A significant risk in female heart patients: Paradoxical low-flow, low-gradient AS
According to the 2020 ACC/AHA Valvular Guidelines, severe aortic stenosis (AS) is defined as an aortic Vmax ≥4 m/s or mean ΔP ≥40 mm Hg and AVA typically < 1.0 cm2 (or AVAi ≤ 0.6 cm2/m2).1 There are times, however, when a patient’s AS presents on their echocardiography results in a way that is outside of the norm.
Paradoxical low-flow, low-gradient AS (pLFLG AS), for instance, is a subtype of AS seen in patients who present with D3 guideline criteria of AVA ≤1.0 cm2 (indexed AVA ≤0.6 cm2/m2) with an aortic Vmax <4 m/s or mean ΔP <40 mm Hg AND stroke volume index measuring lower than 35 mL/m2 measured when the patient is normotensive (systolic blood pressure <140 mm Hg) but a normal ejection fraction.1 This cohort represents up to 25% of all cases of severe AS with preserved LV function. These patients are predominantly older women with a small LV cavity with pronounced LV concentric remodeling and a restrictive physiology, leading to a decrease in stroke volume.2 The paradox in this scenario is the fact that the patient’s ejection fraction is normal even though they are exhibiting a low flow state. But a closer look at their echo results confirms that severe AS is the correct diagnosis.
“It really takes a meticulous assessment of the patient’s echocardiography to judge whether or not they have severe AS,” explains Nadira Hamid, MD†, director of interventional echocardiography at the Minneapolis Heart Institute and scientific director of the echocardiography core laboratory at the Minneapolis Heart Institute Foundation. “It is easy to underestimate severe AS if you don’t look closely enough. That was actually a key challenge early on among echocardiographers—you would have specialists assuming the patient did not have severe AS because maybe one of the numbers was not what you would expect.”
“You also have to consider how high blood pressure can impact a patient’s anatomy. When a woman who already has small ventricles has hypertension, the walls of her left ventricle will get very thick, and the cavity of that ventricle will get very small. This can cause the stroke volume of the left ventricle to drop significantly, and they end up with paradoxical low-flow, low gradient aortic stenosis."
Nadira Hamid, MD, Director of Interventional Echocardiography, Minneapolis Heart Institute
Why severe AS is more likely to go undiagnosed in women
Paradoxical low-flow low-gradient AS is much more common in women than men, notes Hamid, who reads echocardiography results on a daily basis in addition to seeing patients. The primary reason for the disparity is the simple fact that women typically have smaller ventricles than men. Women also tend to present with less calcium, which may make it unclear on the initial imaging results that they do have severe AS.3
Another key factor, Hamid adds, is the rise of hypertension.
“You also have to consider how high blood pressure can impact a patient’s anatomy,” Hamid says. “When a woman who already has small ventricles has hypertension, the walls of her left ventricle will get very thick, and the cavity of that ventricle will get very small. This can cause the stroke volume of the left ventricle to drop significantly, and they end up with paradoxical low-flow, low gradient AS. It’s a phenomenon we have seen a lot in the last 10 or 15 years as we learn more about this topic.”
Before cardiologists understood pLFLG AS many women would go undiagnosed for years. In some cases, a female patient may never have received a proper diagnosis and ultimately not referred for TAVR or SAVR.4 Fortunately, fewer patients go undiagnosed today thanks to advances in cardiac imaging, but missed diagnoses do remain a problem. Hamid notes that symptomatology in women differ from men, with severe aortic stenosis often presenting as shortness of breath, fatigue, reduced exercise tolerance, and signs consistent with heart failure. She also highlights seeing the presence of more atypical symptoms in her female patients—such as back pressure originating from the left side and radiating through the chest cavity, frequently due to pulmonary congestion. These atypical presentations are more common among women, and there is a need for broader clinical awareness.3
“By the time these undiagnosed patients finally come to the hospital for these other symptoms, they are very sick,” Hamid says. “We can still treat them with transcatheter aortic valve replacement (TAVR) and help them have a full recovery, but sicker patients are going to be more challenging to treat and create more risks.” 5
Other comorbidities to consider
The increased prevalence of pLFLG AS in women is thought to be driven by different cardiac physiology between sexes; in particular, women tend to have smaller LV cavity size, signs of concentric remodeling, LV hypertrophy, and overall higher rates of hypertension, atrial fibrillation.1,3 Another challenge women face more than men, is the history of previous radiation therapy from a previous breast cancer diagnosis.6
“Radiation therapy can actually cause the leaflets to undergo fibrotic changes and thicken,” Hamid explains. “We see that happen a lot with our patients who have been treated for cancer. It’s different from calcification, but it can lead to similar issues.”6
Developing a care plan for paradoxical low-flow, low-gradient AS
Although there have been concerns that patients with pLFLG aortic stenosis may not benefit from aortic valve replacement (AVR) due to the extent of advanced disease, emerging evidence supports the use of TAVR in this population. Analysis from the Evolut™ Low Risk Trial suggests that patients with paradoxical LFLG severe AS experience a functional and hemodynamic benefit with TAVR compared to surgery out to 2 years.7 However, it remains essential that these cases be reviewed by a multidisciplinary heart team to determine the most appropriate individualized management plan.
“TAVR really revolutionized how we treat aortic stenosis,” Hamid says. “It’s made such a big difference both for cardiologists and our patients. As long as they are stable and we have no other concerns, a patient with paradoxical low-flow, low-gradient severe AS can one hundred percent be treated with TAVR. But it does ultimately come down to the profile of that specific patient.”
Shared decision-making is essential in guiding the treatment approach for patients with aortic stenosis. Hamid underscores the importance of ensuring that patients receive a clear and comprehensive explanation of their clinical data, available treatment options, and the recommendations of the multidisciplinary heart team. In her experience, the majority of patients express a strong preference for TAVR over surgical intervention.
“We discuss everything during those multidisciplinary meetings,” she says. “And when the patient is a woman, we certainly have additional things to consider. We look at the echo result and images, valve size, the body surface area. We review the different valve types, and which one might be the best fit for a female patient. Those are the discussions we are having on a regular basis to ensure we are doing what is best for our patients.”
“Patients never want open heart surgery,” Hamid adds. “They don’t want the scar. They don’t want the longer recovery. They often want to go with TAVR, and we have to respect that preference, as long as they are fully aware of the risk and benefits.” TAVR risks can include death, stroke and bleeding.
Hamid explains that recent clinical evidence has enhanced the way valve selection is discussed with patients. A prime example is the release of the SMART trial women sub-analysis one-year results comparing clinical outcomes and valve performance in female patients with small annuli◊ who received either a supra-annular, self-expanding Evolut™ TAVR or a balloon-expandable SAPIEN™ TAVR. A standout finding was the significantly lower rate of bioprosthetic valve dysfunction (BVD) in women at one year: 8.4% with the Evolut™ valve versus 41.8% with the balloon-expandable alternative (p<0.001).8 These results underscore the superior valve performance‡ of the supra-annular, self-expanding design in this patient population.
Technological innovation continues to advance the future of TAVR and address lifetime management needs as well. The latest-generation Evolut™ FX+ valve features larger frame windows designed to improve coronary access for potential future interventions.9,10 This builds on prior enhancements introduced with Evolut™ FX, including gold markers that improve imaging visibility and help operators align the valve more precisely with the coronaries during implantation.11 Together, these innovations support easier access and facilitate future valve-in-valve TAVR procedures—if necessary.
“I love the Evolut™ valves,” Hamid says. “I have seen patients in my practice benefit from the therapy and valve selection matters in certain populations, especially when it comes to small annulus and women, as we saw from the SMART trial.”
When to refer
Paradoxical LFLG AS represents a complex and often underrecognized subtype of severe AS, particularly prevalent among women due to unique anatomical and physiological factors. Advances in awareness and multidisciplinary collaboration significantly improved therapeutic outcomes for this challenging population. With growing evidence supporting the safety and efficacy of TAVR, early referral and proactive monitoring are essential to ensure timely intervention and optimize long-term patient care. As clinical practice evolves, embracing a patient-centered, team-based approach will be key to addressing the nuanced needs of these patients and improving outcomes across the spectrum of aortic stenosis.
With growing confidence in both the data and technology behind TAVR, the priority now shifts to timely access for patients who stand to benefit and may be missed. For those presenting with pLFLG AS, Hamid emphasizes the importance of effective imaging considerations to capture these patients and timely referral to a valve center—just as would be done for any patient with severe AS. She also supports early referral once peak velocity reaches 3 m/s or higher, ensuring that patients are evaluated before symptoms escalate or opportunities for intervention narrow.
This doesn’t mean patients with moderate AS§ are ready for TAVR. However, Dr. Hamid believes it is important to get patients with moderate AS in the system right away so that the heart team can start to monitor their symptoms over time. Without a referral, that patient may not seek care again on their own for a number of years, or maybe they’ll never see a cardiologist again. That referral helps ensure they are receiving the follow-up care they need and symptom progression is not going unnoticed.
“Now is the time to change our clinical practice,” Hamid says. “I think any patient with moderate AS should be referred to a valve center and start undergoing regular follow-up imaging every six to 12 months. You just don’t know how these symptoms are going to progress. If there is any uncertainty at all, just refer. If the AS remains moderate, we can advise them that we’ll see them again in a year to monitor any progression. There are upcoming trials evaluating early intervention even in moderate AS. The data is yet to come.”
In conclusion, symptomatic severe aortic stenosis remains underdiagnosed and undertreated, with pLFLG AS representing a particularly complex and frequently overlooked subtype that disproportionately affect women. As evidence affirms TAVR’s safety and effectiveness, early referral and careful monitoring are vital for timely intervention and optimal long-term care. Going forward, a patient-centered, team-based approach will be key to addressing the complex needs of this population and advancing standards throughout aortic stenosis management.
†Dr. Nadira Hamid did not receive compensation for this piece. However, she has received compensation from Medtronic Medical Education programs.
‡ Valve performance as defined as freedom from bioprosthetic valve dysfunction (BVD) through 12 months. BVD is defined as a composite including any of the following: hemodynamic structural valve dysfunction (mean gradient ≥ 20 mmHg), non-structural valve dysfunction (severe prothesis-patient mismatch or ≥ moderate aortic regurgitation), clinical thrombosis, endocarditis, and aortic valve reintervention.
§Evolut TAVR is indicated to treat patients who have been diagnosed with symptomatic severe aortic stenosis
◊In patients with small annuli (area ≤ 430 mm2) in all-comers trial, consisting of majority low surgical risk participants (52.1%)
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References:
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- Pibarot P, Dumesnil J, Low-Flow, Low-Gradient Aortic Stenosis with Normal and Depressed Left Ventricular Ejection Fraction. JACC. Novemeber 2012;60(19): 1845-53
- Iribarren AC, Al Badri A, Wei J, et al. Sex differences in aortic stenosis: Identification of knowledge gaps for sex-specific personalized medicine. Am Heart J Plus. September 2022;21:100197
- Tribouilloy C, Bohbot Y, Rusinaru D, et al. Excess Mortality and Undertreatment of Women With Severe Aortic Stenosis. J Am Heart Assoc. January 5, 2021;10(1):e018816
- Rice CT, Barnett S, O’Connell SP, et al. Impact of gender, ethnicity and social deprivation on access to surgical or transcatheter aortic valve replacement in aortic stenosis: a retrospective database study in England. Open Heart. September 2023;10(2):e002373.
- Belzile-Dugas E, Fremes S, Eisenberg MJ. Radiation-induced aortic stenosis: an update on treatment modalities. JACC Adv. 2023;2(1):100264
- Anwaruddin, S, Forrest, J, Gada, H. et al. The Role of Transcatheter Aortic Valve Replacement in Low-Flow Low-Gradient Aortic Stenosis: Insight from the Evolut Low Risk Trial. JACC. 2022 Mar, 79 (9_Supplement) 653.
- Medtronic computational data model on file compared to the Evolut platform. Bench top computational model may not be indicative of clinical performance. Evolut FX+ Test Report: DO1106198 Rev. A
- Tchétché D, Mehran R, Blackman DJ, et al. Transcatheter Aortic Valve Implantation by Valve Type in Women With Small Annuli: Results From the SMART Randomized Clinical Trial. JAMA Cardiol. Published online October 9, 2024.
- Feroze R, et al. Coronary Cannulation Following Transcatheter Aortic Valve Replacement with Self-Expanding Evolut FX+ System: The CANNULARE TAVR II Study. Structural Heart. April,2025; 10048
- Yoon SH et al. Commissural and Coronary Alignment After Transcatheter Aortic Valve Replacement Using the New Supra-Annular, Self-Expanding Evolut FX System. Circ Cardiovasc Interv. 2023 Apr;16(4):e012657.
Michael has more than 19 years of experience as a professional writer and editor. He has written at length about cardiology, radiology, artificial intelligence and other key healthcare topics.