Effect of Nebivolol on the Blood Flow in Hearts of Adults With High Blood Pressure and Abnormal Filling of Heart

Effects of Nebivolol on Left Ventricular and Left Atrial Morphodynamics in Adults With Hypertension and Isolated Diastolic Dysfunction

To investigate whether treatment with Nebivolol in subjects with high blood pressure and abnormal filling of left ventricle (LVDD) improves exercise time by improving Left Ventricular deformation and filling.

Background:

The left ventricle (LV) ejects blood with a wringing motion, where the LV apex rotates counterclockwise and the base rotates in clockwise directions respectively. Rapid untwisting and recoil of LV during isovolumic relaxation and early diastole releases energy stored in ejection for LV suction and rapid early diastolic restoration. The LV geometry and its rotational mechanics also give rise to intracavitary blood flow rotation resulting into LV intracavitary vortex ring formation. LV torsion and vortex ring formation confer morphodynamic advantages that gain importance as blood flow velocities, heart rate and rates of change of momentum increase with exertion for improving LV efficiency. We have recently characterized the significance of LV twist mechanics and vortex ring formation in human hearts using novel high resolution speckle and contrast particle tracking echocardiography. Although data on a favorable effect of nebivolol on exercise capacity and LV diastolic filling exists, the changes in left ventricular (LV) rotational mechanics and blood flow vortex ring formation that may explain the potential hemodynamic benefits seen with nebivolol have not been previously characterized.

Aims:

In patients with hypertension and left ventricular diastolic dysfunction (LVDD) treatment with nebivolol for 6 months improves exercise time by enhancing:

1. LV deformation, torsion and untwisting mechanics
2. LA-to-LV blood flow transport and characteristics of intra-cavitary vortex formation
3. LA reservoir and booster pump function and LA-LV interaction during the conduit phase

Hypotheses:

Treatment with nebivolol in subjects with hypertension and LVDD improves exercise time by improving LV deformation and diastolic filling. As diastole shortens with the tachycardia associated with exercise, the contribution of untwist becomes relatively more important to LV suction and filling. Nebivolol improves LV diastolic filling primarily by enhancing LV untwisting and the rheological efficiency of blood flow transport through vortex formation in early diastole.

Significance:

Patients with LVDD are asymptomatic at rest and often but become markedly symptomatic with exertion. This pilot study will provide data for the first time for correlating the improvement in exercise capacity seen with the use of nebivolol with the changes in LV relaxation, torsional mechanics, LV vortex formation and LA-LV transport functions. The preliminary data will be essential for understanding the underlying pathophysiological mechanisms through which nebivolol improves exercise hemodynamics besides providing data for development of subsequent larger randomized multicentric trials.

Inclusion Criteria:

• History of mild (140-160 / 90-100) to moderate (160-200 / 100-120) hypertension
• LV diastolic dysfunction (>/= Grade1)
• LV ejection fraction >50%
• Indexed left atrial volume >/= 28 mL/m^2
• In sinus rhythm at the time of enrollment
• Willingness to return for the 6-month follow up investigations

Exclusion Criteria:

• Presence or history of any of the following at baseline:

  1. History of mitral valve disease of greater than mild severity or prosthetic mitral valve, congenital heart disease or permanent pacemaker
  2. Calculated creatinine clearance <50 mL/min
  3. Terminal Illness with expected Survival of <1 year
  4. Previous Heart Transplant
  5. Individuals who are institutionalized
  6. Systolic BP>180 mm Hg or diastolic BP > 120 mm Hg

• Medical treatment for elevated BP with:

  1. Calcium channel blocker (e.g. verapamil, nifedipine);
  2. Alpha blocker (e.g. prazosin);
  3. Alpha agonist (e.g. α-methyldopa, hydralazine, clonidine)

• Patient unwilling or unable to provide informed consent for study participation

• Pregnancy (current, or anticipated within the study period)

• Secondary Hypertension

• Previous echo contrast allergy

• Poor echocardiography window

• Previous stroke, known carotid stenosis

• Contraindication for beta-blocker therapy (sinus bradycardia <50 beats/min);

• 2nd or 3rd degree AV conduction block

• Overt congestive cardiac failure (NYHA Class III-IV)

• Known bronchospastic disease

• Known hepatic dysfunction (SGOT/PT > twice above normal levels)