The Enigma of HFpEF
Heart Failure with Preserved Ejection Fraction (HFpEF)
Why It Hides in Plain Sight — and Why We Finally Have Weapons to Fight It
Case Presentation: A Case That Looks Like Everything — and Nothing
A 68-year-old woman presents to her primary care physician with progressive exertional dyspnea. She can no longer walk up a flight of stairs without stopping. She's gained 15 pounds over three years despite "trying to eat right." She has hypertension managed with amlodipine, type 2 diabetes on metformin, and a BMI of 36. Her A1C is 7.4%. She takes no statin. An echocardiogram ordered for "shortness of breath" comes back: LVEF 62%. Left atrial enlargement. Grade II diastolic dysfunction. E/e' ratio of 14.
Her cardiologist reassures her: "Your heart is pumping fine. Your ejection fraction is normal."
But her heart is not fine. It's stiff. It can't relax. It fills under pressure like trying to inflate a balloon inside a clenched fist. She has heart failure with preserved ejection fraction — HFpEF — and for decades, the medical profession had almost nothing specific to offer her.
No targeted drug. No clear guideline pathway. Just a collection of comorbidities, each generating its own referral, and a patient caught in the middle wondering why she can't breathe.
This is the enigma. And her story is not unusual — it's the norm.
Flying Under the Radar: Why HFpEF Hides in Plain Sight
HFpEF now accounts for more than half of all heart failure cases in developed countries, and its prevalence is rising faster than HFrEF as the population ages, gains weight, and accumulates metabolic comorbidities. Yet it remains one of the most under-recognized and under-treated conditions in cardiovascular medicine.
Why? Because HFpEF doesn't announce itself the way a massive heart attack does. There's no dramatic troponin spike. No wall motion abnormality on echo. No EF of 25% that triggers an automatic heart failure consult. Instead, HFpEF arrives quietly — carried in on the shoulders of conditions we already know but too often treat in isolation:
CardioAdvocate Checklist
If you have or are at risk for HFpEF, here's what to advocate for:
Know Your Numbers
Ask About Your Treatment
Manage Your Comorbidities
Coordinate Your Care
Questions to Ask Your Doctor
- "I was told my ejection fraction is normal, but I still can't breathe with exertion. Could I have HFpEF?" A normal EF does not mean a normal heart. HFpEF is defined by diastolic dysfunction and elevated filling pressures — not by how hard the heart squeezes. Ask about an exercise echocardiogram or invasive hemodynamic testing if resting studies are borderline.
- "I'm on a diuretic for fluid retention. Should I also be on an SGLT2 inhibitor?" Empagliflozin and dapagliflozin are the only FDA-approved drugs specifically for HFpEF. They don't just remove fluid — they improve cardiac energetics and reduce hospitalization. If you're not on one, there should be a reason.
- "I'm overweight and have heart failure. Could a GLP-1 medication help my heart, not just my weight?" The STEP-HFpEF and SUMMIT trials showed that semaglutide and tirzepatide dramatically improve heart failure symptoms, exercise capacity, and quality of life in obese HFpEF patients. This is about more than cosmetic weight loss — it's about treating a disease driver.
- "My doctor said spironolactone is controversial for HFpEF. Should I take it anyway?" The TOPCAT trial had data integrity issues in some regions, but the Americas subgroup showed clear benefit. Most heart failure experts do prescribe spironolactone in HFpEF, especially when used carefully with potassium monitoring. Ask your cardiologist where they stand.
- "Is it too late for me? I've had symptoms for years." It's not too late. Even in established HFpEF, the therapies discussed here can reduce hospitalizations, improve quality of life, and in some cases reverse structural changes. But earlier intervention is always better. Don't wait.
Deep Dive
Hiding in Plain Sight
HFpEF now accounts for more than half of all heart failure cases in developed countries, and its prevalence is rising faster than HFrEF as the population ages, gains weight, and accumulates metabolic comorbidities. Yet it remains one of the most under-recognized and under-treated conditions in cardiovascular medicine.
Why? Because HFpEF doesn't announce itself the way a massive heart attack does. There's no dramatic troponin spike. No wall motion abnormality on echo. No EF of 25% that triggers an automatic heart failure consult. Instead, HFpEF arrives quietly — carried in on the shoulders of conditions we already know but too often treat in isolation:
This is why HFpEF is not a single disease — it's a convergence syndrome. A clinical phenotype that emerges when multiple cardiometabolic insults overwhelm the heart's capacity to relax, fill, and adapt to demand. But Packer's adipokine hypothesis challenges even the word "multiple" — because these insults may not be truly independent. They may all trace back to one source: biologically transformed visceral adipose tissue pumping out a toxic cocktail of proinflammatory, profibrotic, and antinatriuretic adipokines while simultaneously suppressing the cardioprotective adipokines (like adiponectin) that would normally keep the heart healthy. And because each contributing condition is managed by a different specialist in a different silo, the whole picture is routinely missed.
The Adipokine Hypothesis — Pissed Off Fat as the Unifying Theory of HFpEF
In October 2025, Dr. Milton Packer — the same physician-scientist whose neurohormonal hypothesis transformed the treatment of HFrEF over three decades ago — published a 105-page, 1,800-reference State-of-the-Art Review in JACC that may do the same for HFpEF. The paper, "The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction," proposes a bold and unifying idea: HFpEF is not a heterogeneous collection of comorbidities acting independently on the heart. It is fundamentally a disease of dysfunctional visceral adipose tissue — what CardioAdvocate has long called adiposopathy, or "pissed off fat."
Here is the core argument: When visceral fat expands beyond its healthy capacity — driven by nutrient excess and sedentary behavior — the adipocytes undergo a biological transformation. They become hypertrophied, inflamed, and metabolically deranged. This "pissed off fat" then secretes a fundamentally altered suite of signaling molecules called adipokines — polypeptides, bioactive lipids, metabolic byproducts, and microRNAs that act on the heart, kidneys, and vasculature through both endocrine (bloodstream) and paracrine (direct tissue-to-tissue) pathways. Epicardial fat, which sits directly on the heart with no fascial barrier, is especially dangerous because it delivers inflammatory adipokines straight into the adjacent myocardium.
Packer classifies these adipokines into three domains. Domain I adipokines (like adiponectin) are the "good guys" — cardioprotective molecules secreted by healthy fat that suppress inflammation and protect the heart. In adiposopathy, these are suppressed. Domain II adipokines are compensatory molecules the body produces in response to the stress of excess fat — but their protective effects are overwhelmed and insufficient. Domain III adipokines (like leptin, TNF-α, and IL-6) are the villains — prohypertrophic, proinflammatory, profibrotic, and antinatriuretic molecules whose secretion skyrockets in adiposopathy. These Domain III adipokines directly cause cardiac hypertrophy, microvascular dysfunction, myocardial fibrosis, sodium retention, plasma volume expansion, and systemic inflammation — every single hallmark feature of HFpEF.
The result is an imbalance: the protective adipokines go down, the destructive ones go up, and the compensatory ones can't keep pace. HFpEF develops not because of many unrelated comorbidities, but because dysfunctional fat is simultaneously driving hypertension (through sodium retention and sympathetic activation), diabetes (through insulin resistance and metabolic inflammation), kidney disease (through renal fibrosis and glomerular hyperfiltration), atrial fibrillation (through atrial inflammation and fibrosis), and direct myocardial damage (through cardiac hypertrophy and fibrosis) — all from the same adiposopathic source.
Packer's Three Adipokine Domains at a Glance
| Domain | Role | Key Players | What Happens in Adiposopathy | Effect on the Heart |
|---|---|---|---|---|
| Domain I "The Good Guys" |
Cardioprotective adipokines secreted by healthy fat | Adiponectin, SFRP5, omentin, C1q/TNF-related proteins | ↓ SUPPRESSED | Loss of anti-inflammatory and anti-fibrotic protection |
| Domain II "The Overwhelmed" |
Compensatory molecules upregulated in response to fat stress | Natriuretic peptides (ANP, BNP), FGF21, GDF15 | ↑ but OVERWHELMED | Insufficient compensation — can't keep pace with Domain III |
| Domain III "The Villains" |
Proinflammatory, profibrotic, antinatriuretic adipokines | Leptin, TNF-α, IL-6, resistin, aldosterone, endothelin-1 | ↑↑↑ SKYROCKETING | Cardiac hypertrophy, fibrosis, sodium retention, volume overload, inflammation |
Critically, Packer emphasizes that "obesity" as measured by BMI is the wrong metric. Central adiposity — measured by waist-to-height ratio (≥0.5) — is present in more than 95% of HFpEF patients and more reliably identifies the visceral fat that matters. Many patients with excess visceral adiposity and adipokine dysregulation do not meet the BMI threshold for "obesity" but still carry the metabolic burden that drives HFpEF. This is why CardioAdvocate emphasizes waist-to-height ratio as a more meaningful marker of cardiometabolic risk than BMI alone.
As JACC Editor-in-Chief Dr. Harlan Krumholz noted, the hypothesis is "bold, densely argued and deliberately provocative" — not the final word, but a framework that "provokes new questions, offers a coherent structure for scientific exploration, and invites rigorous challenge." For patients, the implications are immediate: ask about your waist-to-height ratio, advocate for medications that target visceral adiposity (GLP-1 agonists, SGLT2 inhibitors), and understand that treating the fat may be treating the heart failure at its root.
The Graveyard of Failed Therapies
For clinicians who trained in the era of HFrEF breakthroughs, HFpEF has been humbling. Drug after drug that transformed outcomes in reduced ejection fraction failed spectacularly when applied to preserved EF.
The CHARM-Preserved trial tested candesartan. Negative. I-PRESERVE tested irbesartan. Negative. PEP-CHF tested perindopril. Underpowered and inconclusive. Beta-blockers, which anchor HFrEF therapy, showed no mortality benefit in HFpEF and may actually worsen exercise tolerance by exacerbating chronotropic incompetence — the heart's inability to increase rate with exertion.
The logic was straightforward: if neurohormonal blockade fixes reduced EF, it should fix preserved EF too. But HFpEF played by different rules. The problem wasn't a weak pump. It was a stiff pump, a sick vasculature, an inflamed metabolic milieu, and a body that couldn't decongest itself. Through the lens of the adipokine hypothesis, the reason is now clear: these drugs were targeting the wrong pathway. HFrEF is driven by neurohormonal activation (catecholamines, angiotensin II, aldosterone released from the nerves, kidneys, and adrenals). HFpEF is driven by adipokine dysregulation (inflammatory mediators released from dysfunctional fat). Blocking the renin-angiotensin system alone couldn't untangle the complexity of adiposopathy — because the disease source was the fat, not the failing pump.
The result? For years, the therapeutic approach to HFpEF was essentially: If you're overweight — lose weight. If you have hypertension — treat your blood pressure. If you have diabetes — control your glucose. If you're old — well, get younger. It was the clinical equivalent of throwing your hands in the air. Treat the comorbidities, manage the volume with diuretics, and hope for the best.
Pharmaceutical companies poured billions into HFpEF programs, only to watch trial after trial crash against the same wall: the disease was too heterogeneous, too multifactorial, and too different from HFrEF to yield to a single-target approach. HFpEF earned its reputation as the enigma of cardiology — the condition with a name but no cure.
The TOPCAT Saga — A Cautionary Tale of Global Trial Design
Perhaps no trial better illustrates HFpEF's complexity than TOPCAT, which tested spironolactone — a mineralocorticoid receptor antagonist — in 3,445 patients with HFpEF. The primary result was negative: spironolactone did not significantly reduce the composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization.
But the story didn't end there. Post-hoc analysis revealed a striking geographic discrepancy. In the Americas cohort, spironolactone reduced the primary endpoint by 18%. In the Russia/Georgia cohort, there was no signal whatsoever. All-cause mortality was 21.8% in the Americas but only 8.4% in Eastern Europe — suggesting the Russian/Georgian patients may not have actually had HFpEF or may not have been taking the drug. Canrenone levels (a spironolactone metabolite) were undetectable in a concerning proportion of Eastern European participants.
The controversy reshaped how the HF community views spironolactone in HFpEF. While the FDA label doesn't include HFpEF, most heart failure specialists use spironolactone in clinical practice, guided by the Americas subgroup data, the biologic plausibility of MRA benefit, and the drug's low cost and long track record. The 2022 AHA/ACC/HFSA Heart Failure Guideline assigns MRAs a Class 2b recommendation in HFpEF — acknowledging uncertainty while not discouraging use.
The Breakthrough Era — We Finally Have Weapons
After decades of failure, the 2020s brought a seismic shift. For the first time, therapies demonstrated clear, reproducible benefit in HFpEF — and some of them came from entirely unexpected directions.
SGLT2 Inhibitors — The Game Changers
SGLT2 inhibitors were developed to lower blood sugar in diabetes. Their mechanism of action — blocking glucose reabsorption in the kidney, causing glycosuria — seemed modest. No one predicted they would become the most important heart failure drugs in a generation.
Empagliflozin (Jardiance) was the first to cross the finish line. The EMPEROR-Preserved trial (NEJM, 2021) enrolled 5,988 patients with HFpEF (LVEF >40%) and demonstrated a 21% relative risk reduction in cardiovascular death or heart failure hospitalization. Empagliflozin received FDA approval for HFpEF in September 2021 — making it the first drug ever specifically approved for this population. Manufactured by Boehringer Ingelheim and Eli Lilly.
Dapagliflozin (Farxiga) followed with the DELIVER trial (NEJM, 2022), enrolling 6,263 patients with LVEF >40% and showing an 18% relative risk reduction in the composite endpoint. FDA expanded dapagliflozin's HF indication to include the full EF spectrum in May 2023. Manufactured by AstraZeneca.
What's remarkable about SGLT2 inhibitors isn't just that they work — it's how quickly they work. Benefits emerged within weeks, suggesting mechanisms well beyond glucose lowering: natriuresis, plasma volume reduction, improved myocardial energetics (a shift from fatty acid to ketone body metabolism), reduced inflammation, and decreased interstitial fibrosis. The 2022 AHA/ACC/HFSA Guidelines give SGLT2 inhibitors a Class 2a recommendation in HFpEF — the strongest recommendation of any therapy for this population.
Finerenone — The Next-Generation MRA
While spironolactone's story in HFpEF remained complicated, a new non-steroidal MRA entered the arena. Finerenone (Kerendia), manufactured by Bayer, showed promise in the FINEARTS-HF trial (NEJM, 2024), demonstrating a 16% reduction in total worsening heart failure events and cardiovascular death across the HFmrEF and HFpEF spectrum. Finerenone offers a more targeted approach than spironolactone with potentially less hyperkalemia — a critical advantage in a population already juggling multiple medications that affect potassium.
Sacubitril/Valsartan — Close, but Not Quite
Sacubitril/valsartan (Entresto), manufactured by Novartis, is the cornerstone of HFrEF therapy. But in HFpEF, the PARAGON-HF trial (NEJM, 2019) narrowly missed its primary endpoint (p=0.06). However, subgroup analysis revealed potential benefit in two populations: patients with lower EF (45–57%) and women. In women with LVEF ≤57%, there was a 25% reduction in total heart failure hospitalizations.
The FDA subsequently expanded Entresto's indication to include LVEF "below normal," giving clinicians latitude to use it in the HFmrEF-to-low-HFpEF range. The 2022 Guidelines assign it a Class 2b recommendation in HFpEF, acknowledging its limited applicability. In clinical practice, many specialists reserve Entresto for HFpEF patients at the lower end of the EF spectrum, particularly women.
The Obesity Revolution — GLP-1 and GIP/GLP-1 Agonists
If SGLT2 inhibitors changed the HFpEF landscape, GLP-1 receptor agonists may redefine it. For the first time, we have therapies that attack HFpEF at its metabolic root — the obesity phenotype that drives the majority of cases.
Semaglutide — STEP-HFpEF
Semaglutide (Wegovy for weight management; Ozempic for diabetes), manufactured by Novo Nordisk, was tested in the landmark STEP-HFpEF trial (NEJM, 2023). The results were striking: 529 patients with HFpEF and obesity (BMI ≥30) randomized to semaglutide 2.4 mg weekly achieved:
- KCCQ-CSS improvement: +16.6 points (semaglutide) vs. +8.7 points (placebo) — a dramatic quality-of-life gain
- Weight loss: 10.7% body weight reduction
- 6-minute walk distance: +17.1 meters improvement vs. placebo
- CRP reduction: Significant decrease in systemic inflammation
The STEP-HFpEF DM trial extended these findings to patients with HFpEF, obesity, and type 2 diabetes. In both trials, the benefits were not merely due to weight loss — inflammation markers dropped, filling pressures improved, and functional capacity increased in ways that exceeded what weight reduction alone would predict.
Tirzepatide — SUMMIT
Tirzepatide (Zepbound for weight management; Mounjaro for diabetes), manufactured by Eli Lilly, is a dual GIP/GLP-1 receptor agonist that may take this story even further. The SUMMIT trial (NEJM, 2025) enrolled 731 patients with HFpEF and obesity (BMI ≥30, LVEF ≥50%) and delivered results that made the cardiology world take notice:
- Worsening HF events: 8.0% (tirzepatide) vs. 14.2% (placebo) — HR 0.54 — a 46% relative risk reduction
- Weight loss: 15.7% body weight vs. 2.2% (placebo)
- KCCQ-CSS at 52 weeks: +19.5 vs. +12.7 points
A 46% relative risk reduction in worsening heart failure events from a weight-management drug. If you needed evidence that obesity isn't a bystander in HFpEF — it's a driver — SUMMIT provided it.
Oral Semaglutide — SOUL Trial: Hot Off the Press
Just as this article was being updated, a secondary analysis of the SOUL randomized clinical trial landed in JAMA Internal Medicine (February 2026), and it adds a critical new dimension to the semaglutide story: oral semaglutide (Rybelsus, Novo Nordisk) may reduce heart failure events in patients with type 2 diabetes — and the benefit was concentrated in HFpEF.
The SOUL trial enrolled 9,650 participants with T2D and established atherosclerotic cardiovascular disease or chronic kidney disease. Among the 2,229 participants (23%) with a history of heart failure at baseline, oral semaglutide reduced the composite of HF hospitalization, urgent HF visits, or cardiovascular death with a hazard ratio of 0.78 (95% CI 0.63–0.96). But here's the headline: when stratified by HF subtype, the benefit was dramatically concentrated in HFpEF — HR 0.59 (95% CI 0.39–0.86) — a 41% relative risk reduction. In HFrEF, the signal disappeared entirely (HR 0.98).
This is remarkable for several reasons. First, this was a cardiovascular outcomes trial — not a heart failure–specific trial — and HFpEF benefit still emerged. Second, this was oral semaglutide — a pill, not an injection — which dramatically changes the accessibility equation for patients who cannot or will not use injectable GLP-1 agonists. Third, the near-complete absence of benefit in HFrEF reinforces a critical point: HFpEF and HFrEF are fundamentally different diseases that require different therapeutic strategies. What works in one does not automatically translate to the other — and in this case, what works in HFpEF does not work in HFrEF.
The SOUL data add oral semaglutide to a growing arsenal of GLP-1–based therapies that are rewriting the playbook for HFpEF — not by fixing the heart directly, but by attacking the metabolic inflammation, adiposopathy, and insulin resistance that create the disease in the first place. Over a median follow-up of nearly 4 years, these benefits were achieved without an increase in serious adverse events — a critical safety signal for a population already burdened with polypharmacy.
A Spectrum, Not a Binary — Why One Drug Will Never Be Enough
Here's the uncomfortable truth about HFpEF: it's not one disease. It's a syndrome with at least 3–4 overlapping phenotypes, each driven by different pathophysiology and each potentially requiring different treatment:
- The Metabolic/Obese Phenotype. The most common in Western populations — and the one most powerfully explained by Packer's adipokine hypothesis. Driven by adiposopathy ("pissed off fat"), insulin resistance, systemic inflammation, and epicardial fat that secretes proinflammatory adipokines directly into the adjacent myocardium. This is the phenotype targeted by STEP-HFpEF and SUMMIT — and where GLP-1/GIP agonists and SGLT2 inhibitors show their most dramatic effects, precisely because these drugs shrink visceral fat depots and restore healthier adipokine signaling.
- The Aging/Vascular Phenotype. Characterized by arterial stiffness, isolated systolic hypertension, and age-related myocardial fibrosis. Common in elderly patients, particularly women. Blood pressure optimization and potentially SGLT2 inhibitors are the primary tools here.
- The Atrial Fibrillation–Predominant Phenotype. Where left atrial myopathy and AF drive symptoms more than ventricular dysfunction. Rate and rhythm control become critical alongside standard HFpEF therapy.
- The Cardiometabolic Stress Phenotype. Where chronic hypertensive heart disease transitions to overt HFpEF under metabolic stress — renal dysfunction, anemia, volume overload. These patients often have the worst prognosis.
This heterogeneity explains why single-target drugs failed for so long — and why the future of HFpEF therapy will likely involve phenotype-guided, combination treatment rather than one-size-fits-all approaches. The right drug for the right patient at the right time.
Earlier Is Better — Can We Prevent HFpEF?
Perhaps the most important insight from recent research is this: HFpEF may be preventable. If obesity, hypertension, diabetes, and sedentary behavior drive the disease, then aggressively treating these conditions before they culminate in heart failure could stop HFpEF from developing in the first place.
There is growing evidence that diagnosing and treating HFpEF earlier in its course — when structural abnormalities are mild and functional capacity is still partially preserved — can stop or even reverse disease progression. The key is recognizing that HFpEF exists on a spectrum:
Stage A (at risk) → Stage B (structural changes, no symptoms) → Stage C (symptomatic HFpEF) → Stage D (advanced, refractory).
By the time most patients are diagnosed, they're already Stage C. We're catching them too late. The metabolic damage has been accumulating for years — myocardial fibrosis, left atrial dilation, microvascular dysfunction, arterial stiffening. Each year of undertreated hypertension, each decade of untreated obesity, each period of uncontrolled diabetes adds another layer of injury that becomes harder to reverse.
The paradigm shift is clear: stop treating comorbidities as separate line items and start seeing them as upstream drivers of a common downstream catastrophe.
Related CardioAdvocate Content
- Drinking Buddies — AFib and Its Cardiometabolic Companions — The AF-HFpEF bidirectional relationship
- Under Pressure — Hypertension — The number one driver of diastolic dysfunction
- The Sweet Spot — Diabetes — Metabolic inflammation and myocardial fibrosis
- The Quiet Storm — CKD — Volume overload, electrolyte disturbances, and HF
- When the Heart Gives Out — HFrEF — The other half of heart failure
- Day Dreamer — OSA — Sleep apnea and cardiac remodeling
- Barking Up the Wrong Tree — MASLD/MASH — Metabolic liver disease and cardiometabolic overlap
- The Older Adult — Age-Related CV Risk — Aging, arterial stiffness, and diastolic dysfunction
- Who Needs a Specialist? — When to refer for advanced HF care
HFpEF spent decades as cardiology's most frustrating riddle — a disease we could name but couldn't treat. That era is ending. With Packer's adipokine hypothesis, we may finally have a unifying theory that explains why the old drugs failed and why the new ones work: HFpEF is, at its core, a disease of pissed off fat — adiposopathy driving adipokine dysregulation that damages the heart, kidneys, and vasculature simultaneously. We now have SGLT2 inhibitors with FDA approval and Class 2a guideline backing. We have GLP-1 and GIP/GLP-1 agonists that address the metabolic root of the most common HFpEF phenotype. We have MRAs and ARNi with selective benefit. And we have a growing understanding that HFpEF isn't a single entity but a spectrum of disease — one that demands personalized, phenotype-guided therapy.
But here's the hard truth: most HFpEF patients are still not receiving even the therapies we already have. They're told their EF is "normal." They're shuffled between specialists. Their obesity isn't treated as a cardiac disease. Their hypertension isn't at target. Their exercise intolerance is attributed to "just getting older."
The enigma was never really about not having answers. It was about not asking the right questions soon enough. And the most important question of all may be the simplest: what's the waist-to-height ratio?
Be your own advocate. Ask the questions. Demand the workup. Start the conversation.
CardioAdvocate helps people understand what matters — and how to speak up about it.
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