3.2. Discussion
In our study a statistically significant interaction was observed between preoperative inotrope use and race with respect to long-term mortality. To our knowledge this is the first study to examine long-term mortality among black CABG patients receiving preoperative inotropes. The use of preoperative inotropes was associated with increased risk of long-term mortality in blacks compared with whites. Possible explanations for this finding may include differences in heart failure etiology, drug metabolism and physiologic response to inotropes.
Racial differences in short-term mortality in patients with acute decompensated heart failure who received inotropic therapy was examined in the OPTIME-CHF (Outcomes of a Prospective Trial of Milrinone for Exacerbations of Chronic Heart Failure) study [
4]. This prospective randomized trial reported statistically significant lower 60-day mortality (unadjusted analysis) among black patients who received milirinone, compared with whites. However, no difference in mortality was detected after the adjustment for baseline differences. Even though the OPTIME-CHF trial excluded patients who received inotropic therapy for cardiogenic shock and those with preserved systolic function, the adjusted results correspond closely to our findings over the same 60-day time period. The majority (74%) of blacks enrolled in the OPTIME-CHF trial had non-ischemic heart failure. In contrast, patients in our study were assumed to have cardiac ischemia secondary to underlying coronary artery disease requiring surgical bypass.
The OPTIME-CHF study also compared the use of inotropes in ischemic
versus non-ischemic heart failure patients [
20]. Those enrolled in the study with non-ischemic heart failure tolerated or even benefited from the use of inotropes in comparison with ischemic heart failure patients who experienced increased mortality and hospitalization rates. The results of the study suggest that a differential response to inotropes by race may be attributable to differing etiologies of heart failure.
While patients in our study were primarily treated for ischemic heart disease, an increased rate of diabetes and hypertension was observed among black patients, which is frequently associated with diabetic or hypertensive cardiomyopathy. Altered inotropic responses have been reported in diabetic cardiomyopathy and hypertensive-diabetic cardiomyopathy within the laboratory setting. Specifically, inotropes administered to diabetic and hypertensive rodents have higher sensitivity and effect on the myocardium which presumably leads to increased mortality [
21]. Conceivably, similar effects might underlie the differential mortality outcome that is seen in black patients on inotropic agents. Another contributing factor, as noted in prior studies, may be that black patients receive life-saving cardioprotective therapies less often than whites [
22]. While inotropic agents may improve mitochondrial function in noninfarcted myocardial tissue, free calcium in the cytosol can lead to activation of proteolytic enzymes, proapoptotic signal cascades, mitochondrial damage and eventually, necrosis and disrupted membranes [
23].
Our findings are important to contrast with the African-American Heart Failure Trial (A-HeFT) [
24] of combination isosorbide dinitrate and hydralazine in black patients. This trial showed that nitric oxide medications are more effective in black patients than whites. Isosorbide dinitrate functions by being converted to nitric oxide (NO), an active intermediate compound which activates the enzyme guanylate cyclase [
25]. This stimulates the synthesis of cyclic guanosine 3’, 5’-monophosphate (cGMP) that in turn activates a series of protein kinase-dependent phosphorylations in the vascular smooth muscle cells and results in the dephosphorylation of the myosin light chain of the smooth muscle fiber. Subsequently, the release of calcium ions by the myosin light chain results in the relaxation of the smooth muscle cells and vasodilation. It is generally known that NO induces protein kinase G (PKG) which has a dual effect: (1) inhibition of inositol trisphosphate receptor (IP3) receptor resulting in calcium release from sarcoplasmic reticulum (SR) into cytoplasm, and (2) increased phospholamban phosphorylation, SERCA2a activity and calcium uptake into the SR [
26,
27,
28]. Both effects will reduce the calcium release from SR into the cytoplasm and sequester more of the calcium inside the SR. Additionally, isosorbide dinitrate has been noted to have a weak positive inotropic effect on the myocardium [
29]. Blacks with heart failure have been observed to exhibit greater NO reduction while whites have modestly reduced NO [
30]. It can, therefore, be postulated that isosorbide dinitrate has a positive inotropic effect that is greater among black patients, although the vasodilatory effect of NO is likely to be the predominant factor. However, as reported in A-HeFT, blacks with heart failure had better outcomes (e.g., decreased mortality, improved quality of life at 6 months) when randomized to a combination of isosorbide dinitrate and hydralazine, which inhibits destruction of NO. While it is presumed that this effect is more pronounced in black patients, white patients were not enrolled in the above study as a referent group. Moreover, our database did not allow us to ascertain the prevalence of phosphodiesterase inhibitors as inotropic therapy in our patient cohort. This is a potentially important variable given that these agents are known to exhibit a NO-potentiating effect.
We cannot rule out that the differential long-term mortality observed in our study may be explained by factors unrelated to the preoperative use of inotropic agents. For example, residents of rural areas have limited access to medical care compared with urban regions and this effect may have been potentiated among black patients owing to historic racial barriers in the South [
31,
32]. Furthermore, blacks traditionally prioritize health to a lesser degree than whites, postpone seeing a doctor, often do not have a regular physician, and generally are less trusting of health care providers [
33,
34,
35]. Other contributing factors may include suboptimal follow-up care, inappropriate specialist referral, non-adherence to treatment regimens, community segregation, differences in socioeconomic position and educational achievement, and other social determinants of health [
36]. The use of inotropic agents in this population also might simply represent a surrogate marker of severity that is further compounded by the above mentioned factors. However, in previous studies of racial differences in long-term mortality following CABG surgery, blacks with chronic lung disease or renal failure requiring dialysis were observed to have equal or more favorable outcomes than whites [
7,
8].
Our study is strengthened by its large racially dichotomous population and systematic data collection. Nonetheless, various limitations should be noted when interpreting our results. Although we adjusted for patient demographics and several comorbidities associated with long-term mortality following CABG, residual confounding may still exist due to the non-randomized nature of this study and limited sample size within the inotrope group. Stable or asymptomatic compensated heart failure patients or patients whose symptoms improved after medical therapy were not categorized as being in heart failure by the STS definition and this may have further resulted in incomplete adjustment when added pairwise to our multivariable Cox regression model. Type, dose, duration and reason for inotrope use were not recorded in our STS database and this information frequently was incomplete or not available in retrospective scans of medical charts. Accordingly, we were unable to determine the differential clinical impact, for example, of being on dopamine for 3 h preoperatively versus 2 days of high dose epinephrine. The possibility also exists that some patients may have received low-dose inotropic agents for indications other than heart failure or cardiogenic shock after acute MI (e.g., decreased renal profusion). However, any bias resulting from including these cases in our analyses likely would have been toward the null.
The absence of individual and area-level socioeconomic measures such as residential history was another potential limitation of our study. We were unable to sufficiently estimate socioeconomic position using zip codes because a large percentage of patients in our region have postal office boxes. However, eastern North Carolina is largely homogenous with respect to socioeconomic status and it is unlikely that the inclusion of this information in our models would have substantively altered any study findings. Race was self-reported and there could have been potential misclassification of this variable. Additionally, genetic data were not collected and, therefore could not be accessed as a potential cofounder in our analyses. Chance or an unexplained paradox specific to our patient population also may underlie our findings.
The status of several variables in our analysis may have changed over time. We did not adjust for these variables in a time-dependent manner due to their potential to be in the causal pathway. Similarly, intraoperative and postoperative variables were not included in our multivariable models.
Cause of death is not recorded in the National Death Index and POAF status may have been unrelated to their mortality. Although we adjusted for known clinically relevant variables, we acknowledge that other unmeasured factors could have influenced our results due to the retrospective nature of this study.
The results of this study are from a rural region with a unique population and may not generalize to other regions of the country. However, because our data were collected from a single unified health system, this might have partially controlled for other healthcare-related factors.
