SNOWMASS, COLO. (FRONTLINE MEDICAL NEWS)The plethora of comorbidities typically present in patients with heart failure with preserved ejection fraction is increasingly thought to be a key driver of the cardiac structural remodeling and poor clinical outcomes characteristic of this increasingly common condition.

“The new message is that even though HFpHF [heart failure with preserved ejection fraction] is a problem of the heart involving diastolic filling and structural remodeling of the ventricle, it’s also a problem of factors outside the heart. Outcomes are driven not just by the cardiac abnormalities, but by the comorbidities that are so common in this elderly population,” Dr. Akshay S. Desai said at the annual Cardiovascular Conference at Snowmass.

“The evolving theoretical model is one that emphasizes the role these comorbidities play, not just in remodeling of the heart, but also in microvascular inflammation, with its consequences for inflammatory cell migration, transforming growth factor–beta activation, myocardial fibrosis, oxidative stress, endothelial inflammation, and downstream impairment of cyclic guanosine monophosphate signaling,” explained Dr. Desai of Brigham and Women’s Hospital, Boston.

He credited Dr. Walter J. Paulus of the Institute for Cardiovascular Research at VU University Medical Center, Amsterdam, as being the primary developer of the new paradigm, which veers away from the traditional emphasis upon excessive afterload as the primary driver of diastolic dysfunction.

As elaborated in detail by Dr. Paulus, the noncardiac comorbidities that are so highly prevalent in HFpEF – especially obesity, diabetes, chronic obstructive pulmonary disease, hypertension, chronic kidney disease, and anemia – induce a systemic inflammatory state which promotes diastolic left ventricular stiffness, cardiac hypertrophy, and the development of heart failure. Dr. Paulus has buttressed his theoretical framework with endomyocardial biopsy studies that document abnormal myocyte structure and function ( J. Am. Coll. Cardiol. 2013;62:263-71 ).

Dr. Desai said the fresh perspective provided by Dr. Paulus is most welcome because it is easily tested, and also because it points to new pathways for treatment. New therapeutic targets are needed desperately because of the striking lack of progress to date in treatment of HFpEF. No drug has been convincingly shown effective in reducing the morbidity and mortality of HFpEF, although a secondary analysis of the flawed TOPCAT trial did strongly suggest spironolactone may reduce the risks of mortality and heart failure hospitalizations ( Circulation 2015;131:34-42 ).

Clinical trials that are now planned or underway as a consequence of the new HFpEF paradigm are investigating novel treatment strategies targeting low myocardial nitric oxide bioavailability and endothelial dysfunction. Agents under study include statins, interleukin-1 receptor antagonists, oral nitrates aimed at boosting cellular levels of nitric oxide, the oral soluble guanylate cyclase stimulator riociguat (Adempas), and the phosphodiesterase-5 inhibitor sildenafil.

Also, all eyes are on the 4,300 patient, 37-country, phase III, randomized PARAGON HF study which began last summer. PARAGON is evaluating LCZ696, the combined angiotensin receptor neprilysin inhibitor that scored a smashing success in heart failure with reduced ejection fraction in the landmark PARADIGM-HF study ( N. Engl. J. Med. 2014;371:993-1004) .

The rising prevalence of diabetes, obesity, and other proinflammatory chronic conditions could help explain the increasing proportion of patients with heart failure who have HFpEF.

“Depending on where you draw the cut point for preserved ejection fraction, you could say half or as many as 60% of patients hospitalized for decompensated heart failure do so in the setting of preserved ejection fraction,” Dr. Desai observed.

It’s noteworthy that the trajectory of decline following hospitalization for heart failure is similar in HFpEF and heart failure with reduced ejection fraction.

While awaiting the outcome of clinical trials of novel treatments, and with so little evidence-based therapy available at this point, physicians should redouble their efforts to aggressively manage hypertension and other comorbidities in an effort to prevent HFpEF or slow its progression. The favorable TOPCAT results in the Western Hemisphere are also worthy of consideration, the cardiologist argued.

Dr. Desai reported serving as a consultant to 5AM Ventures, AtCor Medical, Novartis, and St. Jude Medical.