The significance of the j-curve in hypertension and coronary artery diseases.

The J-curve effect describes an inverse relation between low blood pressure (BP) and cardiovascular complications. This effect is more pronounced in patients with preexisting coronary artery disease (CAD), hypertension or left ventricular hypertrophy (LVH). The recent large clinical outcomes trials have observed a J-curve effect between a diastolic BP of 70-80 mmHg as well as a systolic BP <130 mmHg. The J-curve phenomenon does not appear in stroke or renal disease. This is because the coronary arteries are perfused during diastole, but the cerebral and renal perfusion mainly occurs in systole. Therefore, caution should be taken to maintain the diastolic blood pressure (DBP) at minimum of 70 mmHg and possibly to maintain the DBP between 80-85 mmHg in patients with severe LVH, CAD or vascular diseases. BP control in high-risk elderly patients should be carefully done as undergoing aggressive therapy to lower the systolic blood pressure below 140 mmHg can cause cardiovascular complications due to the severely reduced DBP and increased pulse pressure.

Introduction

The term "essential hypertension" was first named by Frank a century ago in 1911, and this was based on his perception that hypertension is a disease of increased vascular tone of the small arteries in the whole body.1) Thus, an increase in blood pressure (BP) is necessary to maintain blood flow to target organs through sclerotic arteries. As this notion survived into the 1970s, physicians were reluctant to lower BP in the elderly patients since they regarded hypertension as being compensatory in the aging process.2) The concept was strongly believed because excessive reduction of blood in some hypertensive emergencies led to organ damage such as renal failure, encephalopathy and myocardial ischemia, and the result was stroke, heart attacks and even death.3) However, this idea gradually changed as treating hypertension showed a better prognosis. A large meta-analysis by Lewington et al.4) and that was published in 2002 Lancet about hypertension and mortality was comprised of 61 cohort studies targeting one million subjects with the support of the British Cardiac Society. According to the analysis, vascular mortality in coronary artery disease (CAD) and stroke decreased as the systolic BP decreased from 180 mmHg to 115 mmHg and the diastolic BP declined from 100 mmHg to 75 mmHg. Since then, the principle "the lower, the better" has been widely accepted.

The J-Curve Concept

Reports warning against aggressive lowering of BP continued to exist. This doubt was based on the evidence that a BP of 0 mmHg results in 100% mortality. In 1979, after a study with over 6 years follow-up, Stewart5) reported a 5 times higher risk of myocardial infarction (MI) in hypertensive patients with a diastolic blood pressure (DBP) less than 90 mmHg when compared to those with DBP 100-109 mmHg. About 10 years later, Cruickshank6) reported a strong J-curve phenomenon between MI and the DBP in moderate to severe hypertensive patients only when they had CAD. The DBP at the nadir of the J-curve ranged from 85 to 90 mmHg and the J-curve did not appear in the absence of CAD. In several studies conducted afterwards, the J-curve in heart attacks and other heart diseases was consistently observed whereas no J-curve was observed in stroke and renal diseases.7)

Mechanism of the J-Curve and the Pathophysiologic Approach

Most of the coronary circulation occurs during diastole. During systole, the left ventricular (LV) myocardium contracts and compresses the intramyocardial vessels to impede its blood flow. If the diastolic pressure is too low, then the myocardial perfusion can be affected. Thus, the J or U curve hypothesis that a DBP less than 70 or 60 mmHg may cause myocardial ischemia and increase mortality is widely accepted. The coronary perfusion pressure is determined by the gradient between the coronary and LV diastolic pressures. When the coronary perfusion pressure is lowered to 40-50 mmHg, the blood flow due to coronary perfusion pressure theoretically approaches 0 with exclusion of the LV diastolic pressure.8)

The myocardium autoregulates the perfusion pressure in the range of 45 to 125 mmHg,9) and so the myocardium is capable of enduring various degrees of proximal coronary stenosis. However, in CAD patients, compromised autoregulation reduces the perfusion pressure distal to a stenosis when a decrease in the DBP occurs, resulting in an increased LV filling pressure. It further decreases the coronary perfusion pressure to intensify the vicious cycle of myocardial ischemia. As the LVH gets more severe, the LV endocardial ischemia worsens and myocardial ischemia occurs even in moderately low ranges of DBP.10)11)

Reverse causality

Other explanations about the existence of the J-curve have been proposed. Reverse causality views coexisting chronic illness or a poor health condition as a cause for low DBP, which leads to increased morbidity and mortality.12-14)

According to Established Populations for Epidemiologic Studies of the Elderly,15) 17% of the population showed a decrease in the systolic blood pressure (SBP) greater than 20 mmHg and 22% showed a reduction of the DBP more than 10 mmHg over 3 years.

The group with reduced DBP showed increased all-cause mortality by 1.5 fold, increased cardiovascular mortality by 1.6 fold and increased cardiovascular events by 1.4 fold. Yet, when adjusted for disease and the functional status, there was no significant relationship between BP reduction and the hazard ratio. That is, reduced BP in the elderly is a common event indicating a poor sanitary status and health condition, and its association with increased mortality is an illusion. Such patients generally have a tendency of both low SBP and low DBP; therefore, the PP is not very high.

Increase in pulse pressure

Low DBP is attributed to progressed vascular disease and a rise in the PP due to increased aortic stiffness, and this is not the problem itself. In fact, low DBP is related to the J-curve in isolated systolic hypertension (ISH) patients, but low DBP is not related to the J-curve in patients with low SBP. An example is the Systolic Hypertension in the Elderly Program study16) and the Syst-Eur study17) on elderly ISH patients, where no increase in myocardial ischemia or cardiovascular disease (CVD) risk was shown at a DBP of 55-60 mmHg.

Major Clinical Studies on the J-Curve

The International Verapamil SR-Trandolapril (INVEST)study on 22,000 hypertensive patients with CAD compared verapamil-based treatment and atenolol based treatment and the initial results were reported in 2003. On the analysis of the INVEST study by Messerli et al.18) when considering DBP of 80-90 mmHg as the lowest point, DBP below 70-80 mmHg shows the J-curve as an increased risk of MI appears (Fig. 1). Especially, CAD patients are more sensitive to a reduction in DBP and there is 2-fold CAD risk difference between a DBP of 80 mmHg and 65 mmHg. The J-curve phenomenon was observed in CAD, but not in stroke (Fig. 1). The J-curve effect was more apparent in CAD patients who did not go through revascularization than those who underwent revascularization (Fig. 2).

Fig. 1

The Incidence of the myocardial infarction and stroke as stratified by diastolic blood pressure in the International Verapamil SR-Trandolapril study.18)

Fig. 2

Interaction of the J-Curve with coronary revascularization. The patients who were revascularized better tolerated a lower diastolic blood pressure (DBP) than those who were not.18)

In the Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention study,19) a SBP below 120 mmHg showed a J-shaped increase of cardiovascular mortality in the olmesartan group compared to the placebo group. The Treating to New Targets study20) was conducted to observe the relationship between antihypertensive treatment and the CAD risk in CAD patients. The SBP and DBP were categorized by a 10 mmHg rise, and the primary end point was set as a major cardiovascular event such as death from CAD, nonfatal MI, resuscitation after cardiac arrest and fatal or nonfatal stroke. After a median follow-up of 4.9 years, the lowest BP with the lowest incidence of CVD was 146.3/81.4 mmHg. Especially, a BP less than 110-120/60-70 mmHg showed the J-curve relationship as the incidence of CVD increased. Yet as SBP decreased, the stroke incidence also declined.

According to the Ontarget study21) that targeted the high-risk group, the effect of lowering the SBP was mainly a reduction of the incidence of stroke. As the SBP is reduced below 130 mmHg, there was no difference in the MI incidence whereas there was a J-shaped increase in the CVD mortality.

Controlling Blood Pressure in Diabetes and the J-Curve

The hypertension optimal treatment (HOT) study,22) which aimed to determine the DBP target in hypertensive patients, divided approximately 19,000 patients with essential hypertension and who were 50-80 years old (median age: 61.5) into three levels target DBPs (below 80, 80-85 and 85-90 mmHg) and then treatment was begun. As a result, the incidence of CVD was lower in the lower target DBP groups, with the lowest incidence for a DBP of 83 mmHg and a SBP of 139 mmHg. There was no extra benefit in terms of the cardiovascular event even when the DBP was lowered below 90 mmHg in the non-diabetic patients, but maintaining the DBP below 80 mmHg in diabetic patients led to about 50% of extra benefit in reducing events. In only the smokers, the J-curve was found in the group with a target DBP below 80 mmHg as this group showed a 2-fold increase in cardiovascular events compared to the group with a target DBP below 90 mmHg. Based on these results, the target BP in hypertensive patients with diabetes was set as 130/80 mmHg.

However, this is supported by only a few studies, and specifically there is no evidence that using anti-hypertensives in the patients with BP 130-140/80-90 mmHg offers any extra benefit. The recent data from the Action to Control Cardiovascular Risk in Diabetes-blood pressure study,23) which investigated the difference between intensive BP lowering and standard antihypertensive therapy in patients with either diabetes or MI, in contrast to the expected outcome, showed no significant difference between the intensive BP lowering group with a target SBP below 120 mmHg and the standard treatment group with a target SBP below 140 mmHg. In addition, a retrospective analysis of the INVEST trial to examine the benefit of intensive BP control in diabetic patients with CAD revealed that lowering the BP below 130 mmHg did not offer any additional benefit and even the J-curve phenomenon was observed as excessive reduction of BP resulted in a higher mortality rate (Fig. 3).

Fig. 3

Results of the peoprotion of events in Action to Control Cardiovascular Risk in Diabetes-blood pressure (effects of intensive blood-pressure control in type 2 diabetes mellitus) (A) and the Adjusted risk of all-cause mortality in International Verapamil SR-Trandolapril (B).23)

Studies Contradicting the J-Curve Concept

Reported in 1995, the 16 years of follow-up study of Multiple Risk Factor Interventional Trial (MRFIT)24) investigated 5,440 patients with prior hospitalization of 2 weeks or more for MI at the initial screening of MRFIT. In the first 2 years of the follow-up, all-cause mortality was high in those patients with a SBP <120 mmHg and those with a DBP <70 mmHg. Afterwards, the lowest SBP and DBP strata showed a decreasing pattern of mortality. If a low DBP is the cause of death, then the high mortality rate should have continued for 15 years. Therefore, the authors stated that the high mortality is not due to a low diastolic pressure, but rather, it was due to a defect in the LV function that led to lower DBP and SBP. It has also been suggested that the low DBP results from LV dysfunction and a reduced stroke volume and this leads to increased mortality.

Glynn et al.25) followed 22,071 men and 39,876 women in the PHS and WHS for a median of 13.0 years and 6.2 years, respectively, and they observed an association of the SBP and DBP with the risk of MI, stroke, coronary artery bypass, angioplasty and cardiovascular death. In this study, both women and men with lower SBP had a lower incidence of CVD and they did not show the J-curve relationship. There was a gender difference in DBP, as a lower DBP reduced CVD with a slight J-curve shown below 60 mmHg in men, but there was no association or the J-curve relationship between the DBP and CVD observed in the women.

The HOT study, consistent with the study of Cruickshank et al.6) reported a J-shaped relationship between DBP below 85 mmHg and the risk of MI only in the patients with CAD, but not in those without CAD.

According to the Cardiovascular Health Study by Psaty et al.26) the BP level and CVD risk showed a linear relationship and the J-curve between DBP and incidence of MI was not observed for patients with DBP below 69 mmHg.

Why Does the J-Curve Appear in Coronary Artery Disease, but Not in Stroke or Renal Disease?

Coronary perfusion occurs in diastole, whereas cerebral perfusion mainly occurs in systole. Cerebral perfusion is capable of autoregulation in the range of 40-125 mmHg, so it is resistant to low BP. As a result, the J-curve phenomenon does not hold true for the incidence of stroke. Renal perfusion also occurs mainly in systole, and so no J-curve is observed as well.

Realistic Approach to Manage the J-Curve

Even today, the J-curve phenomenon in antihypertensive therapy is still controversial and there have been only limited studies on its relation to SBP. In light of the results from previous several studies, the occurrence of increased myocardial ischemia resulting from aggressive lowering of the DBP should be considered during antihypertensive therapy. Although most of the studies have shown the J-curve for DBP below 70-80 mmHg, this phenomenon does not appear in stroke or renal disease. Therefore, since the appearance of the J-curve in patients with clinically severe LVH, CAD or vascular diseases is highly probable, caution should be taken to maintain the DBP at minimum of 70 mmHg and possibly to maintain the DBP between 80-85 mmHg.

The SBP is suggested to be controlled according to a rule "moderation is the best thing", rather than the old golden rule "the lower the better". In other words, as 2009 revised European Guidelines on Hypertension Management27) stated, maintaining a BP of 130-139/80-85 mmHg in patients with hypertension seems to be appropriate using the current evidence-based medicine (Fig. 4). Since ISH patients already have low DBP in many cases and the PP reduction by decreasing the SBP has benefits for preventing CVD that outweigh the risks caused by a reduced DBP, based on the Syst-Eur study,17) lowering the SBP while maintaining the DBP above 55-60 mmHg is suggested if the patients do not have CAD. If they have coexisting vascular diseases like CAD, then BP control is suggested after reperfusion procedures such as PCI or CABG. A careful approach should be used for BP control in high-risk elderly patients as undergoing aggressive therapy to lower the SBP below 140 mmHg can cause cardiovascular complications due to the severely reduced DBP and increased PP.

Fig. 4

The pre- and post-treatment systolic blood pressure clinical benefit in a clinical hypertension study on diabetic patients.18)

Conclusion

The current national and international antihypertensive treatment guidelines recommend a BP goal of <140/90 mmHg, and <130/80 mmHg in patients with CAD, chronic renal disease and other CVD. However, the recent large clinical studies have shown the J-curve phenomenon in patients with a DBP <80 mmHg as well as in patients with a SBP <130 mmHg, and the studies demonstrated no significant differences in the risk of cardiovascular complications between aggressive antihypertensive therapy and standard therapy. Yet the J-shaped curve does not appear for stroke patients, and this shows a relationship consistent with the principle "the lower the better".