Download Lowgrade systolic murmurs in healthy middleaged individuals

Original Article
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doi: 10.1111/j.1365-2796.2011.02480.x
Low-grade systolic murmurs in healthy middle-aged
individuals: innocent or clinically significant? A 35-year
follow-up study of 2014 Norwegian men
J. Bodegard1, P. T. Skretteberg1, K. Gjesdal1,2, K. Pyörälä3, S. E. Kjeldsen1,2, K. Liestøl4, G. Erikssen5 & J. Erikssen2
1
Department of Cardiology, Oslo University Hospital, Ullevaal; 2Faculty of Medicine, University of Oslo, Oslo, Norway; 3Institute of Clinical Medicine,
Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland; 4Department of Informatics, University of Oslo; and 5Department of
Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
Abstract. Bodegard J, Skretteberg PT, Gjesdal K,
Pyörälä K, Kjeldsen SE, Liestøl K, Erikssen G, Erikssen J (Oslo University Hospital, Oslo; University
of Oslo, Oslo; University of Eastern Finland, Kuopio; University of Oslo, Oslo; Oslo University Hospital, Oslo). Low-grade systolic murmurs in
healthy middle-aged individuals: innocent or clinically significant? A 35-year follow-up study of
2014 Norwegian men. J Intern Med 2012; 271:
581–588.
Objective. To determine whether a low-grade systolic
murmur, found at heart auscultation, in middle-aged
healthy men influences the long-term risk of aortic
valve replacement (AVR) and death from cardiovascular disease (CVD).
Setting and subjects. During 1972–1975, 2014 apparently healthy men aged 40–59 years underwent
an examination programme including case history, clinical examination, blood tests and a
symptom-limited exercise ECG test. Heart auscultation was performed under standardized conditions, and murmurs were graded on a scale from
I to VI. No men were found to have grade V ⁄ VI
Introduction
Systolic murmurs detected at auscultation in healthy
middle-aged and older individuals may be associated
with various degrees of aortic valve sclerosis. Aortic
valve sclerosis is thought to form the basis of most
systolic murmurs in people in these age groups and is
associated with a 50% increased risk of death from
cardiovascular disease (CVD) [1–3]. CVD and aortic
valve sclerosis demonstrate similar histological and
biochemical properties, and thus it has been proposed that sclerosis of the aortic valve could be a marker of atherosclerosis in other vessel beds [4, 5]. To
murmurs. Participants were followed for up to
35 years.
Results. A total of 1541 men had no systolic murmur;
441 had low-grade murmurs (grade I ⁄ II) and 32 had
moderate-grade murmurs (grade III ⁄ IV). Men with lowgrade murmurs had a 4.7-fold [95% confidence interval
(CI) 2.1–11.1] increased age-adjusted risk of AVR, but
no increase in risk of CVD death. Men with moderategrade murmurs had an 89.3-fold (95% CI 39.2–211.2)
age-adjusted risk of AVR and a 1.5-fold (95% CI 0.8–
2.5) age-adjusted increased risk of CVD death.
Conclusions. Low-grade systolic murmur was detected
at heart auscultation in 21.9% of apparently healthy
middle-aged men. Men with low-grade murmur had
an increased risk of AVR, but no increase in risk of
CVD death. Only 1.6% of men had moderate-grade
murmur; these men had a very high risk of AVR and a
1.5-fold albeit non-significant increase in risk of CVD
death.
Keywords: aortic valve replacement, cardiac auscultation, cardiovascular disease, risk prediction, systolic
murmur.
our knowledge, there have been no previously reported studies of the association between the intensity (loudness) of auscultatory systolic murmurs in
healthy individuals and either echocardiographyverified aortic sclerosis or clinical endpoints.
We hypothesized that because a systolic murmur
may indicate the presence of aortic valve sclerosis, it
may be associated with an increased risk of CVD or
progression to aortic valve stenosis requiring an
aortic valve replacement (AVR). The Oslo Ischemia
Study provided the opportunity to assess the 35-year
ª 2011 The Association for the Publication of the Journal of Internal Medicine
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Prognostic significance of systolic murmurs in middle age
predictive value of systolic murmur at heart auscultation with regard to the risk of future AVR and CVD
mortality in a cohort of Norwegian men between 40
and 60 years of age.
Study population and methods
The Oslo Ischemia Study was a prospective study of
2014 apparently healthy men working in five governmental institutions in Oslo, Norway. A total of 2341
eligible men were invited to participate in the study,
and 2014 (86%) accepted the invitation [6, 7]. Individuals were included if, after scrutiny of their company
health records, they were found to be healthy and free
from a number of diseases ⁄ conditions including
known or suspected CVD, diabetes mellitus, cancer
and advanced pulmonary, liver or renal diseases [6].
Subjects receiving treatment with any chronic drug
regimens were also excluded, as were those who were
judged to be unable to perform a symptom-limited
bicycle exercise test for orthopaedic, muscular or
neurological reasons [8]. Subjects with self-reported
diagnoses of any of the afore-mentioned conditions
since last visiting their company physician were
examined, but excluded from our data file. All individuals with a recent febrile illness had to wait at least
14 days before being examined.
Subjects underwent a baseline examination between
August 1972 and March 1975, including a thorough
structured case history, a full clinical examination,
height ⁄ weight measurements, spirometry testing,
chest X-ray, fasting blood tests (lipid profile, blood
glucose and an intravenous glucose tolerance test), a
resting ECG and a symptom-limited bicycle exercise
ECG test. All subjects underwent an identical examination programme in strictly the same order after
having given their informed consent.
The clinical examination took place in a quiet room at
an ambient temperature of 20–22 C. Blood pressure
was measured in the recumbent position after resting
for 5 min, and heart and respiratory rates were measured for 1 min. At heart auscultation, both the bell
and membrane of the stethoscope were applied with
the participants sitting, lying on their back and in the
left lateral recumbent position [8]. Auscultation was
performed during quiet respiration and during breath
holding in inspiration and expiration. Systolic murmurs were graded from I to IV; no murmurs of grade V
or VI were found. In all subjects, the second heart
soundwasjudgedtobenormal.Systolicmurmurswere
subdivided into two groups: grade I or II was classified
as low grade and grade III or IV as moderate grade.
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Journal of Internal Medicine, 2012, 271; 581–588
Resting and exercise 12-lead ECGs were read according to the Minnesota code [9].
All men who were still alive were invited for a followup examination performed in 1980–1982, approximately 7 years after the baseline study. Prior to the
second examination, 92 men (4.6%) had died; 1756
(91.4%) of those still alive were re-examined with only
minor deviations from the baseline protocol. The clinical examinations were performed by the same physician (J.E.) for the baseline examination and re-examination after 7-years. Registration of auscultation
data at re-examination was blinded to the baseline
auscultation data.
Follow-up procedures
With permission from the Norwegian Data Inspectorate and the Norwegian Board of Health, we obtained a
complete update of cause-specific deaths from Statistics Norway. This national statistics bureau keeps a
record of all deaths in all Norwegians, and the present
mortality data are complete up to 1 January 2007.
Also with permission, we conducted a nationwide
survey of all files on men admitted to Norwegian hospitals up to 31 December 2008. Morbidity and hospitalization data registration was truncated at 1 January 2007 in line with the registered mortality data.
The following cardiovascular events were noted: nonfatal, hospital-verified myocardial infarction, stroke,
coronary artery bypass grafting, percutaneous coronary intervention, AVR and aortic or peripheral arterial surgery.
In the present analysis, we only used the first event of
any type (myocardial infarction, stroke, etc.). Myocardial infarction and ⁄ or stroke diagnosed in conjunction with major surgery were not included. When two
consecutive, different CVD events were detected,
their interval had to exceed 6 months for both to be
included.
Statistical methods
Differences in baseline data between groups were
tested by Student’s t-test, Wilcoxon test and Fisher’s
exact test according to data distribution and type. All
P-values are two-tailed and considered significant if
P < 0.05.
Kaplan–Meier plots were produced to illustrate the
time course of the cumulative incidence of mortality
and morbidity events during follow-up. Cox proportional hazard regression was used when calculating
J. Bodegard et al.
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Prognostic significance of systolic murmurs in middle age
relative risk after inclusion of further covariates. The
Cox model included variables previously identified as
important prognostic factors [10, 11] Diagnostic plots
of log S(t) versus log (t) indicated that the proportional
hazard assumption was acceptable. The linearity
assumptions were tested by evaluating regression results with the variables split into categories. All models were computed using jmp 8 software, SAS Institute Inc., Cary, NC, USA [12].
Results
Amongst the 2014 subjects, 1541 (76.5%) had no
systolic murmur; the remaining 473 (23.5%) men
had a systolic murmur, all with preserved second
heart tone. Low-grade systolic murmur was found in
441 men (grade I, n = 219; grade II, n = 222), and 32
had moderate-grade systolic murmur (grade III,
n = 27; grade IV, n = 5). Men with low-grade murmur
were less often smokers and had slightly higher systolic blood pressure and higher fasting blood glucose
levels compared with those with no murmur (Table 1).
These men also had higher systolic blood pressure at
100 W, greater physical fitness and more frequently
developed ST-segment depression than those with no
murmur. Men with moderate-grade systolic murmur
were slightly older, had higher systolic and diastolic
blood pressures, slightly larger heart volume, a higher resting heart rate and a lower ability to increase
their heart rate and blood pressure during exercise
compared with those with no murmur (Table 1).
The incidence of AVR was higher in men with lowgrade murmur (2.9%) compared with those with no
murmur (0.6%; P < 0.001) and markedly higher
(43.8%; P < 0.0001) in men with moderate-grade
murmur (Table 2). None of the men in the study had
undergone mitral valve replacement.
Figure 1 shows Kaplan–Meier plots for the cumulative incidences of AVR, CVD events, CVD death and
all-cause death. Men with moderate-grade murmur
Table 1 Baseline data categorized on the basis of cardiac auscultation in 2014 apparently healthy men
No murmur
Low grade (I ⁄ II)
Moderate grade
n = 1541
n = 441
(III ⁄ IV) n = 32
Age (years)
49.9 (5.5)
49.6 (5.6)
51.9 (4.8)*
Smoking (%)
46.1
35.8**
43.8
BMI (kg m)2)
24.5 (2.8)
Systolic BP (mmHg)
129.1 (17.5)
24.6 (2.6)
132.8 (18.1)***
25.2 (2.1)
139.4 (23.7)**
Diastolic BP (mmHg)
86.9 (10.4)
87.5 (10.3)
91.2 (11.1)*
Cholesterol (mmol L)1)
6.40 (1.21)
6.69 (1.13)
6.76 (1.23)
Triglycerides (mmol L)1)
1.33 (0.71)
1.29 (0.70)
1.36 (0.77)
Fasting blood glucose (mmol L)1)
4.44 (0.54)
4.50 (0.62)*
4.60 (0.60)
ESR, mm ⁄ h
7.42 (6.81)
7.25 (6.18)
7.41 (7.35)
401.5 (57.6)
406.3 (61.7)
16.9 (2.42)
17.7 (2.88)
)2
Relative heart volume (mL m )
PQ (PR) interval (ms)
LVH (%)
Resting heart rate (beats min)1)
2.4
61.1 (9.5)
5.4
427.6 (78.4)*
17.4 (2.62)
15.6
62.1 (10.5)
64.7 (9.7)*
Symptom-limited bicycle exercise test
D heart rate (beats min)1)a
101.8 (14.7)
100.5 (14.0)
Systolic BP at 100 W (mmHg)
180.8 (23.9)
183.5 (24.9)*
D systolic BP (mmHg)a
85.7 (19.7)
86.7 (20.3)
Physical fitness (kJ kg)1)
1.91 (0.78)
2.01 (0.82)*
ST-segment depression ‡0.50 mm (%)
12.3
16.6*
95.7 (14.8)*
187.5 (29.5)
74.7 (27.4)**
1.76 (0.72)
18.8
All numbers within parenthesis are one SD. Significant difference from the group with no murmur: *P < 0.05, **P < 0.01,
***P < 0.001. BMI, body mass index; BP, blood pressure; ESR, erythrocyte sedimentation rate. Relative heart volume was calculated using measurements from a chest x-ray, PQ (PR) interval measured from resting ECG. LVH, left ventricular hypertrophy
on resting ECG according to Minnesota code 3.1 and 3.3. aD heart rate and D systolic BP show the difference between resting and
maximal values.
ª 2011 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2012, 271; 581–588
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Aortic valve replacement (%)
No murmur
Low grade (I ⁄ II)
Moderate grade
n = 1541
n = 441
(III ⁄ IV) n = 32
10 (0.7)
13 (3.0)
CVD event (%)a
739 (48.0)
208 (47.2)
14 (43.8)
20 (62.5)
CVD death (%)
399 (25.9)
115 (26.1)
13 (40.6)
All-cause death (%)
902 (58.5)
247 (56.0)
29 (90.6)
Table 2 Number of events categorized on the basis of cardiac
auscultation in 2014 apparently
healthy men
CVD, cardiovascular disease. aComposite of the following as the first event: CVD death,
non-fatal myocardial infarction, non-fatal stroke or CVD surgery ⁄ intervention except aortic
valve replacement.
Cardiovascular events
Aortic valve replacement
100%
100%
90%
Cumulative incidence
80%
Cumulative incidence
90%
No murmur
Low grade murmur
Moderate grade murmur
70%
60%
50%
40%
30%
No murmur
Low grade murmur
Moderate grade murmur
80%
70%
60%
50%
40%
30%
20%
20%
10%
10%
0%
0%
0
5
10
15
20
25
30
35
0
5
10
20
25
30
35
All cause death
Cardiovascular death
100%
100%
90%
90%
No murmur
Low grade murmur
Moderate grade murmur
70%
60%
50%
40%
30%
70%
60%
50%
40%
30%
20%
20%
10%
10%
0%
0
5
10
15
No murmur
Low grade murmur
Moderate grade murmur
80%
Cumulative incidence
80%
Cumulative incidence
15
Observation time (Years)
Observation time (Years)
20
25
30
Observation time (Years)
0%
35
0
5
10
15
20
25
30
35
Observation time (Years)
Fig. 1 Cumulative incidence of aortic valve replacement, cardiovascular disease (CVD) events, CVD death and all-cause death
during 35 years of follow-up.
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Prognostic significance of systolic murmurs in middle age
had a markedly higher incidence of AVR than men in
the other groups, and the incidence of AVR also increased in the low-grade murmur group during the
second half of the follow-up. Three men had AVR during the first 5 years of follow-up: one man in the lowgrade murmur group at 4.6 years and two men in the
moderate-grade murmur group, both with grade IV
murmurs, at 3.7 and 4.1 years, respectively. The
median interval from baseline to AVR was 14.3 years
in the whole study cohort. Men with moderate-grade
murmur had higher cumulative incidences of CVD
events, CVD death and all-cause death than those in
the other two groups, whereas men with either a lowgrade or no murmur had similar cumulative incidences of these events.
Cox model analyses showed that the group with lowgrade murmur had a 4.7-fold higher age-adjusted
risk of AVR, but no increased risk of CVD events, CVD
death or all-cause death, compared with the group
with no murmur (Table 3). Compared with men with
no murmur, those with moderate-grade murmur had
an 89.3-fold, 1.7-fold, 1.5-fold and 1.5-fold increased
age-adjusted risk of AVR, CVD events, CVD death
and all-cause death, respectively; all these increased
risks except for CVD deaths were significant. The increased risk of AVR persisted after adjusting for multiple baseline CVD risk factors (age, smoking status,
total cholesterol and systolic blood pressure). Statistical significance was lost for CVD events and allcause death in the multiple-adjusted analyses.
The reproducibility of auscultatory findings between
baseline and re-examination 7 years later amongst
the 1756 men who took part in both examinations is
demonstrated in Table 4. Of the men with no murmur
at baseline, approximately one-fifth developed a systolic murmur; almost all of them had a low-grade
murmur after 7 years. By contrast, more than half of
the men with low-grade systolic murmur at baseline
had no murmur at the 7-year re-examination. The
incidence of AVR is demonstrated according to the
classification of auscultatory findings at both examinations. There was a higher incidence of AVR
amongst those men in whom the loudness of the systolic murmur increased between the two examinations. The incidence of AVR remained low in those
men in whom low-grade murmur was no longer present after 7 years and those in whom a low-grade murmur was first detected at the 7-year re-examination.
The incidence of AVR was, however, significantly
higher in those men who had a low-grade murmur at
both baseline and 7-year follow-up examinations
compared with those who had no murmur at both
examinations or low-grade murmur at the baseline or
at the 7-year re-examination alone (3.0% vs. 0.4%,
0.8% or 1.2%; P < 0.001).
The majority of the 242 men who changed from lowgrade to no systolic murmur had a grade I murmur
(54.5%) and demonstrated an AVR incidence of
0.76% (data not shown). The remaining 45.5% of subjects decreased from a grade II murmur and had a
similarly low AVR incidence (0.91%).
Discussion
The results of our study show that there is a relatively
high prevalence (21.9%) of low-grade systolic murmur (grade I ⁄ II) in apparently healthy middle-aged
working men. Subjects with low-grade murmur had a
4.7-fold increased risk of AVR, but no increased risk
of CVD death within the following 35 years compared
those with no murmur. Men with moderate-grade
murmur (grade III ⁄ IV) had an 89-fold increased risk
of AVR. The age-adjusted risk of CVD death was
increased by 1.5-fold, but did not reach statistical
significance.
The relationship between aortic valve sclerosis verified by echocardiography and the risks of CVD death
and all-cause death were examined in the Cardiovascular Health Study in a cohort of adults aged 65 years
and above [13]. In total, 29% of the study cohort had
aortic valve sclerosis without significant obstruction
and 2% had calcified aortic stenosis. It is likely that
the prevalence of aortic valve sclerosis would have
been lower in our study of healthy middle-aged men
than that observed in the Cardiovascular Health
Study. Unfortunately, as in other population-based
echocardiographic studies of aortic valve sclerosis,
no information was provided regarding heart auscultation findings and their relationship with aortic valve
sclerosis. Aortic valve sclerosis was associated with a
1.7-fold and a 1.4-fold increase in age- and sex-adjusted risk of CVD death and all-cause death, respectively, in the Cardiovascular Health Study. In the
present study, the small group of men with moderategrade systolic murmur had risks of CVD death and
all-cause death of the same magnitude, as those observed in individuals with aortic sclerosis in the Cardiovascular Health Study.
To our knowledge, the only other population-based
study of the prognostic significance of systolic murmurs is the 15-year follow-up study of a cohort of
70-year-old subjects in Gothenburg, Sweden [14]. In
that study population, about 50% of men and women
ª 2011 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2012, 271; 581–588
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Table 3 Hazard ratios for different endpoints categorized on the basis of cardiac auscultation of 2014 apparently healthy men
No murmur
Low grade (I ⁄ II)
Moderate grade
n = 1541
n = 441
(III ⁄ IV) n = 32
Age-adjusted HR (95% CI)
1.00
4.74 (2.08–11.11)
89.26 (39.16–211.15)
Multiple-adjusted HR (95% CI)a
1.00
5.07 (2.21–11.96)
102.71 (42.88–257.26)
Aortic valve replacement
CVD eventb
Age-adjusted HR (95% CI)
1.00
0.97 (0.83–1.13)
1.71 (1.06–2.59)
Multiple-adjusted HR (95% CI)a
1.00
0.97 (0.83–1.13)
1.57 (0.98–2.40)
1.00
1.07 (0.86–1.31)
1.50 (0.82–2.51)
1.00
1.06 (0.86–1.30)
1.21 (0.65–2.03)
Age-adjusted HR (95% CI)
1.00
1.01 (0.88–1.17)
1.52 (1.03-2.16)
Multiple-adjusted HR (95% CI)a
1.00
1.03 (0.89–1.87)
1.31 (0.88–1.87)
CVD death
Age-adjusted HR (95% CI)
a
Multiple-adjusted HR (95% CI)
All-cause death
CVD, cardiovascular disease. aAdjusted for age, smoking status, total cholesterol and systolic blood pressure; bComposite of
the following as the first event: CVD death, non-fatal myocardial infarction, non-fatal stroke or CVD surgery ⁄ intervention except
aortic valve replacement.
Systolic murmur at 7-year follow-up
Low grade
Moderate grade
No murmur
(I ⁄ II)
(III ⁄ IV)
Total
1076
252
7
1335
0.4%a
1.2%
28.6%
Low grade (I ⁄ II)
242
134
17
0.8%
3.0%
23.5%
Moderate grade (III ⁄ IV)
3
6
19
0.0%
16.6%
52.6%
Systolic murmur at baseline
No murmur
Table 4 Reproducibility of cardiac
auscultatory findings and incidence of AVR among 1756 men
who participated both at baseline and at the 7-year follow-up
examination
393
28
a
The percentage values represent men having had an aortic valve replacement during
follow-up after the 7-year re-examination.
had at least one clinical manifestation of CVD at baseline (coronary heart disease, heart failure or hypertension). During follow-up, systolic murmur was
found to be a predictor of mortality in women, but not
in men when adjustment was made for CVD at baseline. The prevalence of systolic murmur was 24% in
men and 36% in women. Our study cohort was younger and healthier than the Gothenburg cohort. Thus,
the prevalence of systolic murmur (23.5%) in the
present study seems to be high, possibly because a
standardized optimal protocol was used for heart
auscultation.
The number of individuals with AVR (n = 37; 2.0%)
was small in our study, but seems close to the
586
ª 2011 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2012, 271; 581–588
expected number for a population-based study. Only
2.9% of men with low-grade systolic murmur received
AVR during the follow-up period. In this group, one
AVR was performed at 4.6 years, but this man had
AVR surgery because of an aortic dissection caused
by Marfan syndrome. The second AVR in the lowgrade murmur group was performed at 12.3 years.
Hence, it seems reasonable not to refer a healthy middle-aged individual with a low-grade murmur for further examinations, such as echocardiography, within
the first 5 years after auscultation.
Several observations suggest that aortic valve sclerosis, presumed to be the most common cause of systolic murmurs in middle-aged and older people, is
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Prognostic significance of systolic murmurs in middle age
closely linked to atherosclerotic CVD [3, 15, 16].
Cross-sectional population-based studies have
shown that CVD risk factors, including raised blood
pressure, elevated serum cholesterol and smoking,
are related to the presence of aortic valve sclerosis
detected by echocardiographic methods [13, 17, 18].
In our study, men with moderate-grade systolic murmur were on average 2 years older than men in the
other groups and exhibited subtle pathophysiological aberrations at baseline: higher resting systolic
and diastolic blood pressures, lower ability to increase their maximal blood pressure and heart rate
during exercise, lower physical fitness and slightly
larger hearts. In contrast to previous reports, we
found no association between total serum cholesterol and the prevalence of systolic murmurs [13]. In
this context, it is of interest to note that several randomized controlled trials have failed to demonstrate
a reduction in the progression of calcified aortic
stenosis, despite intensive cholesterol-lowering
treatment [19–22].
The impaired ability to raise systolic blood pressure
and heart rate observed in our study in men with
moderate systolic murmur may be an early sign of restricted blood flow through the aortic valve. ST-segment depression in the exercise ECG was more common amongst men with systolic murmur and could
possibly be explained by coronary atherosclerosis,
endothelial dysfunction or imminent left ventricular
hypertrophy, as suggested by increased heart size
shown on chest X-ray. Indeed, generalized endothelial dysfunction has been observed in patients with
aortic valve sclerosis [23, 24].
Our study has several strengths: the study design
was prospective, all data sets are virtually complete
and the findings refer to an apparently healthy population of middle-aged men followed for up to 35 years.
We have no work-up bias, and all event data are
based on cause-specific death records and complete
hospital records. The study group has not interfered
with patient care, therefore bias is minimized.
Comparison of the auscultatory findings at baseline
and the 7-year examination recorded by the same observer provided information not only on the repeatability of the findings but also on their predictive value with regard to the risk of AVR. In more than half of
the men with low-grade murmur at baseline, no murmur was detected after 7 years. Grade I murmurs
and grade II murmurs decreased to no murmur with
a low incidence of AVR in a similar number of men. Of
importance, however, those men in whom low-grade
murmur was detected both at baseline and at the
7-year examination had a significantly higher risk of
AVR during the rest of the follow-up compared with
those in whom low-grade murmur was heard only at
one of the two examinations. The repeatability of
moderate-grade murmurs between the baseline and
7-year examinations was much better. The incidence
of AVR was highest during the rest of the follow-up
period in those men who had moderate-grade murmur at both examinations, but was also high in those
men in whom moderate-grade murmur was diagnosed at the 7-year examination irrespective of the
murmur classification at baseline. Because the classification of murmurs according to their loudness is
subjective, a change of one or even two grades in
either direction in the loudness of a murmur may occur. Thus, the main variability between the baseline
and 7-year examinations is because of observer variation, but differences in the haemodynamic state and
changes in the composition of extracardiac tissues
may also have had an influence on the audibility and
loudness of murmurs.
At the time of the baseline examination (1972–1975),
echocardiography was not a routine clinical method.
Standardized screening at that time, however, gave
us the opportunity to study the long-term clinical
course amongst middle-aged men with systolic murmurs detected by heart auscultation. Today, echocardiography is the gold standard for routine detection of aortic valve sclerosis, although it should be
remembered that echo-assessment is a subjective
method and that only 20% of subjects with valve sclerosis were found to have calcification according to
one study [2, 25]. Congenital bicuspid aortic valve,
although less common than previously believed, can
also lead to aortic valve stenosis [26, 27] and could,
therefore, interfere with our analysis of the effects of
CVD risk factors. Finally, our study was limited to
Caucasian men.
Conclusions
Low-grade systolic murmur was found in more than
one-fifth of apparently healthy middle-aged men with
normal exercise capacity. Low-grade systolic murmur does not carry any increased risk of CVD death,
but does increase by five-fold the risk of receiving an
AVR.
Men with low-grade systolic murmur have a late
development of AVR requirement, and we suggest
that an auscultatory follow-up at 5 years could safely
replace an immediate referral for echocardiography.
ª 2011 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2012, 271; 581–588
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The prevalence of moderate-grade systolic murmur
was very low (<2%), but men in this group had a very
high risk of requiring AVR and a trend towards increased risk of CVD. These men should be considered
for both CVD risk-reducing measures and close
follow-up regarding AVR.
Conflict of interest
No conflict of interest to declare.
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Correspondence: Johan Bodegard, MD, PhD, Department of
Cardiology, Oslo University Hospital, Ullevaal, PB 4956, Nydalen,
0424 Oslo, Norway.
(fax: +47 22 11 91 81; e-mail: [email protected]).