At Penn Medicine, the Heart Failure Program is bringing advances in research, technology, and expertise to bear on secondary mitral regurgitation (SMR), a leading cause of moderate-to-severe valvular heart disease among older adults in the United States.
"Mitral regurgitation is categorized as primary or secondary," says Lee Goldberg, MD, MPH, Section Chief of Advanced Heart Failure and Cardiac Transplant at Penn Medicine. "The two types are very different, physiologically, in that primary MR is a disease of the valve and chordae tendineae, while secondary MR is really a disease of the left heart."
By comparison to primary mitral regurgitation (MR) of similar magnitude, secondary SMR has a poorer event-free survival, and worse long-term outcomes. For those treating SMR, these dire findings are complicated by minimal symptoms in the early course of disease.
"The first signs of SMR tend to occur when the patient has no other obvious signs of cardiovascular disease," Dr. Goldberg says. "Generally, the first recorded symptom will be a systolic heart murmur appreciated in primary care. Later there may be abnormalities on electrocardiography, and this and other events in the patient's history eventually leads to a diagnosis." But without interaction and communication between treatment teams, the early signs may be misinterpreted, or the accumulation of signs and symptoms unnoticed. What this means, Dr. Goldberg adds, is that patients with SMR require a seamless, systematic approach to care between specialties and the presence of advanced treatments and expertise—all of which has been evolving at the Penn Heart Failure Program for the last two decades.
Diagnostics: Determining MR Severity is Key for Evaluation
The American Society of Echocardiography has established guidelines and standards for transthoracic echocardiography (TEE) that categorize SMR as mild, moderate or severe. While a visual assessment may be enough when SMR is clearly mild or severe, for other cases echocardiography can provide quantitative measurements, including effective regurgitant orifice area (EROA), regurgitant volume (RVol) and regurgitant fraction (RF) to clarify degree of MR.
TEE is further used during treatment planning, as well as in the operating room and for reevaluations throughout care. According to Roy Arjoon, MD, an imaging cardiologist at Penn Presbyterian Medical Center, this reliance upon technology makes quality imaging a focal point of SMR management at Penn Medicine.
Treatment: Medications and Pacing
Treating SMR, which is also known as functional MR, calls for first trying to maximize heart failure medications to tackle root causes—LV dysfunction and remodeling. Updated 2022 joint heart failure guidelines recommend that this medical management be led by a heart failure specialist when SMR is involved.
The revised guidelines call for a new class of medications—sodium-glucose cotransporter-2 (SGLT2) inhibitors—across the heart failure spectrum. Their use extends to LVEF below 40 percent (heart failure with reduced ejection fraction, or HFrEF), LVEF from 40 percent to 49 percent (mildly reduced ejection fraction, or HFmEF) and LVEF of more than 50 percent (preserved ejection fraction, or HFpEF).
The updated Guidelines also call for swapping in an angiotensin receptor-neprilysin inhibitor (ARNi) when possible, a finding supported by the Pharmacological Reduction of Functional, Ischemic Mitral Regurgitation (PRIME) study, which demonstrated a clear benefit in SMR reduction versus an angiotensin receptor blocker.
HFrEF and HFmEF patients may also need cardiac resynchronization therapy (CRT) to address SMR.
Ventricular synchrony has been shown in multiple studies to promote positive remodeling and reduce SMR in combination with Guidelines management, and there is growing evidence that this pairing improves survival.
Decisions: Open Mitral Valve Surgery vs Advanced Heart Failure Therapy
To some degree, traditional surgery still plays a role for symptomatic SMR, though less so than for primary MR. The updated Guidelines retain a Class 2A recommendation for mitral valve surgery when patients with severe SMR already need aortic valve replacement or coronary artery bypass grafting. While durable and a potential way to address symptoms, surgery introduces morbidity and mortality risks, with no demonstrated survival benefit.
"Because Stage D heart failure patients may also require more advanced intervention, the multidisciplinary Penn team will often consider whether patients may benefit from a left ventricular assist device or cardiac transplant before addressing SMR," Dr. Goldberg notes. "This is particularly relevant in patents with home inotrope dependency or LVEF under 20 percent."
Some patients may not yet need advanced heart failure therapies or meet the criteria. They may benefit more from a mitral valve intervention, though the approach depends on the type of heart failure diagnosed.
For HFpEF, clinicians can consider mitral valve surgery when patients have severe, persistent SMR symptoms and concomitant atrial fibrillation, a Class 2B recommendation. For remaining symptomatic SMR patients—those with LVEF less than 50 percent—clinicians can turn to an emerging range of options. These approaches represent part of the wave of heart failure advances in recent years and offer alternatives that avoid cardiopulmonary bypass.
Turning to Transcatheter Edge-to-Edge Repair (TEER) as an Alternative, in the Right Cases
To decide whether to pursue mitral valve interventions with LVEF less than 50 percent, Penn and other heart failure teams have turned to the framework of "disproportionately severe" SMR.
"The concept of disproportionately severe SMR is that the degree of mitral regurgitation is more significant than what might be expected for the degree of severity of LV dysfunction," says Paul Fiorilli, MD, co-director of Penn's Transcatheter Valve Program. "In the trials of TEER for secondary MR, patients with disproportionately severe MR had the largest benefit from mechanically fixing the mitral valve. We can identify these patients using data from the echocardiogram."
The results can guide patient selection for an alternative called transcatheter edge-to-edge repair (TEER), formerly known as transcatheter mitral valve repair.
"These are the patients that we are trying to tease out," remarks Dr. Fiorilli. "In the right, carefully selected patient, TEER can be a great option and afford both symptomatic relief and a mortality benefit."
The MitraClip TEER device was the first approved catheter-based SMR intervention for SMR. A novel percutaneous device, MitraClip is introduced via the femoral vein and fastened edge-to-edge to the middle scallops of the posterior and anterior leaflets of the mitral valve to create a double orifice-improving coaptation (or joining) that replicates the Alfieri surgical repair.
The FDA approval was based largely on findings from the Cardiovascular Outcomes Assessment of MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation [COAPT] trial, for which Penn Medicine was a study site through the Division of Cardiovascular Medicine.
Results showed a 47 percent relative risk reduction for heart failure hospitalizations and a 38 percent decline for all-cause mortality compared to medical therapy alone—the first SMR intervention to achieve a mortality benefit. SMR reductions were also sustained. The trial drove home the critical importance of patient selection and maximizing GDMT—both pre- and post-procedurally.
The COAPT outcomes were stunning, says Dr. Fiorilli, leading to a class 2A guidelines recommendation and a steady increase in TEER referrals to the program. Addressing concerns in the field about potential MitraClip narrowing of the valve opening, a Penn-led retrospective study demonstrated that patients benefited even if pressure gradients increased.
Identifying Limits With MitraClip and Other TEER Devices for SMR
Issues remain with TEER durability, however, despite its apparent effectiveness for certain patients with SMR. TEER does not include annuloplasty, and is contraindicated or impossible in some patients. The left ventricle may be too large, for example, or there may be significant untreated pulmonary hypertension. Valve anatomy can pose challenges, too, including calcification, leaflet damage or restricted size, and limited mitral valve area. The path of reversed flow can also pose a barrier, as can the presence of severe tricuspid regurgitation (TR). Moreover, recent reports suggest that as many as 30 percent of patients have both SMR and TR. These and the aforementioned findings suggest that a substantial portion of patients may not be candidates for TEER.
A second TEER device, the PASCAL Precision System, also studied at Penn, has yet to be FDA approved for SMR. Thus, for Penn and other heart failure programs, the search for alternative therapies goes on.
Developing Further Options, Through Transcatheter Delivery or Off-Pump Approaches
While the Penn team anticipates further TEER advances—with potential increases in patient eligibility—the program is also working to develop other options for broader application.
If approved, some interventions would provide transcatheter mitral valve replacement. Others would feature transcatheter mitral annuloplasty, either through direct reinforcement or indirect support targeting nearby structures. New devices could also help reconstruct mitral chordae, through minimally invasive off-pump surgery.
For the tricuspid valve, transcatheter repair or replacement could also address TR.
To these ends, Penn clinical studies include:
Contact the Penn Heart Failure Program
To reach the Penn heart failure team, please call 215-615-0800.