Hypertensive left ventricular hypertrophy

Cardiology Review® OnlineAugust 2004
Volume 21
Issue 8

From the Baker Heart Research Institute and Cardiovascular Medicine, Alfred Hospital, Melbourne, Australia

Left ventricular hypertrophy (LVH) has been shown to be an independent risk factor for cardiovascular morbidity and mortality1 and predicts cardiovascular complications in patients with hypertension.2 Evidence from experimental and animal studies suggests that norepinephrine plays a role in promoting hypertrophy3; however, whether such a relation also exists in humans has not yet been proven. To assess whether sympathetic activation is associated with LVH in humans, the differences in regionalization of sympathetic outflow to various organs must be taken into account; therefore, sympathetic tone must be studied in the heart directly.4 To address this issue, we used isotope dilution methodology to examine sympathetic activity in a group of hypertensive patients with echocardiographic evidence of LVH (EH ), a group of hypertensive patients without echocardiographic evidence of LVH (EH—), and normotensive control subjects with normal ventricular mass.

Patients and methods

We studied 26 patients with essential hypertension and 10 normotensive control subjects. Antihypertensive therapy was discontinued for those patients taking medication (n = 11) at least 4 weeks prior to the study. Two-dimensional guided M-mode echocardiography was performed in cases and control subjects, and left ventricular dimensions were measured according to the recommendations of the American Society of Echocardiography (ASE). Left ventricular mass was calculated according to the recommendations of the ASE and corrected following the suggestions of Devereux and colleagues.5 Fifteen of the 26 hypertensive patients had evidence of LVH. The remaining 11 hypertensive patients and all normotensive control subjects had a normal left ventricular mass index. All participants received a tracer infusion of 3H-labeled norepinephrine via a peripheral vein at 0.6 to 0.8 µCi/min, after a priming bolus of 12 µCi, to measure norepinephrine kinetics by isotope dilution.4 An arterial line was established, and a coronary sinus thermodilution catheter was introduced via the venous sheath and placed under fluoroscopic control in the region of interest for blood sampling and determination of blood flow by thermodilution.4 Plasma concentrations of neurochemicals were determined by high-performance liquid chromatography with electrochemical detection. Calculation of norepinephrine kinetics was performed using equations previously described.4 A two-sided P value of < .05 was considered to indicate statistical significance.


The table summarizes the characteristics of the study cohort, including total systemic and cardiac norepinephrine kinetics. Posterior wall and interventricular septal

wall thickness were higher in the EH group compared with the EH— group and normotensive control subjects. Left ventricular internal diameter was similar for both hypertensive groups, but higher in the EH group compared with normotensive control subjects. There was a significant difference in left ventricular mass (238 ± 39 g in the EH group, 176 ± 47 g in the EH– group, and 139 ± 28 g in normotensive control subjects) and left ventricular mass index (138 ± 17 g/m2, 106 ± 11 g/m2, and 87 ± 15 g/m2, respectively; P < .001) among the three groups. Left ventricular mass index tended to be higher in the EH– group compared with normotensive control subjects. Mean arterial plasma norepinephrine concentration was similar in all three groups. The norepinephrine spillover from the whole body was similar in the two hypertensive groups, but significantly higher compared with normotensive control subjects (both P < .05). However, norepinephrine spillover from the heart was only increased in the EH group (more than twofold), whereas no difference in cardiac

norepinephrine spillover was evident in the EH— and normotensive groups (11.7 ± 6.2 ng/min in the normotensive control subjects, 13.1 ± 7.2 ng/min in the EH– group, and 28.6 ± 17.4 ng/min in the EH group; P < .01; figure). A reduction in cardiac neuronal norepinephrine reuptake or alterations in myocardial blood flow did not account for the higher cardiac norepinephrine spillover in the EH group because fractional transcardiac extraction of tritiated norepinephrine across the heart and coronary sinus plasma flow were similar in all three groups (table). Therefore, the increase in cardiac sympathetic outflow was most likely due to increased cardiac norepinephrine release, which is also mirrored by significantly higher mean norepinephrine concentrations in coronary sinus plasma in the EH group compared with the EH– and normotensive groups (P < .05; table). Left ventricular mass index and cardiac norepinephrine spillover correlated significantly for hypertensive and normotensive subjects combined (r = .52; P < .001). When only the two hypertensive groups were considered, a positive correlation was evident only between left ventricular mass index and cardiac norepinephrine spillover (r = .44; P < .05).


We investigated the relationship between cardiac sympathetic tone and hypertensive LVH in humans and showed that hypertensive LVH is associated with increased sympathetic activity in the heart. Because sympathetic tone for the whole body was unrelated to the presence of LVH, our data strongly suggest that increased cardiac sympathetic nerve firing and norepinephrine release exert trophic effects on the heart and are directly related to the development of hypertensive LVH.

Several experimental and animal studies have identified norepinephrine as a myocardial hypertrophic hormone.3 Whether such a role for norepinephrine exists in humans, however, is unclear. The findings of our study support the hypothesis that norepinephrine exerts a trophic effect on the myocardium in hypertensive individuals. Left ventricular mass was substantially higher in the EH— group than in the normotensive group. This is in line with the well-described effect of increased afterload on left ventricular structure in hypertension6 and indicative of an important contribution of increased blood pressure to left ventricular mass in both hypertensive groups. Based on the correlation between cardiac norepinephrine spillover and left ventricular mass index, cardiac sympathetic activity only explains approximately 25% of the variation in left ventricular mass. Despite the obvious importance of cardiac norepinephrine release in LVH, it is clear that other contributing elements, such as hemodynamic and humoral factors, are involved.

The possibility that antihypertensive medications may have affected left ventricular mass in our study may exist. Four of the 11 patients

in the EH— group and 7 of the 15 patients in the EH group had previously been on antihypertensive therapy. All antihypertensive medications were discontinued at least

4 weeks before the study, however, reducing the possibility of drug effects on sympathetic tone during the study. Eight of the 11 previously treated subjects were taking an angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker, with a similar distribution in both groups (three patients in the EH— group and five patients in the EH group). Potential long-term effects of previous therapy, therefore, probably did not affect the overall difference in norepinephrine spillover between the two hypertensive groups.

Several factors are known to influence left ventricular mass and sympathetic activity, including age, obesity, and severity of hypertension.7 Care was taken to match both hypertensive groups for these factors; therefore, it is unlikely that our finding of an interrelationship between left ventricular mass and cardiac sympathetic activity was influenced by them. Mean body mass index (BMI) for both hypertensive groups was in the overweight range, however, compared with the normotensive control group. We have previously shown that lean hypertensive patients have increased cardiac sympathetic activity, whereas cardiac norepinephrine spillover in obese hypertensive patients does not differ from that of their normotensive obese counterparts.8 The higher BMI in both hypertensive groups, therefore, could be expected to ameliorate cardiac norepinephrine spillover, making the marked differences between the EH group and the two other groups even more noteworthy.

It has been suggested that an impairment of neuronal norepinephrine reuptake could contribute to increased norepinephrine spillover from the heart in hypertension.9 We observed a tendency toward increased left ventricular mass with a reduction of neuronal norepinephrine reuptake. Such a defect could lead to exposure of cardiomyocytes to increased levels of norepinephrine by amplifying the neuronal signal. Whether alterations of norepinephrine reuptake as a mechanism to increase cardiac norepinephrine spillover could in fact contribute to LVH warrants further study.

Taking the available evidence into consideration, the following possible sequence of events might induce hypertensive LVH: An increase in cardiac sympathetic nerve activity leads to a specific hemodynamic profile, which is characterized by an increase in heart rate, cardiac output, vascular resistance, and blood pressure. Adaptive cardiac structural changes are then induced by the increase in left ventricular workload, which is further potentiated in the presence of high cardiac norepinephrine levels or other humoral factors such as angiotensin II, or both. Finally, this combination of events culminates in a phenotype resembling LVH. Established target-organ structural changes maintain the severity of hypertension and may subsequently lead to a downregulation of sympathetic drive.10

Such a scenario may also help to partly explain the discrepancy that exists between the proposed importance of norepinephrine in the development of LVH and the variable effects of antihypertensive therapy with antiadrenergic drugs on regression of LVH beyond blood pressure—related effects. Conflicting results have shown that these range from a complete absence of effect11to a pressure-unrelated reversal of LVH.12,13 The majority of studies including beta-receptor blockers demonstrated the ability of this drug class to reduce hypertensive LVH beyond blood pressure–related effects.12,13 In addition, a meta-analysis assessing the ability of the major antihypertensive drug classes to reduce hypertensive LVH further substantiated the notion of beneficial effects of antiadrenergic therapy on LVH.14


This study shows that there is an association between increased cardiac sympathetic activity and hypertensive LVH in humans. Although such an association does

not necessarily prove that increased cardiac norepinephrine release is related to the development of hypertensive LVH, the available evidence strongly suggests a cause-and-effect relationship.

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