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ABSTRACT
The J-curve effect describes an inverse relation between low blood pressure (BP) and cardiovascular complications. This ef-
fect is more pronounced in patients with preexisting coronary artery disease (CAD), hypertension or left ventricular hyper-
trophy (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, cau-
tion 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. (Korean Circ J 2011;41:349-353)
KEY WORDS: Hypertension; J-curve; Coronary artery disease; Diastolic pressure; Systolic pressure; Stroke.
349
350 J-Curve in Hypertension and CAD
was observed in stroke and renal diseases.7) 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
Mechanism of the J-Curve and isolated systolic hypertension (ISH) patients, but low DBP is
the Pathophysiologic Approach not related to the J-curve in patients with low SBP. An exam-
ple is the Systolic Hypertension in the Elderly Program stu-
Most of the coronary circulation occurs during diastole. Dur- dy16) and the Syst-Eur study17) on elderly ISH patients, where
ing systole, the left ventricular (LV) myocardium contracts no increase in myocardial ischemia or cardiovascular disease
and compresses the intramyocardial vessels to impede its blo- (CVD) risk was shown at a DBP of 55-60 mmHg.
od flow. If the diastolic pressure is too low, then the myocar-
dial perfusion can be affected. Thus, the J or U curve hypothe- Major Clinical Studies on the J-Curve
sis that a DBP less than 70 or 60 mmHg may cause myocardial
ischemia and increase mortality is widely accepted. The cor- The International Verapamil SR-Trandolapril (INVEST)
onary perfusion pressure is determined by the gradient be- study on 22,000 hypertensive patients with CAD compared
tween the coronary and LV diastolic pressures. When the co- verapamil-based treatment and atenolol based treatment and
ronary perfusion pressure is lowered to 40-50 mmHg, the the initial results were reported in 2003. On the analysis of
blood flow due to coronary perfusion pressure theoretically the INVEST study by Messerli et al.18) when considering DBP
approaches 0 with exclusion of the LV diastolic pressure.8) of 80-90 mmHg as the lowest point, DBP below 70-80 mmHg
The myocardium autoregulates the perfusion pressure in shows the J-curve as an increased risk of MI appears (Fig. 1).
the range of 45 to 125 mmHg,9) and so the myocardium is ca- Especially, CAD patients are more sensitive to a reduction in
pable of enduring various degrees of proximal coronary ste- DBP and there is 2-fold CAD risk difference between a DBP
nosis. However, in CAD patients, compromised autoregula- of 80 mmHg and 65 mmHg. The J-curve phenomenon was
tion reduces the perfusion pressure distal to a stenosis when observed in CAD, but not in stroke (Fig. 1). The J-curve effect
a decrease in the DBP occurs, resulting in an increased LV was more apparent in CAD patients who did not go through
filling pressure. It further decreases the coronary perfusion revascularization than those who underwent revasculariza-
pressure to intensify the vicious cycle of myocardial ischemia.
As the LVH gets more severe, the LV endocardial ischemia 20
MI
worsens and myocardial ischemia occurs even in moderately Stroke
Incidence (%) of MI/stroke
Reverse causality 10
Other explanations about the existence of the J-curve have
been proposed. Reverse causality views coexisting chronic ill- 5
ness or a poor health condition as a cause for low DBP, which
leads to increased morbidity and mortality.12-14)
0
According to Established Populations for Epidemiologic ≤60 61-70 71-80 81-90 91-100 101-110 >110
Studies of the Elderly,15 17% of the population showed a de- Fig. 1. The Incidence of the myocardial infarction and stroke as
crease in the systolic blood pressure (SBP) greater than 20 stratified by diastolic blood pressure in the International Verapamil
SR-Trandolapril study.18)
mmHg and 22% showed a reduction of the DBP more than
10 mmHg over 3 years.
6
The group with reduced DBP showed increased all-cause Patients with revascularization
mortality by 1.5 fold, increased cardiovascular mortality by 5 Patients without revascularization
when adjusted for disease and the functional status, there was
no significant relationship between BP reduction and the haz- 3
tion (Fig. 2). and then treatment was begun. As a result, the incidence of
In the Randomized Olmesartan And Diabetes MicroAl- CVD was lower in the lower target DBP groups, with the low-
buminuria Prevention study,19) a SBP below 120 mmHg show- est incidence for a DBP of 83 mmHg and a SBP of 139 mmHg.
ed a J-shaped increase of cardiovascular mortality in the ol- There was no extra benefit in terms of the cardiovascular event
mesartan group compared to the placebo group. The Treating even when the DBP was lowered below 90 mmHg in the non-
to New Targets study20) was conducted to observe the relation- diabetic patients, but maintaining the DBP below 80 mmHg
ship between antihypertensive treatment and the CAD risk in in diabetic patients led to about 50% of extra benefit in reduc-
CAD patients. The SBP and DBP were categorized by a 10 ing events. In only the smokers, the J-curve was found in the
mmHg rise, and the primary end point was set as a major car- group with a target DBP below 80 mmHg as this group show-
diovascular event such as death from CAD, nonfatal MI, re- ed a 2-fold increase in cardiovascular events compared to the
suscitation after cardiac arrest and fatal or nonfatal stroke. Af- group with a target DBP below 90 mmHg. Based on these
ter a median follow-up of 4.9 years, the lowest BP with the results, the target BP in hypertensive patients with diabetes
lowest incidence of CVD was 146.3/81.4 mmHg. Especially, was set as 130/80 mmHg.
a BP less than 110-120/60-70 mmHg showed the J-curve re- However, this is supported by only a few studies, and specifi-
lationship as the incidence of CVD increased. Yet as SBP de- cally there is no evidence that using anti-hypertensives in the
creased, the stroke incidence also declined. patients with BP 130-140/80-90 mmHg offers any extra bene-
According to the Ontarget study21) that targeted the high- fit. The recent data from the Action to Control Cardiovascular
risk group, the effect of lowering the SBP was mainly a re- Risk in Diabetes-blood pressure study,23) which investigated
duction of the incidence of stroke. As the SBP is reduced be- the difference between intensive BP lowering and standard an-
low 130 mmHg, there was no difference in the MI incidence wh- tihypertensive therapy in patients with either diabetes or MI,
ereas there was a J-shaped increase in the CVD mortality. in contrast to the expected outcome, showed no significant
difference between the intensive BP lowering group with a
Controlling Blood Pressure target SBP below 120 mmHg and the standard treatment gr-
in Diabetes and the J-Curve oup with a target SBP below 140 mmHg. In addition, a retro-
spective analysis of the INVEST trial to examine the benefit
The hypertension optimal treatment (HOT) study,22) which of intensive BP control in diabetic patients with CAD reveal-
aimed to determine the DBP target in hypertensive patients, ed that lowering the BP below 130 mmHg did not offer any
divided approximately 19,000 patients with essential hyper- additional benefit and even the J-curve phenomenon was
tension and who were 50-80 years old (median age: 61.5) into observed as excessive reduction of BP resulted in a higher
three levels target DBPs (below 80, 80-85 and 85-90 mmHg) mortality rate (Fig. 3).
1.0 10
0.2 Standard
0.8
0.1
Proportion with event
Intensive
0.6
0.0
0 1 2 3 4 5 6 7 8
0.4
1.0
0.2 p=0.20
0.0 0.5
0 1 2 3 4 5 6 7 8 <110 110-<115 115-<120 120-<125 125-<130
Years Systolic blood pressure (mmHg)
No. at risk No. at risk 35 98 306 757 1,059
Intensive 2,362 2,273 2,182 2,117 1,770 1,080 298 175 080 No. of deaths 12 17 038 069 0,112
Standard 2,371 2,274 2,196 2,120 1,793 1,127 358 195 108
A B
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)
352 J-Curve in Hypertension and CAD
170 BP Δ
162 Benefit
160 Partial benefit
155 154
No benefit
150 148
153 145
143 144 144 143
140
SBP (mmHg)
110
100
HOT UK S.Eur ABCD IDNT REN ADV
SHEP MHOPE HT NT IR AM PROG
Fig. 4. The pre- and post-treatment systolic blood pressure clinical benefit in a clinical hypertension study on diabetic patients.18)
Chang Gyu Park, et al. 353
DBP in many cases and the PP reduction by decreasing the 10) Harrison DG, Florentine MS, Brooks LA, Cooper SM, Marcus ML.
The effect of hypertension and left ventricular hypertrophy on the low-
SBP has benefits for preventing CVD that outweigh the risks
er range of coronary autoregulation. Circulation 1988;77:1108-15.
caused by a reduced DBP, based on the Syst-Eur study,17) low- 11) Polese A, De Cesare N, Montorsi P, et al. Upward shift of the lower
ering the SBP while maintaining the DBP above 55-60 mmHg range of coronary flow autoregulation in hypertensive patients with
is suggested if the patients do not have CAD. If they have co- hypertrophy of the left ventricle. Circulation 1991;83:845-53.
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existing vascular diseases like CAD, then BP control is sug- blood pressure in old age: a prospective birth cohort study. Eur Heart
gested after reperfusion procedures such as PCI or CABG. A J 1998;19:1872-8.
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Blood pressure change and survival after age 75. Hypertension 1993;
elderly patients as undergoing aggressive therapy to lower the
22:551-9.
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od pressure among older adults. J Clin Epidemiol 2001;54:961-7.
The current national and international antihypertensive tr- 16) Somes GW, Pahor M, Shorr RI, Cushman WC, Applegate WB. The
role of diastolic blood pressure when treating isolated systolic hyper-
eatment guidelines recommend a BP goal of <140/90 mmHg,
tension. Arch Intern Med 1991;159:2004-9.
and <130/80 mmHg in patients with CAD, chronic renal 17) Fagard RH, Staessen JA, Thijs L, et al. On-treatment diastolic blood
disease and other CVD. However, the recent large clinical stu- pressure and prognosis in systolic hypertension. Arch Intern Med
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18) Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggres-
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mmHg, and the studies demonstrated no significant differ- artery disease be dangerous? Ann Intern Med 2006;144:884-93.
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tion of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:
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this shows a relationship consistent with the principle “the sis of blood pressure and cardiovascular events in the Treating to New
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