Determine if cilostazol improves symptoms and NTproBNP levels (heart failure blood marker) in heart failure with preserved ejection fraction (HFpEF) - a prevalent syndrome without targeted evidence-based treatment.

This will be assessed in a prospective 1-month single blinded study with 2 cross-overs n-of-1 study design with placebo and cilostazol

Heart failure (HF) is the #1 reason for hospital admissions. About half of the patients with HF have a preserved ejection fraction (HFpEF). There is no targeted evidence-based treatment for HFpEF. We recently reported that elevating the heart rate with pacemakers conveys clinical benefits e.g. reduction in heart failure symptoms, lowering filling pressures and an increase in walk distance. Cilostazol is a PDE3 inhibitor that increases the heart rate by about 5-8 beats per minute and has other potentially beneficial HFpEF effects such as peripheral vasodilation, lusitropic effects and dromotropic effects. By activating proteinkinase A, cilostazol may also phosphorylate titin, which may reduce myocardial stiffness.

n-of-1 study design using the standard dose cilostazol formulation of 100mg twice a day approved for peripheral vascular disease. The investigators and patients are blinded. The patients serve as their own controls with two crossovers (Week 1: cilostazol or placebo - Week 2: placebo or cilostazol - Week 3: cilostazol or placebo - Week 4: placebo or cilostazol).

Inclusion Criteria:

• >18 yrs

• LVEF ≥ 50% (on last assessment, <2 years)

• Diagnosis of HFpEF or Shortness of breath with NYHA Class ≥ 2 and one of the following:

  1. pulmonary edema on chest imaging or documented on exam or on loop diuretics
  2. NTproBNP >400 ng/ml in the last 24 months
  3. HFpEF>50% hospitalization in the last 3 years
  4. Qualitative echo: > mild diastolic dysfunction on echo report and > mild left ventricular hypertrophy and left atrial dilation or quantitative echo: left ventricular hypertrophy [men ≥115 g/m², women ≥95 g/m² or relative wall thickness >0.42 or any LV wall thickness >1.2cm and has LA dilation (>28ml/m2)

Exclusion Criteria:

• <18yo
• resting heart rate >100/min
• patients with LVEF <50%
• advanced end-stage heart failure,
• symptomatic COPD on home O2,
• uncontrolled severe HTN (SBP >160/100 mmHg)
• patients with life expectancy <6 months,
• end-stage liver cirrhosis,
• more than moderate valve disease,
• infiltrative myocardial disease
• constrictive pericarditis or myocarditis,
• patients unable to participate in follow up,
• pregnant patients or patients without reliable contraceptive agent for the duration of study participation),
• left ventricular outflow tract obstruction,
• bleeding dyscrasias, blood dyscrasias,
• Patients on oral ketoconazole, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, erythromycin, clarithromycin or azithromycin](streamdown:incomplete-link)

1 month

Data on non-serious adverse events was not collected