Complex Arrhythmias in Mitral Regurgitation With and Without Mitral Valve Prolapse: Contrast to Arrhythmias in Mitral Valve Prolapse Without Mitral Regurgitation PAUL KLIGFIELD, MD, CLARE HOCHREITER,MD, HARVEY KRAMER, MD, RICHARD B. DEVEREUX, MD, NATHANIEL NILES, MD, RANDI KRAMER-FOX, MS, and JEFFREY S. BORER, MD
Atrial and ventricular arrhythmias were characterized by ambulatory electrocardiography in 31 patients with nonischemic mitral regurgitation (MR), 17 of whom had echocardlographlc evidence of mitral valve prolapse (MVP) and 14 of whom had other causes of MR. Frequent and complex arrhythmias were common and equally prevalent in each MR subgroup, whether or not MVP was present. Multiform ventricular ectopy was found in 77 % (24 of 31), ventricular couplets in 61% (19 of 31), and ventricular salvos or ventricular tachycardia in 35 % (1 i of 31) of pattents with MR. Arrhythmias in patients with MR were significantly more prevalent than in 63 patlents with MVP who
had no evidence of MR. Among patients with MVP, excess arrhythmias associated with MR were most striking with respect to frequent ventricular premature complexes (41% with MR vs 3 % without MR), muttiform ventricular ectopic activity (66 % vs 43%), ventricular couplets (65% vs 6%), and ventricular salvos or ventricular tachycardia (35 % vs 5 % ) (p <0.005 for each comparison). These data demonstrate that complex arrhythmias are common in patients with nonischemic MR irrespective of etiology, and that these arrhythmias are more strongly associated with hemodynamically important MR than with MVP alone. (Am J Cardiol 1965;55:1545-1549)
Although arrhythmias are commonly observed in patients with mitral regurgitation (MR),l their potential significance has not been explored and quantification of ambulatory rhythm abnormalities has not been performed in MR subgroups stratified for underlying etiology. Ventricular arrhythmias may be related to mortality in medically treated patients2 or to postoperative sudden deaths in patients who have undergone mitral valve replacement, since recognition of a small subset of patients with primary valvular disease among survivors of prehospital cardiac arrest4y5 suggests that these arrhythmias are not necessarily benign.
Interpretation of arrhythmia prevalence data from patients with nonischemic MR is limited by the common occurrence of arrhythmias in patients with mitral valve prolapse (MVP) ,s-le who contribute importantly to the MR population. l1 It is thus unclear whether the high prevalence of rhythm disorders observed among patients with MR might be more related to the presence of MVP, the presence of MR, or the combined effect of both disorders. Therefore, to determine the prevalence of arrhythmias in nonischemic MI3 and to determine the influence of etiology on these arrhythmias, we quantified and compared atrial and ventricular arrhythmias detected by ambulatory electrocardiography in subgroups of patients with MR due to MVP, MR not due to MVP, and MVP alone.
From the Division of Cardiology, Department of Medicine, New York Hospital-Ccfnell Medical Center, New York, New York. This study was supported in part by Grants ROl HL-25604 and HL-22006 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received November 13, 1984; revised manuscript received February 19, 1985, accepted February 20,1985. Address for reprints: Paul Kligfield. MD, Division of Cardiology, The New York Hospltal-Comell Medlcal Center, 525 East 68th Street, New York, New York 10021.
Methods Study population: The study population consists of 94 patients who are foIlowed as members of 2 larger ongoing prcepective evaluations of patients with MR and patients with MVP. Included are 31 patients with hemodynamically important nonischemic MR, of whom 17 had echocard?ographic 1545
ARRHYTHMIAS IN MITRAL REGURGITATION
TABLE I Geometric and Functional Characteristics of Subgroups Determined by Echocardiography and Radionuclide Cineangiography A MR Without MVP (n = 14)
Age W) Functional class (% NYHA Ill-IV) Left atrial diameter
LV Internal dimension diastole (cm) Fractional shortening (%) Rest LV ejection fraction (%)
(A y”, 8)
B MR With MVP (n = 17)
57 f 4 26-76 43% 21%
5.0 f 0.3
4.8 f 0.3
5.8 f 0.2
:z : 3::
50 f 4 YiG2
(B ,“, C)
C MVP Without MR (n = 63) 43 f 2 19-66 70% 0%
3.0 f 0.1
6.2 f 0.2
5.0 f 0.1
38 f 1.7 49 f 1.7
38 f 1.0 NA
LV = left ventricular; MR = mitral regurgitation; MVP = mitral valve prolapse; NA = not available; NS = not significant.
evidence of MVP and 14 had no clinical or echocardiographic evidence of MVP (4 patients with rheumatic mitral disease, 3 with ruptured chordae, 1 patient with infective endocarditis and 6 of unknown etiology). Also included are 63 patients with echocardiographic evidence of MVP without clinical or echocardiographic evidence of hemodynamically important MR. Clinical details of this MVP subgroup were recently reported in detail.12 None of the 94 patients had clinical evidence of ischemic heart disease and none had findings of additional mitral stenosis or aortic valve disease. Clinical characteristics of patient subgroups are listed in Table I. Patients with MR without MVP were older than patients who had MVP without MR, but age differences between MR subgroups with and without MVP, and MVP subgroups with and without MR, were not significant. In contrast to the patients with MR, patients with MVP without MR tended to be predominantly female, although differences among subgroups were not statistically significant (Table I). Catheterization was performed in 15 of the 31 patients with MR and in each confirmed the clinical diagnosis of grade 3+ or 4+ MR. Among the other 16 patients, estimation of the presence and severity of MR was based on clinical evaluation and echocardiography. Digitalis was being taken by 3% of the patients with MR at the time of evaluation, including 29% (5 of 17) of patients with, and 50% (7 of 14) of patients without, associated MVP. Only 1 patient with MR, who had underlying MVP, was taking a type 1 antiarrhythmic drug. Digitalis was being taken by 11% (7 of 63) of patients with MVP without important MR at the time of evaluation. None of these patients were taking diuretics, 8% (5 of 63) were taking type 1 antiarrhythmic drugs, and 24% (15 of 63) were taking @blocking drugs at the time of evaluation. Stratification of patient subgroups according to drug use was performed and an analysis of potential drug effects on study findings is presented in the results. Echocardiography and radionuclide cineangiography: All patients underwent M-mode and 2-dimensional echocardiography. MVP was defined when continuous echocardiographic interfaces representing the mitral valve leaflets demonstrated both posterior systolic motion and movement of at least 2 mm behind the line connecting the C-D points.13 With these M-mode criteria, the diagnosis of MVP in our laboratory is 95% reproducible.14 Two-dimensional echocardiograms were examined for MVP when M-mode recordings were not conclusive. Radionuclide cineangiograms for determination of left ventricular ejection fraction were performed at rest in all patients with MR according to methods similar to those w; previously reported.15J6
Ambulatory electrocardiography: Two-channel, continuous ambulatory electrocardiograms were recorded in all patients using modified CM1 and CM5 leads and were scanned on an Avionics Trendsetter@. Supraventricular rhythm evaluation included quantification of the mean number of atrial premature complexes per 1,000 total beats, peak density of atria1 premature complexes per 1,000 beats and qualitative tabulation of atrial couplets, paroxysmal atrial tachycardia and atrial flutter or atria1 fibrillation. Ventricular rhythm evaluation included quantification of mean number of ventricular premature complexes per 1,000 total beats, peak density of ventricular premature complexes per 1,000 beats and qualitative tabulation of ventricular complexity by the Lown classification17J8 to include grades 3 (multiform ventricular premature complexes), 4A (ventricular couplets), 4B (ventricular salvos or ventricular tachycardia), and 5 (earlycycle ventricular complexes). A mean ventricular premature complex density of lO/l,OOOor greater was used to partition ventricular ectopic frequency grades 1 and 2. Statistical methods: Mean values are presented with the standard error of the mean as the index of dispersion. The unpaired Student t test was used to test the statistical significance of differences between means in our subgroups, and the chi-square test with Yates’ continuity correction was used for the comparison of proportions. Simple log transformation was used for the t test comparison of data with nonparametric distribution, including mean and peak densities of atrial and ventricular premature complexes. Differences with p values exceeding 0.05 were not accepted as significant.
Results Arrhythmias in mitral regurgitation: Atria1 and ventricular arrhythmias were both frequent and complex in patients with MR. Prevalence data according to etiology are listed in Table II and are illustrated in Figures 1,2 and 3. All patients with MR, regardless of etiology, had ventricular premature complexes. Among the total MR population, frequent ventricular premature complexes, exceeding a mean of 10 per 1,000 beats, were observed in 42% (13 of 31), 77% (24 of 31) had multiform ventricular ectopy, 61% (19 of 31) had ventricular couplets, and 35% (11 of 31) had ventricular salvos or ventricular tachycardia. When ventricular arrhythmias in patients with MR were ranked according to peak Lawn grade, 32% had peak grade 4A and an additional 29% had peak grade 4B complexity.
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100 FIGURE 1. Group prevalence of ventricular arrhythmias in patients with mitral regurgitation (MR) without mitral valve prolapse (MVP), MR with MVP, and MVP without MR. Each patient must be represented once in the appropriate mean ventricular premature complex (VPC) density category and may also be represented in as many VPC complexity categories as are applicable. The numbers along the horizontal axis refer to the corresponding Lown cornplexity category. However, in this display arrhythmias are represented according to actual prevalence rather than according to mutually exclusive hierarchy of complexity. VT = ventricular tachycardia.
q q q
75 Group prevalence (%)
MR, no MVP b-t=141 MVP, with MR (n=17) MVP, no MR (n=63)
q q Group prevalence (%)
MR,noMVP(n=14) MVP, with MR (n=17) MVP, no MR (n=63)
FIGURE 2. Peak grading of ventricular arrhythmias in patients with mitral regurgitation (MR) with and without mitral valve prolapse (MVP) and in MVP alone. In this display, each patient is represented only once, in the highest applicable Lown grade. Abbreviations as in Figure 1.
50 p<.oos -
p < ,025
FIGURE 3. Group prevalence of atrial arrhythmias in patients with mitral regurgitation (MR) with and without mitral valve prolapse (MVP) and in MVP alone. Each patient must be reprs sented once in the appropriate mean atrfal prematwe complex (APC) density category and may also be represented in as many APC complexity categories as are applicable. The group prevalence data for APC couplets and atrial tachycardia excludes patients with atria1 fibrillation (AF). PAT = paroxysmal atrial tachycardia.
q q q
MR, no MVP (n=l4) MVP, with MR (n=17) MVP,
no MR (n=63)
Prevalence of Arrhythmias Without Regurgitation
in Mitral Regurgitation,
MR Without MVP (n = 14)
With and Without MR With MVP (n = 17)
P (A vs B)
Mitral Valve prolapse,
and ln Mitral prolapse
MVP Without (n = 63)
MR (C ,“, A)
VP~ofrec&ncy Mean lO/l,OOO APC complexity APC couplets Atrial tach Atrial fibrillation
0%(0/14) 57%(8/14) 43%(6/14) 64%(9/14) 57%(8/14) 36%(5/14) 7%(1/14) 0%(0/14) 29%(4/14) 0%(0/14) 7%(1/14) 29%(4/14) 29%(4/14) 7%(1/14)
% NS 2 NN:
0%(0/17) 59%(10/17) 41 o/0(7/17) 88%(15/17) 65%(11/17) 35%(6/17) 6%(1/17)
37 % (23163) 60 % (38163) 3%(2/63)
%%5” <0.005 NS
43%(27/63) 6%(4/63) 5%(3/63) 2%(1/63)
0%(0/17) 6%(1/17) 0%(0/17) 24%(4/17) 35%(6/17) 29%(5/17) 6%(1/17)
33%(4/12) 58%(7/12) 8%(1/12)
0%(0/12) 75%(9/12) 25%(3/12)
50%(6/12) 50%(6/12) 14%(2/14)
58%(7/12) 50%(6/12) 29%(5/17)
APC = atrial premature complex; MR = mitral regurgitation; ventricular premature complex; VT = ventricular tachycardia.
MVP = mitral
Atrial arrhythmias also were common in patients with MR. Atria1 premature complexes more frequent than 10 per 1,000 beats were observed in 17% (4 of 24) of patients in sinus rhythm, 54% (13 of 24) had atria1 couplets, and 50% (12 of 24) had brief bursts of atria1 tachycardia. Sustained atrial fibrillation was present in 23% (7 of 31) of patients with MR. Effect of etiology on arrhythmias in mitral regurgitation: Mean atrial and ventricular premature complex frequencies in MR were not related to the presence or absence of underlying MVP (Table II). Similarly, subgroup prevalences of atrial and ventricular complexity and peak Lown grade complexity were not related to the etiology of MR. Effect of mitral regurgitation on arrhythmias in mitral valve prolapse: Patients with MVP who had hemodynamically important MR had more frequent and more complex atria1 and ventricular arrhythmias than did patients with MVP alone (Table II). Most strikingly, peak Lown grades 4A or 4B occurred in 65% (11 of 17) of patients with MVP who had MR, but in only 8% (5 of 63) of patients with MVP alone (p <0.005). Sustained atria1 fibrillation was present in 29% (5 of 17) of MVP patients with MR, but in none with MVP alone (p <0.005). Similarly, patients with MR not due to MVP had significantly more frequent and more complex atrial and ventricular arrhythmias than did patients with MVP without MR (Table II). Relation of drugs to arrhythmia complexity: Among the 31 patients with MR, 12 were taking digitalis and 14 were taking diuretic drugs at the time of evaluation. Complex ventricular arrhythmias (ventricular couplets or tachycardia) were present in 83% (10 of 12) of patients with MR taking digitalis and in 47% (9 of 19) not taking digitalis. This trend does not reach statistical significance (p >O.lO). Complex ventricular arrhythmias
2 p; IiS
NS = not significant;
37 % (23/63) 21%(13/63) 0%(0/63) 33%(21/63) 3%(2/63) 5%(3/63) 2%(1/63)
CO.025 N”: <:0”1 <0.025 NS
19%(12/63) 79%(50/63) 2%(1/63)
30%(19/63) 32%(20/63) 0%(0/63)
were present in 71% (10 of 14) of patients with MR who were taking diuretics and in 53% (9 of 17) who were not. This trend is also not statistically significant. In contrast, only 8% (5 of 63) of patients with MVP had complex ventricular arrhythmias, significantly less than any drug-stratified subset with important MR. Discussion These data demonstrate that patients with MR have a high prevalence of frequent and complex atria1 and ventricular arrhythmias. Arrhythmias occur with similar frequency in patients who have MVP as the underlying cause of MR and in patients with MR due to rheumatic or other etiology, when comparable atria1 and ventricular dimensions and comparable ventricular performance are present. These data further indicate that complex arrhythmias in patients with MVP are more closely associated wtih the presence of hemodynamically important MR than with MVP itself. Arrhythmias in mitral regurgitation: Few data are available concerning the prevalence, clinical correlates and prognostic value of atria1 and ventricular arrhythmias in patients with hemodynamically important MR.’ Among observational studies that bear on the significance of arrhythmias in heterogeneous populations, ventricular premature complexes were not significantly related to mortality in a small group of patients with valvular disease followed at the Lahey Clinic.lg However, arrhythmias in that series were detected by routine electrocardiography rather than by ambulatory recording, the patient groups were small, and the disease was not specifically classified according to individual valve lesions. On the other hand, recognition of a small subset of patients with primary valvular disease among survivors of prehospital cardiac arrest4*5 suggests that arrhyth-
June 1, 1985
mias in these patients may bear on mortality. When both patient subgroups with MR in our series are combined, nearly one-third have ventricular premature complex couplets and more than one-fourth have ventricular salvos or ventricular tachycardia as their peak Lown classification. These arrhythmias are associated with sudden death in other ischemic20 and nonischemic21 populations. However, arrhythmias are generally associated with mortality when myocardial performance is poor.21p22 Whether complex arrhythmias in MR are markers for important ventricular dysfunction or for death requires further investigation. Etiology and arrhythmia prevalence in mitral regurgitation: MVP is emerging as the most important cause of clinically important pure MR, having been found in nearly two-thirds of patients undergoing mitral valve replacement in a 13 year series reported by Waller et al.” Our data are consistent with this distribution. Despite differences in etiology, however, arrhythmias are remarkably similar in patients with MR of comparable hemodynamic degree. This suggests that the myocardial response to abnormal loading, rather than specific structural changes, may be important in arrhythmogenesis in MR. Arrhythmias in mitral valve prolapse: The prevalence of atria1 and ventricular arrhythmias among our patients with MVP without MR12 is comparable with findings in the ambulatory MVP population in Framingham by Savage et al6 Ventricular arrhythmias in our MVP subgroup are slightly less frequent and less complex than among those patients with MVP reported by DeMaria et al7 and by Winkle et al.$ Although no significant excess ventricular arrhythmias were associated with MR detected by ventriculography in the patients studied by DeMaria et al,7 this subset was small and was not reported in detail. The effect of MR was not specifically addressed by Winkle et al8 Minor additional difkr~~~~s in arrhythmia prevalence among these studies may be explained by variations in patient selection, symptom status and duration of ambulatory recording22 as well as by the possible effect of adding variable numbers of patients with MR into observations on MVP. Associated MR was not specifically addressed by Wei et a1,g whose 10 MVP patients with malignant arrhythmias clearly represent a highly selected subset of the general MVP population. Effect of drugs on arrhythmia prevalence: The higher prevalence of complex ventricular arrhythmias observed in patients with MR who were taking digitalis compared with those not taking digitalis did not reach statistical significance. Moreover, this trend most likely reflects more severe hemodynamic compromise in these patients rather than drug effect, since Gradman et a123 recently demonstrated a reduction in ventricular ectopy in patients taking digoxin when left ventricular function is normal but less effect in patients with depressed left ventricular performance. The presence of chronic atrial fibrillation in 7 patients of our digitalis subgroup suggests increased left atria1 pressure or diameter as a consequence of more severe MR. Similarly, administration of diuretic drugs24 does not explain the higher prevalence of complex ventricular arrhythmias among our patients with MR: The preva-
lence of complex arrhythmias among patients with MR not taking these drugs was not significantly reduced and remained markedly higher than that found among our patients with MVP alone. It is unlikely that the prevalence of complex arrhythmias among our patients with MVP has been spuriously reduced or increased by treatment with type I antiarrhythmic drugs or with P-blocking drugs, because the prevalence of arrhythmias in our unmedicated patients is not significantly different and because, in addition, the observed prevalence of arrhythmias in patients with MVP in the present study compares closely with that in a random unselected sample of unmedicated MVP subjects detected in the Framingham study.6 References 1. Brlgden
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