The Effects of Active VItamin D on Left Atrial Volume Index
The Effects of Active VItamin D on Left Atrial Volume Index
This is a pilot feasibility study to determine the effects of an activated vitamin D compound
 (paricalcitol) on heart structure (size) and function (ability to relax) in patients with
 normal kidney function and a form of heart failure known as HFPEF (heart failure and
 preserved ejection fraction). This study will also examine heart failure-related
 hospitalizations and changes in cardiac-stretch and biological markers that are believed to
 change along with heart size. Patients in this pilot study will be treated for a period of 48
 weeks with paricalcitol at a dose previously approved by FDA (1 mcg per day) and followed-up
 for 4 weeks after treatment is completed.
Heart failure (HF) is among the top ten causes of hospitalizations in the US. It is estimated
 that ~40-50% of patients with HF have preserved ejection fraction (EF). Patients with heart
 failure and preserved ejection fraction (HFPEF) have normal systolic function, but impaired
 cardiac relaxation. The main causes of HFPEF include left-ventricular hypertrophy (LVH) and
 hypertension, hypertrophic cardiomyopathy, aortic stenosis with a normal EF, coronary artery
 disease and restrictive cardiomyopathies.

 Only a few small clinical trials have tested therapeutic interventions in patients with
 HFPEF, producing either small or negative effects. Relatively few drugs have effects on
 cardiac relaxation and are not candidates for chronic use, as they may have significant side
 effect profiles and/or are inconvenient to administer. Paricalcitol, an FDA-approved
 activated form of vitamin D, has been shown to slow LVH progression and improve parameters
 associated with diastolic function in animal models (see refs). Treatment with paricalcitol
 has also been associated with decreased cardiovascular morbidity and mortality in a
 historical cohort study of patients with end-stage renal disease (see refs).

 This is a single-center, single-arm, pilot study in 20 patients with HFPEF and normal renal
 function on stable medical therapy to evaluate the effects of paricalcitol on cardiac
 structure and function.
Inclusion Criteria:

 -  Sign informed consent.

 -  Willing and able to adhere to all study-related procedures, including study medication
 regimen.

 -  ≥ 18 years old.

 -  Previous clinical diagnosis of heart failure with preserved ejection fraction: NYHA
 Class II-IV.

 -  Satisfy these echocardiographic criteria within the last year: Left ventricular
 ejection fraction ≥ 50%, cardiac magnetic resonance or ventriculogram; Left atrial
 size ≥ 4 cm in long axis or > 5.2 cm in four chamber length; Septal wall thickness >
 1.2 cm (females) or 1.3 cm (males); Doppler evidence of moderate or severe diastolic
 dysfunction (≥ Grade II) by transmitral inflow, pulmonary venous flow, color M-mode
 and/or tissue Doppler (per European Society of Cardiology guidelines).

 -  Experienced ≥ 1 of the following in last 12 months: Hospitalization for acute heart
 failure (primary diagnosis); Long term treatment with loop diuretic; Mean pulmonary
 capillary wedge pressure ≥ 16 mm Hg at catheterization for dyspnea; Left ventricular
 end diastolic pressure (LVEDP) ≥ 19 mm Hg at catheterization for dyspnea; Acute
 treatment with intravenous loop diuretic or hemofiltration.

 -  On stable medical therapy in last 30 days before study entry (defined as no change in
 angiotensin converting enzyme inhibitors [ACEI], angiotensin receptor blockers,
 aldosterone inhibitors, beta-blockers or calcium channel blockers.

 -  Satisfy these criteria at initial lab screening: Estimated glomerular filtration rate
 (eGFR) ≥ 30 ml/min; Corrected serum Ca 8.0-10.0 mg/dL (2.0-2.5 mmol/L); Phos ≤ 5.2
 mg/dL (1.68 mmol/L); Serum albumin ≥ 3.0 g/dL (30 g/L);

 -  Negative serum pregnancy test for females of childbearing potential (within 2 weeks of
 starting study treatment).

 -  Women of childbearing potential must be practicing barrier/oral contraception during
 study-related treatment, or be surgically sterile or one year post-menopausal, be
 non-nursing and non-pregnant.

 Exclusion Criteria:

 -  Taking > 1,000 IU of vitamin D preparation daily within last 30 days.

 -  Received activated vitamin D preparation including paricalcitol (Zemplar®),
 doxercalciferol (Hectorol®) or calcitriol (Rocalctrol®, Calcijex®) within last 90 days
 prior to study entry.

 -  History of nephrolithiasis.

 -  Poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic
 blood pressure > 110 mmHg at Screening; confirmed by repeat).

 -  Secondary hypertension (i.e. renal artery stenosis, primary aldosteronism or
 pheochromocytoma).

 -  Severe hepatic impairment.

 -  Use of known inhibitors (ie, ketoconazole) or inducers (ie, carbamazepine) of
 cytochrome P450 3A (CYP3A) within 2 weeks prior to taking study drug.

 -  HIV positive.

 -  Condition with prognosis < 1 year at study entry other than heart failure.

 -  Significant valvular disease defined as moderate or severe aortic or mitral stenosis,
 mitral or aortic regurgitation.

 -  Infiltrative cardiac disease (sarcoid, amyloid, hemochromatosis, lymphoma, etc.).

 -  Arrhythmogenic right ventricular cardiomyopathy.

 -  Active myocarditis.

 -  Constrictive or restrictive pericarditis.

 -  Acute coronary artery disease symptoms defined as emergency department visit or
 hospital admission with unstable angina, ST-elevation myocardial infarction (STEMI),
 non-ST-elevation myocardial infarction (NSTEMI), percutaneous coronary intervention
 (PCI) or coronary artery bypass graft (CABG) within 90 days before study entry.

 -  Poor echocardiographic windows.

 -  Current active treatment in another investigational study or participation in another
 investigational study within 1 month before screening.

 -  Active malignancies except in situ carcinoma of the cervix, localized squamous or
 basal cell carcinoma of skin.

 -  Other serious concurrent or recent medical or psychiatric condition which, in
 Investigator's opinion, makes the patient unsuitable for participation.