Mild Pulmonary Hypertension & Premature Mortality Among 154,956 Men and Women Undergoing Routine Echocardiography

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Dr. Saggar:
Hello, this is Dr. Rajan Saggar from the University of California in Los Angeles here to discuss an interesting article from the December issue of the "European Respiratory Journal" in 2021, entitled, "Mild pulmonary hypertension and premature mortality among 154,956 men and women undergoing routine echocardiography" by Dr. Stewart Chan and authors and among other Australian investigators.

The rationale for this study is that pulmonary hypertension is known to be a chronic condition with increased blood pressure within the arteries of the lung. And the definitive diagnosis is based on the measurement of mean pulmonary pressure greater than 20 millimeters of mercury via a right heart catheterization. However, the screening test of choice is the echocardiogram during which the estimated, right ventricular systolic pressure can be obtained non-invasively based on the tricuspid regurgitant velocity. And the estimation is based on the Bernoulli equation. The estimated right ventricular systolic pressure, represents a practical way to identify the potential cases of pulmonary hypertension prior to further investigation with the more invasive right heart catheterization. By way of background, the 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension, recommend definitive investigation if the estimated RVSP is greater than 40 millimeters of mercury in the absence of significant respiratory pathology. A prior study done by the National Echocardiography Database of Australia which is termed NEDA, N-E-D-A of more than 150,000 people demonstrated that in right ventricular systolic pressure or RVSP greater than 40 millimeters of mercury was indeed associated with increased mortality across the entire spectrum of the RVSP values. The study also suggested a higher than previously suspected risk of mortality associated with an estimated RVSP less than 40 millimeters of mercury. Hence the study aimed to elucidate the association between the estimated RVSP with mild-to-severe forms of pulmonary hypertension and the association with premature mortality and associated life years lost with a focus on those with milder forms of pulmonary hypertension.

By way of methods, this was a retrospective analysis of this observational cohort in Australia between the years of January 2000 and May of 2019 across 23 centers in Australia. To be included, patients had to be greater than 18 years of age with at least one echocardiogram available. And if multiple were available, the most recent echocardiogram was used for analysis. The exclusion criteria were designed to exclude left heart disease represented by four factors. The LV ejection fraction less than 55%, the E/e prime greater than 12, the left atrial volume index greater than 34 milliliters per meter squared, and or moderate-to-severe mitral aortic valve pathology. The figure on the right shows the breakdown of the patients by RVSP of less than 30 millimeters of mercury compared to 30 to 39.9 millimeters of mercury compared to 40 to 49.9 millimeters of mercury and finally compared to greater or equal to 50 millimeters of mercury. And we can see the all-cause mortality at 24.8% and cardiovascular-related mortality of 7.2% for the entire group.

As mentioned before, the patients were grouped by the estimated RVSP using the Bernoulli equation and the imputation of five millimeters of mercury for the right atrial pressure for all patients. Again, as mentioned, the groups were broken down by the estimated RVSP where normal or no pulmonary hypertension was defined as less than 30 millimeters of mercury, and severely elevated pulmonary hypertension was defined as an estimated RVSP of greater than or equal to 50 millimeters of mercury. The disease-specific survival was determined by the primary cause of death based on the ICD 10 code, life-years lost were obtained by subtracting the actual age of death which was determined from the predicted age based on the National Death Index of Australia which relied on the life expectancy in Australia in 2020 which was 84.9 years in women in 80.7 years in men. Kaplan-Meier and Cox proportional hazards models were used to derive hazard ratios and corresponding 95% confidence intervals for all cause and cardiovascular-related mortality. Multiple logistic regression modeling was used to calculate risk premature mortality.

This first slide shows the results specifically the baseline characteristics with the gender-specific profile. According to increasing estimated RVSP, one can see that the age of the patients increases with increasing estimated RVSP with a slight female predominance in essentially all estimated RVSP groups. Not surprisingly there is increasing evidence for right atrial and right ventricular dilatation as the estimated RVSP increases and with impaired right ventricular function there is also an association with increasing estimated RVSP. Importantly, compared with those patients with an estimated RVSP of less than 30 millimeters of mercury, the normal group those with an estimated RVSP indicative of mild pulmonary hypertension, specifically 30 to 39.9 millimeters of mercury had a higher prevalence of right ventricular dilatation, specifically 8.7% versus 4.6% in the group with an estimated RVSP of less than 30 millimeters of mercury. And this was statistically significant.

The authors provide here a survival profile and adjusted risk for mortality according to the estimated right ventricular systolic pressure, looking at all-cause one-year mortality, all-cause five-year mortality and also looking at all-cause mortality over time as well as cardiovascular-related mortality and respiratory-related mortality. As expected, both absolute and age and sex adjusted risk of mortality steadily increased with higher estimated RVSP values. This finding was evidenced by the large difference between the actual one and five-year mortality rates of 3.9% and 16.7% respectively in those with estimated RVSP of less than 30 millimeters of mercury, the so-called normal group, compared with those with an estimated RVSP of greater than or equal to 50 millimeters of mercury which had a actual one and five-year mortality of 32.5% and 74.5% respectively. Congruent findings were seen with cause-specific mortality during the entire follow-up in terms of all-cause, cardiovascular-related, and respiratory-related mortality.

The slide demonstrates the age and sex-adjusted all-cause mortality per estimated right ventricular systolic pressure. Looking at the four groups, the larger figure and survival curves are the adjusted curves for gender and age. And the smaller inlet is the unadjusted analysis. The patient numbers at risk in three-year intervals and the mortality rates during these specific intervals are shown below and above the X-axis respectively. The four estimated RVSP groups are clearly differentiated in terms of their survival during follow-up with worsening survival with increasing estimated RVSP. And interestingly, the hazard ratio for men versus women was 1.33 supporting the worsening survival of males compared to females with pulmonary vascular disease.

There are two figures in this slide representing the age and sex-adjusted risk of mortality for every five millimeters of mercury estimated RVSP increase. With all-cause mortality on the top figure and cardiovascular-related mortality on the bottom figure. Patients with an estimated RVSP of 35 to 39.9 millimeters of mercury were almost twice as likely to die from all causes with a hazard ratio of 1.90 and cardiovascular disease with a hazard ratio of 1.85. And this was statistically a significant. The risk of mortality rose among those with an estimated RVSP greater or equal to 50 millimeters of mercury with a hazard ratio of 4.79 and 5.63 for all-cause mortality and cardiovascular-related mortality respectively. The reference group here was an estimated RVSP of less than 30 millimeters of mercury which again was considered normal in this study.

To better understand the causes of mortality, the authors analyzed the pattern of cause-specific mortality with increasing estimated RVSP for women and men. And interestingly, the proportion of malignancy-related mortality declined with increasing estimated RVSP as a proportion of cardiovascular and respiratory-related deaths increased. For both men and women, the absolute frequency and proportional contributions of respiratory-related death and cardiovascular-related death rose significantly with increasing estimated RVSP levels.

The slide demonstrates the concept of premature mortality and 54% of men and 55% of women in this cohort died prematurely. Each 5-millimeter per mercury increase in estimated RVSP was associated with increasing premature mortality. Importantly for every 1000 cases at risk, the rate of premature mortality increased by 0.5%, 6.2%, and 9.8% for those with an estimated RVSP of 30 to 39.9, 40 to 49.9, and greater than or equal to 50 millimeters or mercury respectively. This is demonstrated on the figure to the right.

This next slide shows an important point that sex-specific pattern or gender-specific pattern of premature mortality and life-years lost with increasing estimated RVSP in increments of five millimeters of mercury. The mean number of life-years lost and population-attributable risk percentage associated with premature mortality are given for each group. As mentioned earlier, 54% of men and 55% of women died prematurely. Importantly, the estimated RVSP of 30 to of 39.9 millimeters of mercury group accounted for 58% of the total life-years lost among men and 53% of total life-years lost occurring within the broader group of cases with an estimated RVSP of greater than or equal to 30 millimeters of mercury indicative of the entire spectrum of mild-to-severe pulmonary hypertension. And this was due to the much higher number of affected cases compared to the other estimated RVSP groups even with more significant pulmonary hypertension.

By way of discussion in the 154,956 patients referred for echocardiography, milder forms of pulmonary hypertension defined by the estimated RVSP, and absence of left heart disease were associated with increased risk of mortality in both women and men and may contribute to premature mortality and life-years lost. More than 50% of premature deaths had an estimated RVSP of greater than or equal to 30 millimeters of mercury. The author suggested that the current cutoff of an estimated RVSP of greater than 40 millimeters of mercury may not capture all the patients at risk and that perhaps an estimated RVSP greater or equal to 30 millimeters of mercury may merit further investigation.

By way of limitations and conclusions, the study has limited generalizability as patients are being investigated for preexisting cardiopulmonary are conditions, and all patients are isolated to Australia. The authors were unable to review echocardiographic images or other functional parameters. This is a retrospective cohort study, relying on the accurate input of data for echocardiographic parameters as well as the ICD 10 cause of death. Importantly, there is a lack of comorbidity data, medication therapy data, hospitalization data or confirmatory data, or parameters to estimate the pulmonary vascular resistance. This large echocardiographic database nonetheless study, demonstrates increased mortality associated with milder forms of elevated estimated RVSP then are traditionally felt to be clinically relevant. Thank you.

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