What is the best management plan for a middle-aged adult with a history of cardiovascular disease, presenting with heart failure with reduced ejection fraction (HFrEF), mild concentric left ventricular hypertrophy, moderate to severe mitral regurgitation, mild to moderate tricuspid regurgitation, and mild to moderate aortic regurgitation?

Management of HFrEF with Moderate-to-Severe Mitral Regurgitation and Multiple Valvular Pathology

This patient requires immediate initiation of quadruple guideline-directed medical therapy (GDMT) for HFrEF, consisting of an SGLT2 inhibitor, beta-blocker, ACE inhibitor/ARB (or ARNI), and mineralocorticoid receptor antagonist, with subsequent evaluation for transcatheter mitral valve repair once medically optimized. 1, 2, 3

Immediate Pharmacological Management

First-Line Quadruple Therapy (Initiate Simultaneously)

All four medication classes should be started at low doses without waiting to achieve target dosing of one before initiating the next: 1, 2

• SGLT2 inhibitor (dapagliflozin or empagliflozin) - This is the highest priority medication to initiate, as it reduces HF hospitalizations and cardiovascular mortality in HFrEF regardless of diabetes status, with minimal blood pressure effects making it ideal for patients with borderline hemodynamics 1, 3

• Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) - Essential for reducing mortality and HF hospitalization in patients with LVEF <40%, though monitor carefully for bradycardia given the TAPSE of 1.6 cm suggests mild RV dysfunction 1, 2, 4

• ACE inhibitor or ARB - Start with ACE inhibitor unless contraindicated; however, avoid in the setting of significant aortic stenosis (not present here, as only mild-moderate AR exists) 1, 2, 5

• Mineralocorticoid receptor antagonist (spironolactone or eplerenone) - Indicated for symptomatic HFrEF with LVEF <40% to reduce mortality and hospitalization, though monitor potassium and renal function closely 1, 2, 3

Diuretic Therapy for Congestion

• Loop diuretics as needed to manage volume status, given the moderate bilateral atrial dilatation suggesting chronic volume overload 1, 2

Medication Titration Strategy

After initiating all four foundational medications, uptitrate each to target doses over 4-8 weeks: 1, 3

• If patient remains symptomatic despite optimal triple therapy (beta-blocker, ACE inhibitor, MRA), replace the ACE inhibitor with sacubitril/valsartan (ARNI), which reduces HF hospitalizations and death by 20% compared to ACE inhibitors alone 3

• Do not combine ACE inhibitors with ARBs and aldosterone antagonists simultaneously due to increased risk of renal dysfunction and hyperkalemia 3

Addressing the Valvular Pathology

Moderate-to-Severe Mitral Regurgitation

This functional mitral regurgitation is a critical prognostic factor that warrants specific intervention: 6, 7

• The moderate-to-severe MR in the setting of HFrEF (LVEF 40-45%) with mild LV dilatation (LVIDd 5.6 cm) represents ventricular functional MR due to LV remodeling and dysfunction 7

• After 3-6 months of optimal GDMT, if MR remains moderate-to-severe and patient remains symptomatic (NYHA class II-IV), refer for transcatheter edge-to-edge mitral valve repair (TEER), which has demonstrated improved outcomes in HFrEF patients with severe secondary MR 8, 9

• GDMT optimization may reduce MR severity through reverse remodeling, particularly with ARNI therapy 7

Mild-to-Moderate Tricuspid Regurgitation

• The TR in this patient is likely functional, related to RV dilatation (RV base 4 cm) and RA enlargement (23.9 cm²) 6

• Medical optimization of HFrEF is the primary treatment, as reducing RV afterload and improving hemodynamics may reduce TR severity 6

• Monitor TR severity with serial echocardiography; if it progresses to severe TR despite optimal medical therapy, consider transcatheter tricuspid valve repair 6, 8

Mild-to-Moderate Aortic Regurgitation

• The mild-moderate AR with mild aortic root dilatation (3.4 cm) does not require specific intervention at this time 1

• Continue GDMT as afterload reduction with ACE inhibitors/ARBs/ARNI will help manage AR 1

• Monitor aortic root size and AR severity annually with echocardiography 1

Device Therapy Considerations

Evaluate for implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) after 3 months of optimal GDMT: 1, 2

• ICD for primary prevention if LVEF remains ≤35% after 3 months of optimal medical therapy, as this provides high economic value in preventing sudden cardiac death 2

• Assess QRS duration and morphology - if LBBB with QRS ≥150 ms develops or is present, CRT-D provides high economic value for patients with LVEF ≤35% and NYHA class II-IV symptoms 2

• The current heart rate of 96 BPM and TAPSE of 1.6 cm (mildly reduced RV function) should be monitored during beta-blocker titration 4

Critical Monitoring Parameters

Serial reassessment every 2-4 weeks during uptitration, then every 3-6 months: 1, 2

• Renal function and electrolytes - ACE inhibitors can cause increases in creatinine and potassium, particularly when combined with MRAs; dose reduction may be needed if creatinine doubles or exceeds 3 mg/dL 5

• Blood pressure - Asymptomatic hypotension should NOT prevent initiation or uptitration of SGLT2 inhibitors or sacubitril/valsartan, as their effectiveness is maintained at lower blood pressures 3

• Heart rate - Target resting heart rate 50-60 bpm with beta-blocker therapy, but monitor for excessive bradycardia given baseline mild RV dysfunction 4

• Repeat echocardiography at 3-6 months to assess for reverse remodeling (improvement in LVEF, reduction in LV dimensions, improvement in MR severity) 1, 2

Important Warnings

• Never discontinue beta-blocker therapy abruptly in this patient with cardiovascular disease, as severe exacerbation of symptoms, MI, and ventricular arrhythmias can occur 4

• If LVEF improves to >40% (HFimpEF), continue all GDMT to prevent relapse of HF and LV dysfunction, even if patient becomes asymptomatic 2

• Beta-blockers can mask hypoglycemia symptoms if patient has diabetes; monitor glucose carefully 4

• ACE inhibitors cause persistent nonproductive cough in some patients; if intolerable, switch to ARB rather than discontinuing RAAS inhibition 5

Specialty Referral

Refer to advanced heart failure specialist if: 1

• Patient remains NYHA class III-IV despite optimal GDMT after 3-6 months
• Moderate-to-severe MR persists after GDMT optimization for consideration of TEER
• Progressive worsening of TR to severe grade
• Development of refractory symptoms requiring advanced therapies (intravenous inotropes, mechanical circulatory support, transplant evaluation)