BLOCKade of Calcium Channels and Beta Adrenergic Receptors for the Treatment of Hypertension in HFpEF

Heart failure with preserved ejection fraction (HFpEF) is a critical public health problem. Heart failure (HF) affects over 5 million adults in the United States (US), and is a major source of morbidity, mortality, and impaired quality of life. Approximately half of individuals with HF have a preserved left ventricular (LV) ejection fraction (EF), termed HF with preserved EF (HFpEF). While there are several effective pharmacologic therapies for HF with reduced ejection fraction (HFrEF), none have been identified for HFpEF. Hypertension, which is present in approximately 80% of individuals with HFpEF, is the foremost modifiable risk factor for the development and progression of HFpEF. Despite the clinical importance of hypertension in HFpEF, there is limited information on how common antihypertensive agents, particularly calcium channel blockers (CCBs) and β-blockers, effect pathophysiologic mechanisms of HFpEF. This is a mechanistic investigation of the role of dihydropyridine CCBs compared to β-blockers (commonly used antihypertensive agents in clinical practice) in targeting key physiologic abnormalities in HFpEF.


Eligibility Criteria:
Inclusion Criteria:

1. Adults age 18-90 years
2. Diagnosis of hypertension defined by at least two of the following: A) ICD-9 (401.0-404.91) or ICD-10 (I10-I13) codes signifying hypertension; B) Treatment with antihypertensive medication other than a loop diuretic for at least two months; C) History of previous blood pressure readings ≥130/80 mmHg at two separate office visits
3. Stable antihypertensive therapy; defined as no changes in antihypertensive medications in the preceding 30 days
4. A diagnosis of heart failure
5. LV ejection fraction \>50%
6. Elevated filling pressures defined by at least one of the following criteria: A) Mitral E/e' ratio (lateral or septal) \>8 with low e' velocity (septal e' \<7 cm/s or lateral e' \<10 cm/s) and at least one of the following: a. Enlarged left atrium (LA volume index \>34 ml/m2); b. Chronic loop diuretic use for management of symptoms; c. Elevated natriuretic peptides (BNP levels \>100 ng/L or NT-proBNP levels \>300 ng/L); B) Mitral E/e' ratio (lateral or septal) \>14; C) Previously elevated invasively determined filling pressures based on one of the following criteria: a. Resting LVEDP \>16 mmHg; b. Mean PCWP \>12 mmHg; c. PCWP or LVEDP ≥25 mmHg with exercise; D) Previous acutely decompensated heart failure requiring IV diuretics;

Exclusion Criteria:

1. Systolic BP meeting any of the following criteria: A) Current office systolic BP \<100 mmHg; B) Current office systolic BP 100-119 mmHg if not receiving treatment with an antihypertensive agent or if holding antihypertensive medication prior to randomization would be clinically contraindicated, as per the investigator's clinical judgement; C) Current office systolic BP ≥180 mmHg if not receiving treatment with a CCB or β-blocker, or ≥160 mmHg if already receiving a CCB and/or β-blocker prior to the pre-randomization wash-out period; D) Orthostatic hypotension defined as \>20 mmHg decline in office systolic BP 3-5 minutes following the transition from sitting to standing position
2. Resting heart rate \<50 or \>100 bpm
3. Contraindication to withholding CCB or β-blocker therapy (e.g. use of non-dihydropyridine CCB \[diltiazem or verapamil\] or β-blocker for rate control for atrial fibrillation) as per the investigator's clinical judgement
4. Children, fetuses, neonates, prisoners, and pregnant women (women of childbearing age will undergo a pregnancy test during the screening visit) are not included in this research study.
5. Inability/unwillingness to exercise
6. Any the following echocardiographic findings: A) LV ejection fraction \<45% on any prior echocardiogram, unless it was in the setting of uncontrolled atrial fibrillation; B) Hypertrophic, infiltrative, or inflammatory cardiomyopathy; C) Clinically significant pericardial disease, as per investigator judgment; D) Moderate or greater left-sided valvular disease, any degree of mitral stenosis, or prosthetic mitral valve; E) Severe right-sided valvular disease; F) Severe right ventricular dysfunction
7. Active coronary artery disease, defined as any of the following: A) Acute coronary syndrome or coronary intervention in the past 2 months; B) Ischemia on stress testing without either subsequent revascularization or a subsequent angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgement
8. Clinically significant lung disease, defined as any of the following: A) Chronic Obstructive Pulmonary Disease meeting GOLD criteria stage III or greater; B) Treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease; C) The use of daytime supplemental oxygen
9. Primary pulmonary arteriopathy
10. eGFR \<30 mL/min/1.73m2
11. Any medical condition that, under the investigator's discretion, will interfere with safe completion of the study or validity of the endpoint assessments
12. Known history of an allergy or clinically significant sensitivity (as determined by the investigator) to either amlodipine besylate or metoprolol succinate