Relative to the continued advancements in treatment of heart failure with reduced ejection fraction (HFrEF), progression in medical therapy for heart failure with preserved ejection fraction (HFpEF) has been less robust. Angiotensin-receptor and mineralocorticoid-receptor blockade have been tested in large scale randomized trials; however, neither drug improved cardiovascular outcomes or showed mortality benefit.^1,2,3 Phosphodiesterase-5 inhibition was thought to have potential in targeting the multiple pathophysiological disorders that occur with HFpEF; an altered neurohormonal axis, diastolic impairment, vascular dysfunction, and pulmonary hypertension.^4,5 Although tested drug therapy did not show benefit, this particular study suggested that HFpEF is not one entity but rather a disease spectrum. More specifically, Lindman et al. point out that those with HFpEF and diabetes display a distinct set of clinical characteristics, such as worse exercise tolerance, a distinct biomarker profile, and a relatively greater degree of myocardial dysfunction.⁶ As HFpEF is now regarded to have multiple phenotypes, how does one find an appropriate therapy? The answer to this question is complex and presently evolving. Samson et al. provide a recent review regarding HFpEF phenotypes along with the respective associated comorbidities, pathogenesis, and potential therapies. The reported HFpEF spectrum includes hypertension, age, obesity, coronary disease, and pulmonary hypertension. Although the review supports the idea of multiple distinct phenotypes, it notably points out that they are not exclusive.⁷ In an attempt to further understand the specific phenotype of HFpEF with diabetes, Kristensen et al. provide a retrospective analysis of clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with HFpEF enrolled in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction) trial.

I-PRESERVE was a large-scale, multicenter, randomized controlled trial that assessed the effect of irbesartan on patients with HFpEF; primary endpoints included all-cause mortality and cardiovascular-related hospitalizations. Similar to the CHARM (Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity) trial, angiotensin-receptor blockade again did not improve outcomes, albeit in a population more representative of HFpEF (CHARM included subjects with slightly decreased systolic function). The studied population had a mean age of 72 years, was mostly Caucasian (94%), predominantly female (60%), and had a relatively high prevalence of diabetes (27%) that allowed for the retrospective analysis of this HFpEF phenotype subgroup. Patients with diabetes were slightly younger, had a higher BMI, and were more congested as evidenced by clinical exam, symptoms, and plasma NT-proBNP level. HFpEF attributed to ischemia rather than hypertension was more common in the diabetes arm, although 88% of all subjects were labelled as hypertensive. Albeit less than 14% of the study population had a complete echocardiographic examination, this subgroup analysis found that diabetes was associated with greater left ventricular size and hypertrophy. In addition, those with HFpEF and diabetes exhibited worsened parameters of diastolic impairment as measured by tissue doppler, mitral inflow, and left atrial size. Although HFpEF and diastolic dysfunction are not synonymous, greater than 90% of the study's echo subgroup had this echocardiographic abnormality. In regards to outcomes, patients with HFpEF and diabetes had an increased incidence of cardiovascular death and heart failure hospitalization during a median follow-up of 4.1 years (34% vs. 22%).⁸

If we are to define HFpEF according to phenotype, what is the correct interpretation of these findings? As outlined by Samson et al., associated comorbidities of HFpEF are not exclusive and have considerable overlap.⁷ The reported clinical characteristics certainly agree with this notion given the high prevalence of hypertension, coronary disease, obesity, and increased age in the diabetes arm. What can be said of increased congestion in those with HFpEF and diabetes? This parallels findings reported by Lindman et al., in which the corresponding arm experienced reduced exercise tolerance, increased hospitalizations for heart failure and greater use of diuretics. Echocardiographic parameters were also similar, as both studies showed diabetes to be associated with left ventricular hypertrophy and elevated filling pressures (specifically E/e').^6,8,9

Given that the results of this analysis are in agreement with prior literature, what conclusions can be made regarding HFpEF with diabetes? Why do patients with this specific phenotype experience more congestion and carry a worse prognosis? Do we now have sufficient data to guide treatment? Kristensen et al. speculate the role of medical therapy for diabetes in answering such questions; thiazolidinediones associated with sodium and water retention, and dipeptidyl peptidase-4 inhibitors, a relatively new class of oral hypoglycemics that have been associated with heart failure.⁸ However, one must remember that HFpEF in the presence of diabetes is not exclusive of other phenotypes. In reference to I-PRESERVE and RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure), the diabetic arms also had an increased prevalence of obesity and ischemic heart disease. Both trials were representative of an elderly population, albeit the diabetes arm being slightly younger in each study.^1,5,6,8,9 If one proceeds to target medical therapy in diabetes, does this inadvertently negate the impact of age, obesity, and coronary disease on this HFpEF phenotype?

In recognition of HFpEF with diabetes as a distinct yet overlapping phenotype, we propose a common diagnosis as the unifying mechanism: atherosclerosis. As a major macrovascular complication of diabetes, this additional comorbidity accelerates aging of the cardiovascular system and alters the pressure-volume relationship. As previously reported, elderly individuals exhibit increased vascular and ventricular stiffness measured by effective arterial elastance (Ea) and left ventricular end-systolic elastance (Ees), respectively. Ventricular-vascular coupling, represented by the indexed ratio Ea/Ees, is maintained at rest in elderly subjects but becomes less efficient upon exercise.^10,11 Lam et al. found that individuals with hypertension and HFpEF exhibit the same matched increase in ventricular and vascular stiffness. Reduced exercise tolerance in the latter has been attributed to diastolic dysfunction, in which a given end-diastolic volume results in a relatively higher end-diastolic pressure.¹² Patients of this phenotype are thus more sensitive to changes in intravascular volume, less effective in maintaining euvolemia, and more often experience congestion and decreased exercise tolerance.

In regards to management of HFpEF with diabetes, is there is medical therapy available that takes into account the underlying pathophysiological process? Perhaps – although TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) failed to show benefit of spironolactone in HFpEF, a recent post hoc analysis revealed a four-fold increase in the composite event rate between subjects enrolled in the Americas relative to those enrolled in Russia and Georgia. Specific to the former group, spironolactone resulted in a significant reduction in the composite event rate, cardiovascular deaths and hospitalizations for heart failure. Upon review of clinical characteristics, subjects enrolled in the Americas were more representative of the diabetes phenotype; diabetes prevalence was 45% in the Americas compared to just 20% in Russia and Georgia. Overlap with other HFpEF phenotypes is evident given the arm's increased age along with higher prevalence of obesity, dyslipidemia, angina, and coronary disease necessitating revascularization. Myocardial infarction was reported as less prevalent in American subjects; however, incidence of this event was actually increased compared to the population enrolled in Russia and Georgia (5.3% vs 2.1%).¹³ Thus, the reported comorbidities of the American arm support accelerated atherosclerosis as a unifying diagnosis in those with HFpEF and diabetes. In regards to the therapeutic effect of spironolactone, prior literature has shown mineralocorticoid-receptor blockade to improve diastolic dysfunction, a highly prevalent characteristic of HFpEF.^14,15 Moving forward, further investigation of this drug in treating those HFpEF with diabetes is warranted.

Hence Kristensen et al. reaffirmed the associated clinical characteristics of the diabetes phenotype. Their analysis helps us understand the underlying pathogenesis that may be partially reversed with medical therapy. Most importantly, a different approach in treating this disease spectrum has been outlined, one that takes into account not only the specific phenotype, but also its relation to other comorbidities. After a decade of unsuccessful drug therapy for HFpEF, perhaps the next major trial will finally show progression in treating this patient population.

References

1. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-67.
2. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777-81.
3. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383-92.
4. Redfield MM, Borlaug BA, Lewis GD, et al. Phosphdiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial: rationale and design. Circ Heart Fail 2012;5:653-9.
5. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309:1268-77.
6. Lindman BR, Dávila-Román VG, Mann DL, et al. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol 2014;64:541-9.
7. Samson R, Jaiswal A, Ennezat PV, Cassidy M, Le Jemtel TH. Clinical phenotypes in heart failure with preserved ejection fraction. J Am Heart Assoc 2016;5.
8. Kristensen SL, Mogensen UM, Jhund PS, et al. Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction: a report from the I-Preserve trial (Irbesartan in Heart Failure With Preserved Ejection Fraction). Circulation 2017;135:724-35.
9. Lindman BR. The diabetic heart failure with preserved ejection fraction phenotype: is it real and is it worth targeting therapeutically? Circulation 2017;135:736-40.
10. Shim CY. Arterial-cardiac interaction: the concept and implications. J Cardiovasc Ultrasound 2011;19:62-6.
11. Najjar SS, Schulman SP, Gerstenblith G, et al. Age and gender affect ventricular-vascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611-7.
12. Lam CS, Roger VL, Rodeheffer RJ, et al. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 2007;115:1982-90.
13. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Circulation 2015;131:34-42.
14. Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004;110:558-65.
15. Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA 2013;309:781-91.

Keywords: Atherosclerosis, Benzimidazoles, Biomarkers, Biphenyl Compounds, Blood Pressure, Body Mass Index, Cardiovascular System, Comorbidity, Coronary Disease, Cyclic Nucleotide Phosphodiesterases, Type 5, Diabetes Mellitus, Dipeptidyl-Peptidase IV Inhibitors, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Diuretics, Dyslipidemias, Heart Failure, Diastolic, Hypertension, Hypertension, Pulmonary, Hypertrophy, Left Ventricular, Mineralocorticoid Receptor Antagonists, Mineralocorticoids, Myocardial Infarction, Myocardial Ischemia, Natriuretic Peptide, Brain, Obesity, Peptide Fragments, Phenotype, Phosphodiesterase 5 Inhibitors, Spironolactone, Tetrazoles, Thiazolidinediones, Vascular Stiffness

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