Pulmonic stenosis

Background: Many cardiac and infectious diseases have a seasonal incidence. It is not known whether similar variations exist for endocarditis.

Methods: As echocardiography plays a key role in diagnosing endocarditis, patients referred for echocardiography with suspected endocarditis from 1993 through 2001 were identified. The modified Duke criteria were used in establishing endocarditis. The echocardiography date was arbitrarily used to determine season: fall/winter (October to March) and spring/summer (April to September).

Results: For the 1,279 patients referred for echocardiography to rule out endocarditis, there was no seasonal difference between the total number of referred fall/winter and spring/summer patients (645 patients vs 634 patients, respectively). However, endocarditis was found in 41 fall/winter patients (6.4%) and 19 spring/summer patients (3.0%) patients (odds ratio, 2.20; 95% confidence interval, 1.26 to 3.83; p = 0.004). This seasonal disparity was present in 7 of the 9 years studied. No clinical factors could account for this seasonal disparity.

Conclusions: As with many other cardiac diseases, a significant fall/winter predominance for endocarditis was found.

Key words: echocardiography; infection; seasons; valves

Abbreviations: CI = confidence interval; TEE = transesophageal echocardiography; TTE = transthoracic echocardiography

**********

Many infectious diseases as well as various cardiac problems have a seasonal predominance. Among cardiac problems, a fall/winter excess has been demonstrated for myocardial infarction occurrence and mortality (1-3); stroke mortality (4); congestive heart failure hospitalizations and mortality independent of that from myocardial infarction (5,6); sudden arrhythmic death and malignant ventricular arrhythmias (7-9); atrial fibrillation (10); fatal and nonfatal pulmonary embolism (11-13); and aortic dissection. (14,15) However, little information exists concerning any seasonal variation for endocarditis. This study was undertaken to determine if such a relationship exists.

MATERIALS AND METHODS

This study was performed at a 700-bed, university-affiliated teaching hospital that is also a county hospital serving a moderate-sized Midwestern community (2000 census of 1.4 million people for Cuyahoga County). The study population consisted of all patients referred to the echocardiography laboratory for suspected infectious endocarditis from January 1, 1993, through December 31, 2001, as identified from the institutional echocardiographic database. All of the patients with echocardiographic findings suspicious of endocarditis were selected for chart review. The modified Duke criteria were used in defaming cases of endocarditis. (16,17)

The seasonal classification of endocarditis was determined a priori as occurring in fall/winter (October through March) or spring/summer (April through September), (1,13) as determined by the date of the reference echocardiographic study. For patients in whom endocarditis was excluded, the reference date was that of the first study if multiple studies were performed with negative findings; for patients with endocarditis, the date of the first study with a positive finding was used. The Institutional Review Board approved this study.

Statistics

Variability in the proportion of patients with documented endocarditis compared with those without endocarditis during spring/summer and fall/winter was assessed using [chi square] analysis. Clinical and demographic characteristics were compared using an unpaired t test for continuous variables and Fisher Exact Test or [chi square] analysis where appropriate for categorical variables. For all comparisons, a two-tailed p value < 0.05 was considered statistically significant. Crude odds ratios and 95% confidence intervals (CIs) were calculated for significant findings.

RESULTS

A total of 1,279 patients were referred for 1,463 echocardiographic studies for suspected endocarditis during the 9-year study period (from 1993 to 2001). Transesophageal echocardiography (TEE) was performed in 19% of these studies. A total of 65 patients had echocardiographic findings suggestive of endocarditis. Endocarditis was ultimately excluded in five patients. One patient had a possible mass suggestive of a vegetation on transthoracic echocardiography (TTE) that could not be confirmed on TEE. Three patients had prior healed endocarditis without meeting Duke criteria for recurrence, and another patient had suspicious valvular findings without meeting Duke criteria for probable or definite endocarditis and had a benign clinical course. Of the 60 patients found to have findings consistent with endocarditis, 90% met definite endocarditis and 10% met probable endocarditis by the Duke criteria. These endocarditis patients constituted 4.7% of the total patients initially referred for echocardiographic study to rule out endocarditis. All of the patients undergoing TEE were tested either because of inconclusive TTE studies or because of continued clinical suspicion of endocarditis despite a negative TTE findings (Table 1).

Endocarditis Population

For the 60 patients with endocarditis, the mean age [+ or -] SD was 53 [+ or -] 16 years (range, 22 to 86 years). There were 31 men and 29 women. IV drug abuse was a predisposing factor in 24%. None of the patients had HIV infection. Prosthetic valves were present in 12%. Evidence of intrinsic native valve disease (bicuspid aortic valve, mitral valve prolapse, aortic stenosis, or mitral annular calcification) was present in 22%. Hemodialysis was being performed in 15% of the patients. A long-term indwelling catheter, a pacemaker, or implantable cardioverter-defibrillator wires were present in 17%. Staphylococcus species were the causative organisms in 53% and Streptococcus species in 23%, whereas 12% of the patients remained culture negative. The valves involved included an isolated mitral valve (38%), an isolated aortic valve (32%), an isolated tricuspid valve (13%), and an isolated pulmonic valve (2%). Fifteen percent of patients had multiple valve involvement.

Seasonal Results

There was no difference in the number of patients referred for echocardiographic evaluation of endocarditis in fall/winter compared to spring/summer (645 patients vs 634 patients, respectively). However, 41 patients (6.4%) in fall/winter vs 19 patients (3.0%) in spring/summer were found to have endocarditis (odds ratio, 2.20; 95% CI, 1.26 to 3.83; p = 0.004; Table 1). This seasonal predominance did not change when only those patients meeting definite Duke criteria for endocarditis were used (fall/ winter, 38 patients; spring/summer, 16 patients; odds ratio, 2.42; 95% CI, 1.33 to 4.38; p = 0.003). Further, this seasonal disparity was seen in 7 of 9 study years. The monthly distribution of endocarditis cases is shown in Figure 1.

[FIGURE 1 OMITTED]

Among patients with endocarditis, comparison of those with a diagnosis in fall/winter with those with a diagnosis in spring/summer demonstrated no significant differences with regard to any of the clinical parameters assessed (Table 2). Age (53 [+ or -] 16 years vs 52 [+ or -] 15 years), female gender (44% vs 58%), proportion of diagnoses by TEE (71% vs 63%), IV drug use (22% vs 29%), hemodialysis (17% vs 15%), prosthetic valve involvement (12% vs 10%), valve involved, organism, culture negativity, or vegetation size (largest dimension, 12 [+ or -] 6 mm vs 11 [+ or -] 6 mm) were all similar. There was a slightly greater prevalence of intrinsic native valve disease in the fall/ winter patients compared with the spring/summer patients (26% vs 10%), but this did not reach statistical significance (p = 0.19).

Thirty of these patients (50%) underwent echocardiography prior to the study confirming endocarditis a mean of 13.5 [+ or -] 12.6 days before the study (range, 1 to 41 days). Seventeen of these procedures were either for suspected endocarditis (13 patients, 9.0 [+ or -] 10.2 days before the study) or for reasons that could have been associated with endocarditis (evaluating intrinsic valve disease [n = 2] and cerebrovascular events In = 2], 19.9- 18.3 days before the study). Two of these 30 studies were transesophageal (32 days and 15 days before the study). Using the date of these prior studies without evidence confirming endocarditis as the reference date would have changed the season in only three patients, moving all of them from fall/winter to spring/summer (October or November to September). Accordingly, there would still have been a disproportionate fall/winter preponderance (38 fall/winter and 22 spring/summer cases; odds ratio, 1.74; 95% CI, 1.02 to 2.98; p = 0.04).

DISCUSSION

Our study showed a more than twofold greater fall/winter predominance of endocarditis. No clinical factors were identified that could explain this finding. This greater fall/winter incidence of endocarditis is concordant with the growing list of other cardiac diseases showing a similar seasonal variance and suggests that they might share similar seasonal predisposing factors.

Proposed Mechanisms for Seasonal Disease Occurrence

Numerous physiologic changes have been demonstrated with cold exposure and have been implicated as possible mechanisms for seasonal disease variation. Elevated catecholamine levels (18) are believed to result in an increased heart rate, peripheral vascular resistance, (19) and BP. (20,21) With respect to endocarditis, the resultant increased sheer stress could predispose to endothelial denudation creating the initial nidus for vegetation formation in the presence of bacteremia.

Increased blood thrombogenicity has also been observed with colder temperatures. (22) Plasma volume is reduced, platelet aggregability is increased, and clotting factors such as fibrinogen are increased independent of evidence of infection. (23) This would make any nidus for thrombus formation during bacteremia more likely to lead to vegetations.

Seasonal respiratory co-infection may also be a contributing factor. This would not only further elevate catecholamines but could increase blood thrombogenicity. Many of the clotting factors such as fibrinogen are also acute phase reactants and would change with seasonal viral or chlamydial respiratory infection. (24)

Seasonal endocrine changes could also have immunologic consequences. Cold exposure has been shown to alter adrenal function. (25) Furthermore, the role of shortened daylight, via the pineal gland, has been proposed as an additional factor contributing to adrenocortical modulation. (26,27)

Role of Echocardiography

Unlike other cardiac diseases demonstrating a seasonal variation, in which a time of onset can be determined from a thorough history, endocarditis is of more insidious occurrence even when of more acute onset. Therefore, another dating marker was used. As the findings of a valvular vegetation or perivalvular abscess are major criteria in the diagnosis of endocarditis, the date of finding these or their exclusion by echocardiography was used. Practically, the date of echocardiography reflected when endocarditis was entertained as a clinical diagnosis. Echocardiograms were routinely obtained within 48 h of being ordered.

Our study demonstrated a low incidence of endocarditis, with only 5% of those suspected of having endocarditis demonstrating suggestive echocardiographic findings. This is concordant with the low yield in other institutions and might suggest an overuse of echocardiography in this setting. (28,29) As echocardiography has become a key diagnostic test for endocarditis, this should not be surprising; it has assumed the role of an endocarditis screening test in febrile or bacteremic patients.

Although the total number of patients initially studied to rule out endocarditis was the same between seasons, the clinical suspicion likely remained higher in the fall/winter patients than in the spring/ summer patients as reflected by our greater seasonal use of TEE. In our institution, TEE has rarely been used as the first echocardiographic test unless there is known underlying intrinsic valvular disease, a prosthetic valve, or the pretest clinical suspicion of disease is high. Others have validated this approach as a reasonable diagnostic strategy. (30,31) Thus, it is unlikely that the greater fall/winter usage of TEE in our population led to a larger number of patients found to have endocarditis in the absence of a true seasonal variation. Rather, this suggests a higher pretest clinical suspicion of endocarditis. It is unclear how the performance of routine TEE in all suspected endocarditis patients, regardless of pretest probability, would change our results.

Limitations

Cases of endocarditis were identified by the presence of abnormal echocardiographic findings, which could have introduced a bias and an underrepresentation of actual endocarditis cases. However, our results remain valid when echocardiographic findings are instrumental in confirming endocarditis. No patients undergo valvular surgery without an antecedent echocardiogram, and it is rare for patients dying without having at least one echocardiogram. Thus, first diagnosis at surgery or autopsy is unlikely. Identifying patients by echocardiography could further bias to those patients with larger vegetations and more severe disease. As our study was small, this would preclude meaningful subanalysis looking for less striking clinical associations with seasonal variations of endocarditis. Lastly, as our results reflect the findings of one institution, they are subject not only to regional but also to institutional referral bias and should stimulate further confirmation.

Potential Importance

The demonstration of a seasonal pattern in many cardiac diseases has opened new opportunities for understanding their pathophysiologic mechanisms and potentially helps in disease prevention. The seasonal occurrence of endocarditis demonstrated by the present study could lead to similar improvements in our understanding and prevention of this disease.

Manuscript received September 19, 2003; revision accepted May 18, 2005.

REFERENCES

(1) Marchant B, Ranjadayalan K, Stevenson R, et al. Circadian and seasonal factors in the pathogenesis of acute myocardial infarction: the influence of environmental temperature. Br Heart J 1993; 69:385-387

(2) Ornato JP, Peberdy MA, Chandra NC, et al. Seasonal pattern of acute myocardial infarction in the National Registry of Myocardial Infarction. J Am Coll Cardiol 1996; 7:1684-1688

(3) Spencer FA, Goldbert RJ, Becker RC, et al. Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction. J Am Coll Cardiol 1998; 31:1226-1233

(4) Sheth T, Nair C, Muller J, et al. Increased mortality from acute myocardial infarction and stroke: the effect of age. J Am Coll Cardiol 1999; 33:1916-1919

(5) Boulay F, Berthier F, Sisteron O, et al. Seasonal variation in chronic heart failure hospitalizations and mortality in France. Circulation 1999; 100:230-286

(6) Stewart S, McIntyre K, Capewell S, et al. Heart failure in a cold climate: seasonal variation in heart failure-related morbidity and mortality. J Am Coll Cardiol 2002; 39:760-766

(7) Arntz HR, Willich SN, Schreiber C, et al. Diurnal, weekly mad seasonal variation of sudden death: population-based analysis of 24,061 consecutive cases. Eur Heart J 2000; 21:315-320

(8) Peckova M, Fahrenbruch CE, Cobb LA, et al. Weekly and seasonal variation in the incidence of cardiac arrests. Am Heart J 1999; 137:512-515

(9) Fries RP, Heisel AG, Jung JK, et al. Circannual variation of malignant ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators and either coronary artery disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1997; 79:1194-1197

(10) Kupari M, Koskinen P. Seasonal variation in occurrence of acute atrial fibrillation and relation to air temperature and sale of alcohol. Am J Cardiol 1990; 15:1519-1520

(11) Colantonio D, Casale R, Lorenzetti G, et al. Chrono-risks in the episodes of fatal pulmonary embolism. G Clin Med 1990; 71:56:3-567

(12) Gallerani M, Manfredini R, Ricci L, et al. Sudden death from pulmonary thromboembolism: chronobiological aspects. Eur Heart J 1992; 13:661-665

(13) Sharma GVRK, Frisbie JH, Tow DE, et al. Circadian and circannual rhythm of nonfatal pulmonary embolism. Am J Cardiol 2001; 87:922-924

(14) Sumiyoshi M, Kojima S, Arima M, et al. Circadian, weekly, and seasonal variation at the onset of acute aortic dissection. Am J Cardiol 2002; 89:619-620

(15) Mehta RH, Manfredini R, Hassan F, et al. Chronobiological patterns of acute aortic dissection. Circulation 2002; 106: 1110-1115

(16) Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med 1994; 96:200-209

(17) Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30:633-638

(18) Westheim A, Os I, Thaulow E, et al. Haemodynamic and neurohumoral effects of cold pressor test in severe heart failure. Clin Physiol 1992; 12:95-106

(19) Izzo JL, Larrabee PS, Sander E, et al. Hemodynamics of seasonal adaptation. Am J Hypertens 1990; 3:405-407

(20) Minami J, Kawano Y, Ishimitsu T, et al. Seasonal variations in office, home and 24h ambulatory blood pressure in patients with essential hypertension. J Hypertens 1996; 14:1421-1425

(21) Woodhouse PR, Khaw K-T, Plummer M. Seasonal variation of blood pressure and its relationship to ambient temperature in an elderly population. J Hypertens 1993; 11:1267-1274

(22) Kawahara J, Sano H, Fukuzaki H, et al. Acute effects of cold exposure to cold on blood pressure, platelet function and sympathetic nervous activity in humans. Am J Hypertens 1989; 2:724-726

(23) Crawford VLS, Sweeney O, Coyle PV, et al. The relationship between elevated fibrinogen and markers of infection: a comparison of seasonal cycles. Q J Med 2000; 93:745-750

(24) Woodhouse PR, Khaw KT, Plummer M, et al. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease. Lancet 1994; 343:435-439

(25) Hiramatsu K, Yamada T, Katakura M. Acute effects of cold on blood pressure, renin-angiotensin-aldosterone system, catecholamines and adrenal steroids in man. Clin Exp Pharmacol Physiol 1984; 1:171-179

(26) Zhang Z, Inserra PF, Liang B, et al. Melatonin, immune modulation and aging. Autoimmunity 1997; 26:43-53

(27) Pierpaoli W. Neuroimmunomodulation of aging: a program in the pineal gland. Ann N Y Acad Sci 1998; 840:491-497

(28) Kuruppu JC, Corretti M, Mackowiak P, et al. Overuse of transthoracic echocardiography in the diagnosis of native valve endocarditis. Arch Intern Med 2002; 162:1715-1720

(29) Greaves K, Mou D, Patel A, et al. Clinical criteria and the appropriate use of transthoracic echocardiography for the exclusion of infective endocarditis. Heart 2003; 89:273-275

(30) Lindner JR, Case RA, Dent JM, et al. Diagnostic value of echocardiography in suspected endocarditis: an evaluation based on the pretest probability of disease. Circulation 1996; 93:730-736

(31) Irani WN, Grayburn PA, Alfridi I. A negative transthoracic echocardiogram obviates the need for transesophageal echocardiography in patients with suspected native valve active infective endocarditis. Am J Cardiol 1996; 78:101-103

Robert S. Finkelhor, MD; Grace Cater, MD; Amir Qureshi, MD; Douglas Einstadter, MD, Michelle T. Hecker, MD; and Georgene Bosich, RN

* From the Case Western Reserve University at MetroHealth Medical Center, Cleveland, OH.

Correspondence to: Robert S. Finkelhor, MD, Heart and Vascular, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109; e-mail: rfinkelhor@metrohealth.org

COPYRIGHT 2005 American College of Chest Physicians
COPYRIGHT 2005 Gale Group