Anaerobic Metabolism as an Indicator of Aerobic Function During
Exercise in Cardiac Patients
I’XKGi<GXE, MD, MICi~IAKI liiROE, MD, i3lROidASA
ADACHL, MD,
TAKASHI YAJIMA,MD,AKIWK@NOGAMI,MD,HlROSHl
ITO.MD,
[email protected], KOICHI TANIGUCHI.MD.FACC,FUMIAKI MARUMO,MD
TolJw,
J"Jwi
To
determine
WhCthEr
patients
withhart
disease depend mwe
than nwmat ruhjeets on anaerobic mataholirm to pwfxm the
same level of exerti% the rnaerohic threshold, slope of the
increasein enrhon dioxide output with respectto oxygen uptake
(AVCO,IAVOI) and the slope of the increasein oxygen uptake
with resppcct
to the increasein work rate (AVOJAWR)
both b&w
and ahave the anaerobic thrahotd during cxerctw were ewluated. A Mat of 106 palientr with chronic heart diseaseand 42
healthy subjectsperformed a symptom-limited incremental evercisetsl in a amp pattern on z eyeleergcmwtw.
Peakoxygw uptake wassignilirantty lower in the patientswith
heart diseasethan in the nornut subjects. The anaerobic threshold, which was 20 + 4.6 mllmin per kg in normal subjects,
decreased significantly with progressing severity of functional
tlw: 16 ? 2.4, 14.1 + 2.5 and 11.3 * 1.5 mUndn pa kg,
respeetivtly,in patieotr in class1, classII and classIII. The slop
of A~Q~IAWR, which reprzsentr the degreeof aerobic metab+
Initially \pith exercise, carbon dioxide output increases
linearly with oxygen uptake and greater aerobic metabolism
until the slope of the increase in carbon dioxide output with
respect to oxygen uptake (AVC021AVOJ
approximates
the anaerobx threshold (I). Thereafter, as anaerobic slycolysis comF’ements aerobic metabolism, lactic acidosis develops (Z-4). Jicarbonate would be the primary buffer of lactic
acid <La) resulting in the formatton of carbonic acid, which
dissociates to water (H,O) and carbon dioxide (CO,) (2):
I or
where Hi = hydrogen ion. HCO,- = bicarbonate, K* =
potassium. Thus, A!%O,IAi’OI
would become steeper
above the anaerobic threshold because an additional 22 ml of
carbon dioxide over that produced by aerobic metabolism
must be generated from each milliequivalent of laaic acid
between normal subj~ets and patie&
However,~A&JA+O,
above the anaerobic threshold became steeper with incrasing
severityof heart d&se: I.37 t 0.17 in normal subjects versus
1.55* 0.24, 1.67+ 0.3 and 1.8 + 0.35 resp&iwty, in patirnls in
functional classI, classII and tlas 111.
The steeperA~CO,IAi’O, sloppabovelhe anaerobicthreshold
in patientswith heart diseaseresulted from the greater ~maunt of
carbon dloxlde preduetion per unit of oxygen and rrtlected the
greater extent of anaerohie metabolism needed to supplement
energyoutput. Thb ratio. which wasnot intlurnred hy patient ege
or the slopeof the work rate increase,provider a useful indicator
of aeroh!efunelion in patienti with heal disear.
N Am Coil Cordial 1992;20:1?0-6)
buffered by bicarbonate (2). The breakpoint in the carbon
dioxideoutpul-oxygenuptakeplot (V slope analysis). therefore, is rhe anaerobic threshold (3,5,6). Although the an:er.
obic threshold has been used lo identify the severity of
chronic heart failure (7-IO), some reports (ll,l2) have contradicled the concept uf the anaerobic threshold. If there is.
in fact. a threshold phenomenon in lactic acidosis that
represents anaerobic metabolism, the slope of AkCO,lAirO,
above the anaerobic threshold should become steeper with
an increasein anaerobic metabolism without a change in the
s!ol)eof AirCOJAirO, below the anaerobicIhreshold.
We hypotheiired &at al levels of exercise more intense
than those that could be performed with aerobic metabolisn
alone, the greater the degree of circulatory impairment, the
ercatcr the extent that anaemhic metabo!i%n would he
needed to supplement energy output. Thi\ would result in
increasing amounts of c&on dioxide production per unit of
oxygen consumption.
To evaluate lhe contribution of anaerobic metabolism
during exercise.we measuredA~COllAirO,along with the
slope of the increase in oxygen uptake with respect to the
increase in work rate (A902/AWR) (Z-4,13) in patients with
various types of hean direare. We also eumined whether
Methods
Stud) patients (Table I). WC ctudwd I? hcetthy whject\
without evidence of heart d~raw sod IO6 pauenrx $$rlth
chronic bran disease tTob,e iI. Thelc wre 9, men and 57
women: 47 patients were m New York Heart A~~ociatmn
functioned cl%s I. 41 m clws II and I! in ~,a\\ Ill. Their
diagnoses were coronary artery din\c
tn = 301. wlvu!x
heart disease In = ?h). huocrtcn*ive hex, disca% tn = 25).
dilated cardiomyopathy In = 71and other- heart diseare !n =
IR). Excluded from rtudy were ;my parienrx wtb r&t
an%ind. as well as those with pure mitral ~cnow or aortjc
stenosi% The nature and purpose of the study and the wk*
involved were explained and informed conscnt ra, ohtamed
from each subject before his or her voluntary conwtt to
participate.
Exercise pmtoeol. A symptom-limited exercise tc(t aa>
employed using iln upright clectromagnctically braked cycle
ergometer (Siemens-Elema 1308). After a 4-min rest on the
ergomctcr.each subject began the exercise te\t with it 4.min
warm-up at 20 W. htl ‘pm, Mowed by a progressive increase
in work rate tramp patte,n) (141. Although the slope of the
increase in work rate wits initially selected as IO Wlmin
~,~i6s~or:0WimintlW/3s~randomly.l?Wlm~nllW/4aJ
was later added to ihe randomization requence (Table ,).
Meawrements. Heart rate and a I?-lead electrocardiogram IECC) were monitored throughout the tat. CUB blood
pressure wab measured every minute by an automatic indirect manometer (STBP-680F. Collin Denshi) (151.
O.ryxen II~IUPP.curhon dio.ride owpttr und ntin~c wntilotion were measured every IO s at rat and during exercise
with an Aerobic Processor 39, tNihon Denki Sanei). This
system consists of a mixing chamber (2.5 liters), polarogmph
oxygen analyzer. infrared carbon dioxide analyzerand a hoi
wire spirometer. Gas exchange and flow measurements were
corrected for ambient temperature. barometric prersure and
water vapor.
Calculationsof the rlcp of the increaw in carbon dioxide
output ailh respectto oxygen uptake t&iiCOjdVO,)
and the
slope of inrreace in oxygen uptake with respectto the ioereare
in aurk rate (AVOz,~WR, below and above the maerot,ic
thrcctmtd. The BVCOlll’iOi
and 1+0,0WR wure co/colatcd ietw and above the anaerobic thwhold tATt a\
foliow
1VCO,i1VO, below the .AT = IVCO, at the AT - i’C0,
i,, !,I W] ! IVO, ai the AT - VO, ill Xl W].
lVCOI’AVt,,abovc
the AT = [peak *CO: - iiC0, at
Ihe ATI [peak VO, - VO, at rhe AT]
1”O.:1WR hclow the AT = IVO. a, ,he AT - \iO. m
21) ‘hi ! iWRat lbe AT - loi.
LVO,:LWR above the AT = [peak iiD, - VO, a, the
AT] Ima~imai WR
WR at the AT]. where WR = work
rate.
Satisliul methods. Data are reported as mean value I
SD. Ccmpansonc of the variable, related to functiunal
cluwlication. cardiac letion and slope of the ramp w-t were
made by analysis of variance (ANOVA,. Significant difference\ in the F test were then compared by using the
Newman-Keuls multiple range test. Differences were wnridered statt\ticallg stgniticant at the p < 0.05 level.
:
!
Results
Slope of work rate inc-:
anaewbii thre4wld. The
mean value (W/min) of the slope ofthe increase in work rate
was I5 2 5 4.8 in the normal subjects, 14.9 rf 4.4 in patientm clans 1. 14.8 + 4.1 in those in clarr II and 13.3 t 4.7 in
thuae in class III tp = NS). Allhougb relattvely few subject>
pcrformcd the IS-Wimin ramp test, there was no Ggnificant
diKerenie in the severity ofhean disease with respect to the
slope of the work rate increase (10, IS or 20 Winin). Figure
shows the respiratory gas exchange of a typical patient
with heart disease during the ramp test. Ventilatory cquivalent fo- oxy~een(vE#OJ increased after a period of stability. whereas the ventilatory equivalent for carbon dioxide
li/EI~COIl
decreased at the work rate indicated by the
vertical line. Therefore, oxygen uptake at thts work rate was
detincd as the anaerobic threshold. In Figure 2. from the
rame patient. carbon d&de output has been plotted as a
function of oxygen uptake (V slope plot). The easily distinSuished intercept of the two slopes ofcarbon dioxide output
I
J
11:
with respect !u oxygen uplake (AiTOJAi’O,)
is the anaerobic threshold. In this patient, A~C02iA’i~0, helow the
anaerobic threshold was approximately I, whereas Ai’COi
AVO, above the anaerobic threshold was almost 2.
Variables of aerobic function. Heart rate and blood preswe during exercise are sbowr! in Table 2 and the variables
of aerobic function obtained by measuring respiratory gas
exchange during exercise appear m Table 3. The peak
oxygen uptake normalized to each subject’s body weight
was 32.4 2 7.1 mllmin per kg in the normal subjects. The
value was significantly decreased below normal to 25.
4.8. 21.1 C 4.7 and 16.9 * 2.1 mllmin per kg in palients in
class I, class II and clil~s 111.respectively. Similarly. anaerobic threshold. which was 20 i 4.6 mllmin per kg in normal
subjects, was significantly decreased with increasing severity of hear, d,sease: 16 f 2.4, 14.1 + 2.5 and 11.3 2
1.5 mllmin per kg, respectively, in patients in functional
class 1. class II and class III. The maximal work rate and the
work rate at the anaerotic threshold also decreased in
accordance with severity of heart disease (Table 3).
ReMion between oxygen uptake and carbun dioxide output
during exorcise. Oxygen uptake is plotted against work rate
for normal subjects and patients with heart disease in Figure
3A. There was a significant difference m oxygen uptake at
20 W among the four groups by analysis of variance (p =
I*
0.002). Oxygen uptake at 20 W in patients m class 111was
significantly lower than in lhe other three g,aupr (p < 0.05
hy the Newman-Keels multiple range test). The decrease in
oxygen uptake with the severity of heart disease must be
more profound at higher work rata because the slope of the
increase
in oxygen
uptake with rapect to the increase in
work rate (AVOJAWR) was significantly decreased bolh
below and above the anaerobic threshold in relation to
diwse progression (Fig. 3A, Table 3). However, carbon
dioxide output. which tended to be lower at work rates
below the anaerobic threshold in patients with heart disease
than m nor.nal subjects, was essentially the same at work
rates above the anaerobic threshold (Fig. 3B).
The discrepancy between oxygen uptake and carbon
dioxide oulput responses during exercise must influence the
ratm of aiiCO,/L\eOz (V slope plot). Figure 4A shows the
values for oxygen uptake and carbon dioxide output at rest
.wd at 20 W. anaerobic threshold and maximal work raw
from the lowest to the highest oxygen uptake in all subjects
tested, The anaerobic threshold iss ldwer and the upper
slope of AiT02iAir0,
became steeper in patients with hean
disease than in normal subjects. although there was no
diAercnce in the lower slope. The upper slope became
steeper with an increase in funcliwml class (Fig. 48).
i’hr b~(lrreucr of the .slope of the mng test (IO. I5 and
20 Wlmin) on A60,IAWR and A~CO,IA~O,
is demonstrated in Figure 5. Boih the work rate a1 ihe anaerobic
threshold and the maximal work rate increased sipGficantly
with increasing slope ofthe ramp tw: 58.6 + 13.8and 102.7
t 25.6 W for the study at IO Wimin; 74.5 -+_15.9and 134.6 +
25.1 W for the study ni I5 Wlmin and 86.5 * 21.3 and 152.2
+
40.1 w for the swdy at 20 Wimm.
The value of
A+02JAWR for the study at 20 Wlmin was significantly
lower than that for 10 Wlmin. bmb below and above the
anaerobic threshold (by Newman.Keuls’
multiple range
tesl). However. this slopz had no intkosnce on AiiCOliA’>O,
above or below the anaembic threshold (Fit. 58).
There wo1sno relorion berween AVCO,&‘O,
nbove rhe
anaerobic thzsholdand agu in normal subjects ifig. 6). The
relation between lhls slope above the anaerobic threchold
and peak oxygen uptake is shown in Figure 7; the s!ope
increased as the peak oxygen uptake declined. showmg a
significantly negative comAation (r = -0.502). A weak
negative correlation was also noted between the slope above
the anaerobic threshold and anaerobic threshold (y = I.893
- 0.021x. r = -0.297). There was no significant difference in
the anaembic threshold, peak oxygen uptake 0: slope above
the anaercbic threshold with respect to the type of hean
disease.
Di§CUSSiOll
Delorminatim of the anaerobic threshold. The anaerobic
threshold usually is deremdnt-d by .eas exchange analysis as
tbc unypn uptake a which $62 vcnlilatory squivalem for
oxygen (‘JEi’?02) increases after being Rat or decrcascd,
while the vendlamp equivalent for carbon dioxide (irEI
6C02) remains constant or decreases (16.17).This method is
L-=~
.,i .L*
@g! the increase in carbon dioxide
..-,- “..
L.._-:serr.$~,
.I_
output :enerared from lactic acid buliered by bsarboa?!t
would result in ventilatory drive through the chemorecepton. However, chemoreceptors may not behave normally in
patienls with Lund disease or chronic hean failure (19%
In 1986, Beaver et al. (5) studied the relation between
oxygen uptake and carbon dioxide OUtQUlduring exercise in
normal subjects and found that the intercept of oxygen
uptake and carbon dioxide output plots &’ slope plots)
during exercise coincided with the metabolic daclie) acidow
thresixld (that is. Ihe anaerobic thxshold). This metnod of
‘“1 A
I
detanning
the anaerobic lhrcshold does not rely on Ihe
magnitude of the venlilawry adjustment tar metabolic acidosis and ip r&lively unaffected by brealhing irregulantics.
T/w unwrohic ~hr~~rlrold. ac rep, crcntcd by the highest
level of oxygen uptake lhat can be performed without the
development of a sustained lac!i: acidosis. bar been used to
estimate the severity of cardiovascular impairment (7-10)
and effectiveness of cardiac therapy (X-221.
Slope of the iilcrease in carbon dioxide output with rcspecl
to oxygen upldke. If because of aeteriorating hcan function.
the patient wth heart d~s~abe ih more dependent than the
normal subiect on anaerobx metabolism to periorm the
same !cvel of r”crci% addil;onal carbon dioxldc would be
genelated from lacticwad lo thcprorm
study. i! v&ill found
that Ihe slune of the incrcare in carbon dioxide OUIDU~ with
rc~pect 10 oxygen uptake IAVCO,lAi’O,l
above the anaerobic threshold was steeper in patientr with heart disease than
in normal subjects. This difference mw result from decreased oxygen uptake despite the some carbon dioxide
cs:puc as that of normal subjects (Fig. 31 and is evidence of
an increase in anaerobic metabolism reladve to aerobtc
metabolism during exercise in pmients with heart disease. If
lhere war no compensatory increae in anaerobic metabolism. the carbon dioxide oulput in these patients would be
lower ar work rata above the anaerobic threshold. as noted
with oxygen uplake. WC fcund no rclahrn belween Ihc slope
of &i’C0,1Aii02
above the anaerobic threshold and age.
although ii is well known that the anaerobic threshold and
peak oxygen uptake decline with ac (231. The increase in
the slope of oxygen uptake with rernect to the increase in
and peak exerciic. going from the
lowest to hahesloxy$en optake.
work
rate
relation
(AVCJAWR)has also bee” reported to have no
113.23).Although the reason for this nhenom-
to age
enon has not been clarifi&the
explain
why age is not a” important
slope above the ““aerobic
The anaerobic
oxygen
perform
work without
the sleeper
uptake
slope
faclor
for the steeper
above
which
representing
a rubjecr
lactic acidosis.
A%‘CO,lAiiO,above
in patients with heart disuse
in accordance
production
negative correlation
uptake
between
was also found
affected by the patient’s
geak oxygen
per unit of oxygen
with the severity
uptake
of circulatory
this variable
(Fig.
7). This
motivation,
or maximal
not
slightly
that obsenjed in
the anaerdbic
in increasing
consumption
impairment.
A
and peak oxygen
variable
~a”noL be
which can easily affect
work
higher than
lated #he slope of this ratio as (VCO,
QCO, at 20 W) / (ii0,
rate. The maximal
results from the relatively
simply
from
exercise.
which
dioxide
AVO,
as a” independent
tw
Above
ventdatio”
high solubility
%‘O, a,
of this
of rarbon dioxide in
points:
the anaerobic
the respiratory
increases
may increase
slightly.
and other factors
of ihe metabolic
linearity
compensation
AVCO,l
this
and peak
point
at
tc czab3,3
the slope of AirCO,l
depending
related
acidosis
of
We calculated
threshold
disproportionately
output (increase in i’E/i’COJ,
dxation
can sixe
-
of 11~: ramp test, which
tissues (3.IY.24).
We may also have to consider the
AiiO, above the anaerobic threshold.
sensitivity
in the patients
threshold
threrhnld
variable in thar in the prese”~ study it included tbe nonlinear
profoundly influenced by the slope of the ramp test, *x5o:nx
the slope of AirCOdA’?O,above the anaerobicthreshold
was not. This variable
We calcu-
at anaerobic
28 WL which might accourfi for the underestimation
work rate and work rate at the anaerobic threshold were
of aerobic function
I (Z-4.a value
our study.
at anaernhic
pan of the data at the beginning
However.
re9ects the extep. of
anaerobic metabolism. which would result
carbon dioxide
could
1.“~
below the anaerobic rhreqhotd
to be approximately
-
is t”e variab!c
developing
of
might
threshold.
thranold
highest
threshold
same mecham&
ThL Dupe oiAiiCO,/lwOl
has been reported
on chemoreceptor
to the magnitude
and
and the actual oxygen
uptake (3).
indicator
with heart disease.
Figure 6. Relation between the slope ui the incrrax in carbon
dioxide outpm wit’” respect to oxygen uptake “bow the anaerobic
threshold (SZ) and age in “ormaJ subjects (24 me” and 18 women).
yo = years at*.
Fiurr 7. Rclatior ‘ds,eeo the slope cf Ihe increase I” carbon
dioxide outwt wth respecl 10 oxygen uptake above the araerobic
threshold 621 md peak oxygen uptake (VO,) in all 143 subjects
iwed.
during a progreaivc
wing
a cycle
in&w
agomctcr.
cardiovascular
dysfunctmn.
been considered
found ihal AiiOJAWR
ment
in work
Since
rale.
wilh
P~O,IAWR
has
LO raresent
the
cm he mRitcnccd
the steeper
in patients
thin.
variable
(thio i*, normally
sfudy. B Gmilar
with heart diwse
rate m normal s;bjccts
decreased
an additional
work rate increment
presnt
in v&k
wa\
by Ihe ,lope oilhe
the slower Ihc incre-
the AQO,lAWR)
phenomenon
In the
was found in patients
(t ig. 5).
Conclusions. ‘The ‘,teeper 9opc of AVC021Ai10z
above
Ihe anaerobw threshold m our patients resulted from the
greawr
rellecled
cubon
dioxide
pru.+chon
per umt of oxygen;
Ihe grearer exie,,, of imxrobic
to supplement
energy output.
this ratio. which reilcctr
blc metabolism
metabolism
it
needed
We believe that the slope of
the relalive
lo total metabolic
contribution
oianaero-
responses. can serve a~ a