What medications can be used to increase heart‑rate variability (HRV)?

Medications to Increase Heart Rate Variability

Beta-Blockers Are First-Line for Increasing HRV

Beta-blockers are the most effective pharmacologic agents for increasing heart rate variability, with bisoprolol and metoprolol demonstrating significant improvements in both time-domain and frequency-domain HRV parameters in patients with heart disease. 1, 2

Evidence for Beta-Blocker Efficacy

• Bisoprolol 5 mg once daily significantly increased parasympathetic HRV markers including 24-hour rMSSD (p=0.04), 24-hour pNN50 (p=0.04), daytime SDNN (p=0.05), and daytime high-frequency power (p=0.03) after 2 months of treatment in heart failure patients. 1

• Metoprolol controlled-release 200 mg daily and atenolol 100 mg daily both increased high-frequency power by approximately 62-64% and root-mean-square successive difference by 62-70% in patients with stable coronary artery disease, with no significant difference between the two agents. 2

• The increase in HRV with beta-blockade reflects enhanced vagal tone, which may contribute to the mortality reduction seen with these agents in cardiovascular disease and represents a mechanism beyond simple heart rate reduction. 1, 3

Dosing Strategy for HRV Optimization

• Start bisoprolol at 2.5 mg once daily and titrate to 5-10 mg daily, monitoring for hypotension, bradycardia, or heart failure decompensation during up-titration. 4

• Metoprolol can be initiated at 25-50 mg twice daily (immediate-release) or 50-100 mg once daily (extended-release), with gradual titration to 100 mg twice daily or 200 mg daily respectively as tolerated. 2

• Up-titrate slowly with small increments every 1-2 weeks, allowing time for hemodynamic adaptation and HRV improvement to manifest over weeks to months. 4

ACE Inhibitors and Angiotensin Receptor Blockers

• Converting enzyme inhibitors (ACE inhibitors) improve HRV indirectly by reducing cardiac hypertrophy and ventricular fibrosis, which are structural determinants of attenuated HRV in hypertensive heart disease. 5

• ACE inhibitors demonstrated antiarrhythmic effects and normalization of HRV when cardiac hypertrophy was prevented in experimental models of hypertension. 5

Cognitive Behavioral Therapy Shows Unique HRV Benefits

• Cognitive behavioral therapy (CBT) alone for 12 weeks significantly reduced heart rate and increased HRV in panic disorder patients, whereas sertraline combined with CBT did not produce the same HRV improvements despite equivalent symptom reduction. 6

• This finding suggests non-pharmacologic interventions may offer cardiovascular benefits beyond medication in conditions associated with autonomic dysfunction. 6

Agents That Do NOT Increase HRV

Calcium Channel Blockers

• Nondihydropyridine calcium channel blockers (diltiazem, verapamil) are contraindicated in heart failure with reduced ejection fraction and have not been shown to improve HRV. 4, 7

• Dihydropyridine calcium channel blockers (amlodipine, felodipine) showed no survival benefit in heart failure trials and are not recommended for HRV optimization. 4

Selective Serotonin Reuptake Inhibitors

• Sertraline combined with CBT did not produce HRV improvements despite clinical anxiety reduction, suggesting SSRIs do not enhance cardiac vagal control. 6

Clinical Implications and Monitoring

• Reduced HRV is a powerful independent predictor of adverse prognosis in both heart disease and the general population, making HRV improvement a meaningful therapeutic target beyond symptom control. 3

• HRV improvement with beta-blockers may take 2 months or longer to manifest, requiring patience during titration and sustained therapy. 1

• The relationship between increased cardiac vagal control and mortality reduction likely involves decreased myocardial oxygen demand, reduced sympathetic activity, and decreased susceptibility to lethal arrhythmias. 3

Monitoring Parameters

• Assess HRV using 24-hour Holter monitoring with time-domain measures (SDNN, rMSSD, pNN50) and frequency-domain analysis (high-frequency and low-frequency power). 1, 2

• Monitor for beta-blocker adverse effects including bradycardia (<50 bpm), hypotension, heart block, and heart failure decompensation, particularly during initiation and up-titration. 4

• Target heart rate reduction should be gradual, as abrupt or excessive bradycardia may worsen outcomes despite theoretical HRV benefits. 1

Common Pitfalls to Avoid

• Do not use calcium channel blockers as first-line agents for HRV improvement; they lack evidence of benefit and carry harm risk in heart failure. 4

• Do not expect immediate HRV improvement; beta-blocker effects on autonomic parameters require weeks to months of sustained therapy. 1

• Do not discontinue beta-blockers due to asymptomatic low blood pressure if the patient is clinically stable, as HRV benefits accrue over time and low BP alone does not indicate poor tolerance. 4