Heart failure is well known to have a large economic and societal effect. It is an increasing public health problem, with a lifetime risk of 20% for both men and women.¹ Current recommendations stress the need for prevention as well as halting the progression of heart failure.² The methods for accomplishing this, however, need better elucidation. One well-known risk factor for heart failure is hypertension, with 39% of new cases in men and 59% in women ascribed to hypertension.^1,3 Although antihypertensive therapy has been shown to decrease the risk of developing heart failure,^4,5 it is unclear whether blood pressure control alone accounts for the degree of heart failure prevention associated with these therapies.

Independent of blood pressure, electrocardiographic (ECG) left ventricular hypertrophy (LVH) is also associated with an increased risk of new heart failure.^3,6-8 This risk is decreased by the prevention of ECG LVH.⁸ Antihypertensive therapy that reduced blood pressure has been shown to decrease ECG LVH, and regression of ECG LVH has been correlated with a significant reduction in cardiovascular death, myocardial infarction (MI), and stroke, regardless of antihypertensive treatment or degree of decrease in blood pressure.^9,10 Although this may suggest that LVH reduction is mechanistically important in preventing heart failure, it does not prove that reduction of ECG LVH with antihypertensive treatment prevents new-onset heart failure. Therefore, we investigated whether regression of ECG LVH using Cornell product criteria¹¹ during antihypertensive treatment in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study¹² was associated with a decrease in incident heart failure.

Subjects and methods

In this analysis, we used the data collected during the LIFE study,¹² which was a double-blind, randomized trial designed to compare morbidity and mortality between losartan (Cozaar) and atenolol (Tenormin) antihypertensive therapy among 9,193 subjects with essential hypertension and ECG LVH (Cornell voltage-duration product¹¹ or Sokolow-Lyon criteria¹³). From this population, 714 subjects were excluded because of either preexisting heart failure, heart failure within 6 months, or lack of a 6-month electrocardiogram. Antihypertensive treatment regimens were titrated upward throughout the study. Electro-cardiography was performed at baseline, at 6 months, and then annually. Left ventricular hypertrophy was identified by Cornell voltage-duration product (R_aVL + S_V3 with 6 mm added in women) > 2,440 mm·msec¹¹ or Sokolow-Lyon voltage (S_V1 + RV_5/6) > 38 mm.¹³ The secondary endpoint of hospitalization for heart failure was determined by diagnostic and clinical findings and was evaluated by the Endpoint Committee.

Cox proportional hazards models were used to analyze the association between the reduction of Cornell product and heart failure risk. Cornell product change from baseline and blood pressures were entered as time-varying covariates, and baseline risk factors as well as treatment group were regarded as standard covariates. We also analyzed the association between a reduction of Cornell product of 236 mm·msec or more (the median decrease between baseline and last in-study measurement), regarded as a dichotomous time-varying covariate, and heart failure risk. Kaplan-Meier graphs were generated by relating the development of heart failure over time to the presence or absence of reduction in the Cornell product by 236 mm·msec.

Results

New-onset heart failure developed in 214 subjects (2.5%) during the mean follow-up period of 4.7 years (standard deviation, 1.1). As shown in Table 1, subjects with hypertension who had new-onset heart failure were more likely to be African American, be current smokers, have diabetes, be more obese, and have a history of MI, ischemic heart disease, peripheral vascular disease, cerebrovascular event, or atrial fibrillation. On laboratory analysis, subjects who developed heart failure had higher glucose and creatinine levels, greater albuminuria, and lower total cholesterol and high-density lipoprotein levels. Of note, treatment with losartan- or atenolol-based therapy was similar between the 2 groups.

Table 2 shows the baseline and change from baseline to last in-study measurement of blood pressure and ECG LVH values according to the presence or absence of heart failure during follow-up. Compared with subjects without heart failure during the study, those who developed heart failure had similar baseline systolic blood pressure, lower baseline diastolic pressure, and greater severity of ECG LVH by Cornell product and Sokolow-Lyon voltage. Subjects who developed heart failure had greater reductions in systolic pressure, similar decreases in diastolic pressure, less regression of Sokolow-Lyon voltage LVH and, on average, progression of Cornell product LVH, compared with significant regression of Cornell product LVH in those who did not develop heart failure.

The endpoint of new-onset heart failure occurred in 214 subjects: in 137 subjects with an in-treatment decrease in Cornell product LVH < 236 mm·msec (6.8 per 1000 patient-years) and in 77 subjects with a ≥ 236 mm·msec decrease in Cornell product during treatment (4.4 per 1,000 patient-years). In univariate Cox analyses, a ≥ 236 mm·msec decrease in Cornell product was associated with a 43% lower risk of developing heart failure (hazard ratio [HR] = 0.57; 95% confidence interval [CI], 0.44-0.76]. In the Figure, Kaplan-Meier curves show that a reduction of more than 236 mm·msec was associated with an absolute decrease in incidence of heart failure of 1% after 4 years. After adjusting for the possible effects of baseline differences in subject characteristics, differences in baseline ECG LVH, in-treatment blood pressure changes, and treatment regimen, a ≥ 236 mm·msec decrease in Cornell product remained associated with a 36% lower risk of new-onset heart failure (HR = 0.64; 95% CI, 0.47-0.89). These analyses were also performed using change in Cornell product as a time-varying continuous variable.

Figure. Survival curves illustrating the rate of new-onset heart failure (HF) according to time-varying presence or absence of a reduction in Cornell voltage-duration product (CP) left ventricular hypertrophy (LVH) ³ 236 mm·msec from baseline to in-treatment electrocardiogram (ECG). Subject group assignment was adjusted at the time of each ECG based on the value of Cornell product at that time.14 The cumulative number of events and number of patients in each group at risk at study baseline and at annual follow-up are shown below the graph. (Reprinted with permission from Okin PM, Devereux RB, Harris KE, et al, for the LIFE Study Investigators. Reduction of electrocardiographic left ventricular hypertrophy is associated with decreased heart failure hospitalization in hypertensive patients. Ann Intern Med. 2007;147[5]:311-319.)

Discussion

Prior studies have shown ECG LVH at baseline to be a risk factor for heart failure.^6,7 One study showed that baseline severity of Cornell product LVH is a risk factor for the development of heart failure in subjects with diabetes after controlling for other risk factors and treatment.⁷ Moreover, data from the LIFE study show that the ECG strain pattern of ST-segment depression and T-wave inversion in the lateral precordial leads is a predictor of heart failure.¹⁵ This strain pattern has been associated with increased left ventricular mass and depressed left ventricular function.¹⁶

The current study, however, was the first to study the association between ECG LVH regression and heart failure incidence. In this study, regression of ECG LVH with antihypertensive therapy was associated with a lower incidence of heart failure regardless of blood pressure lowering and other heart failure risk factors. There was a 36% lower rate of heart failure in subjects who had a reduction of ECG LVH by Cornell product that was greater than the median reduction (236 mm·msec). A decrease in the Cornell product was also a statistically significant indicator of decreased heart failure when treated as a continuous variable. We believe this was the first study to show this clear relationship.

The literature supports a correlation between left ventricular mass and features of systolic and diastolic dysfunction seen on an electrocar-diogram.^17,18 As seen in the echocar-diographic substudy of the LIFE study, impaired endocardial and mid-wall shortening as well as prolonged isovolumetric relaxation time were associated with increased left ventricular mass.^17,18 This may provide a mechanistic explanation for the results seen in the current study. Specifically, a reduction of Cornell product LVH may suggest an improvement in left ventricular systolic and diastolic function, although this warrants further study.

A limitation of this study is that inclusion mandated ECG LVH; therefore, caution must be used prior to generalizing these results to all hypertensive subjects with less severe disease. Also, the endpoint for this study used hospitalization for heart failure to define new-onset heart failure. This most likely underestimated the incidence of new-onset heart failure, as not all episodes lead to hospitalization.

In conjunction with the increasing prevalence of heart failure in the US population¹ and the known risk factor of preexisting LVH and hypertension for heart failure,^17,18 this study provides support for the use of serial ECG measurements during antihypertensive therapy to monitor the risk of developing heart failure. Also, decreased cardiovascular morbidity and mortality associated with less ECG LVH was previously seen in the LIFE study.¹⁰ The data in this study suggest that a possible goal of antihypertensive therapy should be reduction of ECG LVH as well as blood pressure lowering. This may further reduce the incidence of heart failure. Further study, however, is needed prior to issuing a recommendation to target LVH reduction beyond blood pressure goals with the use of antihypertensive therapy.

Conclusions

The findings of this study show the importance of monitoring ECG LVH in patients treated for hypertension with baseline LVH. A reduction of Cornell product LVH in these patients is associated with fewer hospitalizations for heart failure independent of blood pressure lowering and other heart failure risk factors.

Acknowledgment

This study was supported in part by grant COZ-368 and an Investigator-Initiated grant from Merck & Co., Inc., West Point, Pennsylvania.

References