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Keywords:

  • aortic valve replacement;
  • cardiac auscultation;
  • cardiovascular disease;
  • risk prediction;
  • systolic murmur

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study population and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Conflict of interest
  9. References

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 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 low-grade 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 moderate-grade 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.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study population and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Conflict of interest
  9. References

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 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 echocardiography-verified 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 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study population and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Conflict of interest
  9. References

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 sound was judged to be normal. Systolic murmurs were subdivided into two groups: grade I or II was classified as low grade and grade III or IV as moderate grade.

Resting and exercise 12-lead ECGs were read according to the Minnesota code [9].

All men who were still alive were invited for a follow-up 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 < 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 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study population and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Conflict of interest
  9. References

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, = 219; grade II, = 222), and 32 had moderate-grade systolic murmur (grade III, = 27; grade IV, = 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).

Table 1.   Baseline data categorized on the basis of cardiac auscultation in 2014 apparently healthy men
 No murmur = 1541Low grade (I/II) = 441Moderate grade (III/IV) = 32
  1. All numbers within parenthesis are one SD. Significant difference from the group with no murmur: *< 0.05, **< 0.01, ***< 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. aΔ heart rate and Δ systolic BP show the difference between resting and maximal values.

Age (years)49.9 (5.5)49.6 (5.6)51.9 (4.8)*
Smoking (%)46.135.8**43.8
BMI (kg m−2)24.5 (2.8)24.6 (2.6)25.2 (2.1)
Systolic BP (mmHg)129.1 (17.5)132.8 (18.1)***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/h7.42 (6.81)7.25 (6.18)7.41 (7.35)
Relative heart volume (mL m−2)401.5 (57.6)406.3 (61.7)427.6 (78.4)*
PQ (PR) interval (ms)16.9 (2.42)17.7 (2.88)17.4 (2.62)
LVH (%)2.45.415.6
Resting heart rate (beats min−1)61.1 (9.5)62.1 (10.5)64.7 (9.7)*
Symptom-limited bicycle exercise test
Δ heart rate (beats min−1)a101.8 (14.7)100.5 (14.0)95.7 (14.8)*
Systolic BP at 100 W (mmHg)180.8 (23.9)183.5 (24.9)*187.5 (29.5)
Δ systolic BP (mmHg)a85.7 (19.7)86.7 (20.3)74.7 (27.4)**
Physical fitness (kJ kg−1)1.91 (0.78)2.01 (0.82)*1.76 (0.72)
ST-segment depression ≥0.50 mm (%)12.316.6*18.8

The incidence of AVR was higher in men with low-grade murmur (2.9%) compared with those with no murmur (0.6%; < 0.001) and markedly higher (43.8%; < 0.0001) in men with moderate-grade murmur (Table 2). None of the men in the study had undergone mitral valve replacement.

Table 2.   Number of events categorized on the basis of cardiac auscultation in 2014 apparently healthy men
 No murmur = 1541Low grade (I/II) = 441Moderate grade (III/IV) = 32
  1. 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.

Aortic valve replacement (%)10 (0.7)13 (3.0)14 (43.8)
CVD event (%)a739 (48.0)208 (47.2)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)

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 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 low-grade 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 low-grade or no murmur had similar cumulative incidences of these events.

image

Figure 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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Cox model analyses showed that the group with low-grade 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 all-cause death in the multiple-adjusted analyses.

Table 3.   Hazard ratios for different endpoints categorized on the basis of cardiac auscultation of 2014 apparently healthy men
 No murmur = 1541Low grade (I/II) = 441Moderate grade (III/IV) = 32
  1. 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.

Aortic valve replacement
 Age-adjusted HR (95% CI)1.004.74 (2.08–11.11)89.26 (39.16–211.15)
 Multiple-adjusted HR (95% CI)a1.005.07 (2.21–11.96)102.71 (42.88–257.26)
CVD eventb
 Age-adjusted HR (95% CI)1.000.97 (0.83–1.13)1.71 (1.06–2.59)
 Multiple-adjusted HR (95% CI)a1.000.97 (0.83–1.13)1.57 (0.98–2.40)
CVD death
 Age-adjusted HR (95% CI)1.001.07 (0.86–1.31)1.50 (0.82–2.51)
 Multiple-adjusted HR (95% CI)a1.001.06 (0.86–1.30)1.21 (0.65–2.03)
All-cause death
 Age-adjusted HR (95% CI)1.001.01 (0.88–1.17)1.52 (1.03-2.16)
 Multiple-adjusted HR (95% CI)a1.001.03 (0.89–1.87)1.31 (0.88–1.87)

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%; < 0.001).

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
 Systolic murmur at 7-year follow-up
No murmurLow grade (I/II)Moderate grade (III/IV)Total
  1. aThe percentage values represent men having had an aortic valve replacement during follow-up after the 7-year re-examination.

Systolic murmur at baseline
 No murmur1076 0.4%a252 1.2%7 28.6%1335
 Low grade (I/II)242 0.8%134 3.0%17 23.5%393
 Moderate grade (III/IV)3 0.0%6 16.6%19 52.6%28

The majority of the 242 men who changed from low-grade 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study population and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Conflict of interest
  9. References

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 moderate-grade 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 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 (= 37; 2.0%) was small in our study, but seems close to the 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 low-grade 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 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study population and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Conflict of interest
  9. References

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.

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.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Study population and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Conflict of interest
  9. References
  • 1
    Iung B, Baron G, Butchart EG et al. A prospective survey of patients with valvular heart disease in Europe: the Euro heart survey on valvular heart disease. Eur Heart J 2003; 24: 123143.
  • 2
    Nightingale AK, Horowitz JD. Aortic sclerosis: not an innocent murmur but a marker of increased cardiovascular risk. Heart 2005; 91: 138993.
  • 3
    Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 1999; 341: 1427.
  • 4
    Branch KR, O’Brien KD, Otto CM. Aortic valve sclerosis as a marker of active atherosclerosis. Curr Cardiol Rep 2002; 4: 1117.
  • 5
    Kuusisto J, Räsänen K, Särkioja T, Alarakkola E, Kosma VM. Atherosclerosis-like lesions of the aortic valve are common in adults of all ages: a necropsy study. Heart 2005; 91: 57682.
  • 6
    Erikssen J. Aspects of Latent Coronary Heart Disease. A Prevalence- and Methodological Validation Study in Apparently Healthy, Working Middle Aged Men. Oslo, Norway: University Hospital (Rikshospitalet), Medical Departement B, 1978.
  • 7
    Erikssen J, Enge I, Forfang K, Storstein O. False positive diagnostic tests and coronary angiographic findings in 105 presumably healthy males. Circulation 1976; 54: 3716.
  • 8
    Mundal R, Kjeldsen SE, Sandvik L, Erikssen G, Thaulow E, Erikssen J. Exercise blood pressure predicts mortality from myocardial infarction. Hypertension 1996; 27: 3249.
  • 9
    Åstrand I, Areskog NH, Carlsten A et al. The “Minnesota Code” for ECG classification. Adaptation to CR leads and modification of the code for ECGs recorded during and after exercise by the Scandinavian Committee on ECG Classification. Acta Med Scand Suppl 1967; 481: 126.
  • 10
    Pyörälä K, De Backer G, Graham I, Poole-Wilson P, Wood D. Prevention of coronary heart disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J 1994; 15: 130031.
  • 11
    Sandvik L, Erikssen J, Thaulow E, Erikssen G, Mundal R, Rodahl K. Physical fitness as a predictor of mortality among healthy, middle-aged Norwegian men. N Engl J Med 1993; 328: 5337.
  • 12
    SAS. JMP 8 User Guide. Cary, NC, USA: SAS Publishing, 2008.
  • 13
    Stewart BF, Siscovick D, Lind BK et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol 1997; 29: 6304.
  • 14
    Dey DK, Sundh V, Steen B. Do systolic murmurs predict mortality in the elderly? A 15-year longitudinal population study of 70-year-olds Arch Gerontol Geriatr 2004; 38: 191200.
  • 15
    Aronow WS, Ahn C, Shirani J, Kronzon I. Comparison of frequency of new coronary events in older subjects with and without valvular aortic sclerosis. Am J Cardiol 1999; 83: 599600. A8.
  • 16
    Taylor Jr HA, Clark BL, Garrison RJ et al. Relation of aortic valve sclerosis to risk of coronary heart disease in African-Americans. Am J Cardiol 2005; 95: 4014.
  • 17
    Lindroos M, Kupari M, Valvanne J, Strandberg T, Heikkilä J, Tilvis R. Factors associated with calcific aortic valve degeneration in the elderly. Eur Heart J 1994; 15: 86570.
  • 18
    Messika-Zeitoun D, Bielak LF, Peyser PA et al. Aortic valve calcification. Determinants and progression in the population. Arterioscler Thromb Vasc Biol 2007; 27: 642648.
  • 19
    Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (Astronomer) trial. Circulation 2010; 121: 30614.
  • 20
    Cowell SJ, Newby DE, Prescott RJ et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005; 352: 238997.
  • 21
    Dichtl W, Alber HF, Feuchtner GM et al. Prognosis and risk factors in patients with asymptomatic aortic stenosis and their modulation by atorvastatin (20 mg). Am J Cardiol 2008; 102: 7438.
  • 22
    Rossebø AB, Pedersen TR, Boman K et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359: 134356.
  • 23
    Bodegard J, Erikssen G, Björnholt JV, Gjesdal K, Thelle D, Erikssen J. Symptom-limited exercise testing, ST depressions and long-term coronary heart disease mortality in apparently healthy middle-aged men. Eur J Cardiovasc Prev Rehabil 2004; 11: 3207.
  • 24
    Poggianti E, Venneri L, Chubuchny V, Jambrik Z, Baroncini LA, Picano E. Aortic valve sclerosis is associated with systemic endothelial dysfunction. J Am Coll Cardiol 2003; 41: 13641.
  • 25
    Walsh CR, Larson MG, Kupka MJ et al. Association of aortic valve calcium detected by electron beam computed tomography with echocardiographic aortic valve disease and with calcium deposits in the coronary arteries and thoracic aorta. Am J Cardiol 2004; 93: 4215.
  • 26
    Beppu S, Suzuki S, Matsuda H, Ohmori F, Nagata S, Miyatake K. Rapidity of progression of aortic stenosis in patients with congenital bicuspid aortic valves. Am J Cardiol 1993; 71: 3227.
  • 27
    Pachulski RT, Chan KL. Progression of aortic valve dysfunction in 51 adult patients with congenital bicuspid aortic valve: assessment and follow up by Doppler echocardiography. Br Heart J 1993; 69: 23740.