Can Nebivolol Reverse Inappropriate Left Ventricular Mass in Hypertensive Patients?

In response to chronic pressure overload by arterial hypertension, the cardiac left
ventricle undergoes hypertrophy, that is, increases its wall thickness and, therefore, its
mass, to sustain the elevated workload. Such anatomical remodeling can be considered
adaptive or appropriate. However, in a considerable number of patients with arterial
hypertension, the increase in the left ventricular mass is excessive and, thus,
inappropriate.

Ventricular mass is inappropriate when its amount surpasses the physical need of the
ventricle to sustain the elevated workload. Therefore, ventricular mass can be inappropriate
even in patients without arterial hypertension or without hypertrophy identified by
echocardiography (echo). We can mathematically predict an appropriate amount of mass and
observe the actual mass in individual patients based on ventricular workload and wall
thickness, respectively, noninvasively evaluated by echo. By comparing the observed
ventricular mass to the predicted one, we determine whether its amount is inappropriate. It
follows that by therapeutically normalizing blood pressure in hypertension and thus
eliminating the elevated workload, then any ventricular hypertrophy represents an
inappropriate mass.

Inappropriate ventricular mass is proven to have a detrimental effect on long-term
cardiovascular event-free survival, and ventricular hypertrophy is increasingly recognized
as a potent risk factor of cardiovascular morbidity and mortality, and all-cause mortality.
Ventricular performance is altered in hypertension with inappropriate mass, but this
alteration can be subtle enough to escape detection using current echocardiography measures.
Hence, patients with hypertension, who have inappropriate left ventricular mass, need to be
specifically identified by analysis of the predicted and observed ventricular mass, and the
therapeutic goal must include management of elevated blood pressure as well as reversal of
the excessive ventricular mass.

In this double-blind prospective study, patients with hypertension and inappropriate
ventricular mass will be randomized to therapy with nebivolol or metoprolol to find out
whether nebivolol could reverse inappropriate left ventricular mass, thus providing a
benefit beyond what is achieved by mere blood pressure reduction alone. If confirmed, this
will represent a significant ancillary ability of nebivolol and be a key step towards
therapy of inappropriate ventricular mass, which is a so far unmanaged cardiovascular risk
and a poor event-free prognostic factor.

All candidates must have previously untreated hypertension. The candidates will be picked
from patients with stage-1 hypertension (systolic BP 140-159 mm Hg or diastolic BP 90-99
mm Hg) and those with stage-2 hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥100),
based on JNC-7 guidelines.

Inclusion Criteria:

- Presence of inappropriate LVM.

- Presence of phenotype of inappropriate LVM.

Exclusion Criteria:

The criteria will assure that only patients with hypertension are enrolled, that is,
excluded will be subjects with systolic BP < 140 or diastolic BP < 90 (ie, prehypertension
or normal BP), but without complications or any indication (or suspicion) of end-organ
damage based on a physical exam, clinical history, or laboratory tests.

Specific exclusion criteria are:

- Reactive airways disease including asthma.

- Diabetes mellitus or hypoglycemia; thyrotoxicosis.

- LV dysfunction (ejection fraction < 50%) or heart failure.

- Present or previously documented coronary heart disease or angina.

- Acute myocardial infarction, or history of myocardial infarction.

- Severe bradycardia, heart block greater than first degree or sick sinus syndrome
(unless a permanent pacemaker is in place).

- Hepatic insufficiency or history of cirrhosis.

- Chronic renal failure or renovascular dysfunction.

- Cerebrovascular dysfunction.

- Peripheral vascular disease.

- Pregnant or nursing women; women of childbearing age will be required to take a
pregnancy test at the time of enrollment and use an acceptable method of birth
control.

- Poor echo image quality.