preserved ejection fraction similar to that in patients with reduced ejection fraction. However, similar antagonistic strategies have failed to achieve benefits in this population. These strategies include beta-blockers and vasodilators, classes that have been shown to affect wave reflection and aortic compliance favorably. Impaired nitric oxide–cyclic guanosine monophosphate bioavailability, diminished in many of the aforementioned disease states, has been implicated strongly in heart failure with preserved ejection fraction development and progression (4). In the study by Reddy et al. (1), both rest and exercise-induced arterial noncompliance was ameliorated by the introduction of a novel nitric oxide–cyclic guanosine monophosphate intervention that delivers inorganic sodium nitrite. This intervention resulted in clinical improvements in right atrial pressure, pulmonary capillary wedge pressure, and cardiac output with exercise. Improvements in the augmentation index, a composite of wave reflections and arterial stiffness, were pronounced with exercise. It is of interest to note the lack of a demonstrable benefit in exercise tolerance in well-structured prior studies of nitrates, the precursor of nitrites, because nitrates have also been shown to decrease conduit vessel stiffness while improving vasodilation (5). Assessment of individual exercise-related responses in the study by Reddy et al. (1) suggests that not all patients benefited, and not all benefited to the same degree, thus further reinforcing the heterogeneity of the disease. Moreover, although this effect may be seen to alter hemodynamics in the short term, it remains to be seen whether long-term modulation may cause structural arterial reverse remodeling and improvement in arterial fibrosis leading to improved left ventricular performance and improved outcomes over a longer period of time. Although not a panacea, these data do open the door for studies of nitrites.
Finally, with so many external health care changes affecting academic medicine, the pursuit of such elegant physiological studies is vanishingly rare. For this study, the investigators should be congratulated not only for their meticulous work and results but also for their efforts to provide mechanistic insight into the underlying nature and factors mediating disease progression. As clinicians continue to lump disease processes together in search of modifying health care cost outcomes, studies based on pathophysiology and etiology, especially with heart failure with preserved ejection fraction, take on greater importance. So whether this stiffens our resolve or makes us more compliant in response remains to be seen.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the author and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Butler has received research support from the National Institutes of Health, the European Union, and the Patient-Centered Outcomes Research Institute; and is a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, Janssen, Medtronic, Novartis, Relypsa, and ZS Pharma. Dr. Skopicki has reported that he has no relationships relevant to the contents of this paper to disclose.
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