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Home , Pulmonary heart disease

in Primary

Nariaki KANEMOTO,M.D. and Hiroshi SASAMOTO,M.D.

SUMMARY Through the examination of 171 electrocardiograms (ECG) of 101 patients with primary pulmonary hypertension (PPH), the following con- clusions were obtained. Arrhythmias were found in 27 (26.7%) of the 101 patients. Among the surviving cases, arrhythmias were found in 8 (17.8%) out of 45 pa- tients, but among the deceased cases, the figure was higher, 19 (33.9%) out of 56. There were instances of more than one kind of arrhythmias in the same patient and a total of 34 types of arrhythmias were noted. The main types of arrhythmias were sinus (13 cases), sinus (6 cases), and first degree A-V block (5 cases), which ac- counted for 70% of the total. was observed in only 2 of the survivors but in 11 of the deceased cases, which showed a sig- nificant difference (p<0.05). First degree A-V block were all induced by . Wenckebach type of second degree A-V block was noted in only 1 case and it was also induced by digitalis. Since severe attacks of ventricular arrhythmias were very rare in these cases with PPH, it is difficult to consider the Adams-Stokes syndrome as the cause of syncopal attacks or sudden death. However, it is necessary to further investigate nodal functions by means of continuous ECG monitoring, the overdrive suppression test and His bundle ECGs. Additional Indexing Words: Syncopal attacks Adams-Stokes syndrome Major supraventricular arrhythmias Ventricular arrhythmias Sudden death

N the cases of primary pulmonary hypertension (PPH), the major subjec- I tive symptoms are palpitation, dyspnea, and syncope, and there have also been many cases of sudden death.1) Since there is a possibility that these symptoms occur because of electrical failure, electrocardiographic examina- tions should be done. The authors have already reported various electro- cardiographic findings except those concerning arrhythmias.2) Therefore, this paper deals with an investigation of arrhythmias in PPH.

From the Department of Internal , School of Medicine, Tokai University , Boseidai, Isehara, Kanagawa 259-11, Japan. This study was supported in part by a Research Grant from the Intractable Diseases Division , Bureau, Ministry of Health and Welfare, Japan. Received for publication February 21, 1979. Manuscript revised March 23, 1979. 765 Jap. J. 766 KANEMOTO AND SASAMOTO November, 1979

Table I. Proposed Guideline for the Diagnosis of Primary Pulmonary Hypertension

Primary pulmonary hypertension is a clinical diagnostic name of pulmonary hypertension of

unknown cause.

It is required:

To confirm pulmonary arterial (pre-capillary) hypertension and/or right ventricular hy-

pertrophy due to pulmonary hypertension. To ascertain that the pulmonary hypertension is to be primary.

A. Symptoms and signs that suggest pulmonary arterial hypertension and/or right ventricular

hypertrophy:

I. Cardinal symptoms and signs

1. dyspnea

2. easy fatigability

3. retrosternal pain (pulmonary hypertensive pain) or syncope on exertion

4. right ventricular heave

5. accentuation of P2 and S4, diastolic murmur at pulmonic area, systolic regurgitant

murmur at tricuspid area

II. Laboratory data

1. prominence of the central pulmonary artery trunk and decreased peripheral pul-

monary vasculature on chest roentgenograms

2. right on electrocardiogram

3. normal or slightly disturbed restrictive ventilatory function (almost normal SaO2)

4. right heart catheterization

i) increased pulmonary arterial pressure (mean pressure is 25mmHg or more)

ii) normal pulmonary capillary wedge pressure (12mmHg or less)

5. increased 'a' wave in

B. Procedure suggesting that pulmonary hypertension is to be primary:

There are some cases of primary pulmonary hypertension that show increased rate of

erythrocyte sedimentation rate, increased value of ƒÁ-globulin, immunological disorders,

rarely arthritis, Raynaud's phenomenon and splenomegaly.

After recognizing no existence of primary or congenital cardiopulmonary disease, and

complication of liver cirrhosis, the following histological changes should be observed:

III. Histological findings

Pulmonary vascular lesions that show medial hypertrophy, concentric intimal fibrosis,

necrotizing arteritis, and plexiform lesions.

IV. Diseases to be excluded

Since the following diseases may cause pulmonary hypertension succeeded by right

ventricular hypertrophy, it is necessary to exclude:1

. Diseases primarily affecting air passage of the and the alveoli

chronic bronchitis, bronchial asthma, emphysema, pulmonary fibrosis and pneu-

monitis of various origins, pulmonary granulomatosis (e.g. , berylliosis,

histiocytosis, tuberculosis), collagen diseases, infectious diseases of the lung, malig-

nant tumors of the lung, alveolar microlithiasis, congenital cystic disease of the

lung, pulmonary resection, of severe degree (e.g. mountain sickness and

chronic obstructive diseases of upper respiratory airway.)

(Continued to the next page) Vol.20 No.6 ARRHYTHMIAS IN PRIMARY PULMONARY HYPERTENSION 767

(Continued) 2. Diseasesprimarily affecting the movementsof the thoraciccage kyphoscoliosisand other thoracicdeformities, thoracoplasty, pleural fibrosis, chronic neuromuscularweakness (e.g. poliomyelitis),obesity with alveolar hypoventilation, idiopathicalveolar hypoventilation. 3. Diseasesprimarily affecting the pulmonaryvasculature pulmonarythromboembolism, collagen diseases, and other arteritis, schistosomiasis, sicklecell anemia,pressures on main pulmonaryarteries and veinsby mediastinal tumors,aneurysm, granuloma or fibrosisand pulmonaryveno-occlusive disease. 4. Diseasesprimarily affecting the left valvular heart diseases(especially mitral stenosis)and left . 5. Congenitalheart diseases atrial septal defect, ventricularseptal defect, patent ductusarteriosus and others. [Criteria for the diagnosis] 1. Definitecase To meet items more than half of I and II, and conditionsof III and IV. 2. Probablecase To meet items more than half of I and II, and condition of IV but without histologicalexamination.

SUBJECTSAND METHODS The subjects used in this study were 101 cases of PPH with 171 electrocardio- grams (ECGs). The ECG copies were obtained from hospitals throughout Japan which had reported these cases. These 101 cases included 28 males (of whom 16 have died) and 73 females (of whom 40 have died) ranging in age from 9 to 66 years with a mean age of 30.8 years. By the time of this study, living patients survived 12 to 96 months with an average of 30.5 months. In the dead patients, causes of death were clarified in 38 patients, among which 23 (60.5%) died of right heart failure, 12 (31.6%) died suddenly, 2 died of massive hemoptysis, and 1 pneumonia. These patients died 1 day to 24 months with an average of 7.2 months after the recording of ECGs. The ECGs were obtained with the standard 12 leads, a paper speed of 25 mm/sec and a sensitivity of 1mV=10mm or 5mm. In most cases, there were recordings of 5 to 10sec per lead. These ECGs were investigated for arrhythmias in all of the patients and in the surviving and the deceased groups. Among 32 patients, 2 to 7 ECGs for each patient were obtained but the same found in the same case was counted as only one. The diagnosis of PPH was made independently in each hospital in accordance with the proposed guideline for the diagnosis of PPH by the Ministry of Health and Welfare PPH Research Committee.2)

RESULTS Out of the 101 subjects, 27 (26.7%) were found to have some type of arrhythmia. In the surviving group, there were only 8 out of 45 cases (17.8%) Jap. Heart J. N 768 KANEMOTO AND SASAMOTO ovember, 1979

Table II. Occurrence of Arrhythmias

Table III. Types of Arrhythmias

*p<0 .05 with arrhythmias, while in the deceased group, there were many more cases of arrhythmias, 19 out of 56 (33.9%). There were instances where arrhyth- mias occurred more than once in the same patient and the total number of incidence of arrhythmias was 34 (Table II). Table III shows the types and frequencies of the arrhythmias. There were 13 cases with sinus tachycardia (R-R interval of 0.48 to 0.59sec) in- cluding 11 of the deceased cases which was a significant majority (p<0.05). Fig. 1 shows the ECG of a 35-year-old female who came to the hospital suffering mainly from dyspnea and anasarca. This patient died of right heart failure 2 months later. Therefore, it appears that sinus tachycardia seen in cases of PPH is often caused by right heart failure and is an ominous sign of poor prognosis. Conversely, (R-R interval of 1.04 to 1.32sec) was observed in 6 cases, most of them survived. Fig. 2 shows the ECG of a 24- year-old male who survived. There are atrioventricular (A-V) junctional escaped beats due to sinus bradycardia and arrhythmia. First degree A-V block was found in 5 cases, 4 of them died. All of Vol.20 No.6 ARRHYTHMIAS IN PRIMARY PULMONARY HYPERTENSION 769

Fig. 1. Electrocardiogram (H.S., 35 years old, female) showing sinus tachycardia at a rate of 104 beats per minute.

Fig. 2. Electrocardiogram (H.O., 24 years old, male) showing sinus bradycardia and occasional A-V junctional escaped beats (with the courtesy of Prof. Dr. Hara). Jap. Heart J. N 770 KANEMOTO AND SASAMOTO ovember, 1979 these cases were given digitalis for right heart failure. The PQ interval was 0.22 to 0.30sec. Second degree A-V block was seen in only 1 case. Fig. 3 (A) shows the ECG of a 32-year-old female on digitalis and for right heart failure. Sinus tachycardia and Wenckebach type of second degree A-V block were found. The second degree A-V block disappeared 10 days after the reduction of digitalis (Fig. 3 (B)). Atrial and were observed in 1 case each. Premature beats, however, were rare. Supraventricular premature beats were found in only 3 cases and ventricular premature beats in only 1 case. Fig. 4 shows the ECG of a 41-year-old female with frequent supraven- tricular premature beats causing parasystole and a ventricular premature beat.

Fig. 3. (A) Electrocardiogram (M.K., 32 years old, female) showing second degree A-V block (Wenckebach type). Vol.20 ARRHYTHMIAS IN PRIMARY PULMONARY HYPERTENSION 771 No.6

Fig. 3 (B). Electrocardiogram taken 10 days later, showing sinus rhythm with digitalis induced ST-T changes.

Fig. 4. Electrocardiogram (H.U., 41 years old, female) showing su- praventricular parasystole and occasional ventricular premature beats (with the courtesy of Dr. Mizutani). NJap. Heart J. 772 KANEMOTO AND SASAMOTO ovember, 1979

DISCUSSION Previously, arrhythmias observed in chronic lung disease have been re- ported both as being rare and as being comparatively common.3)-10) This difference in opinion can be due to the following different conditions: (1) underlying diseases, (2) age of the patient, (3) duration of the disease, (4) severity, (5) complications, and (6) method used for the detection of ar- rhythmias. In great majority of the cases, the underlying diseases were pulmonary diseases with dysventilation, such as chronic pulmonary emphysema and chronic bronchitis. The subjects were relatively old on the average, ranging in age from 46 to 64 years and it can be assumed that they had been ill for long periods.3)-10) Complications included respiratory tract infections and resulting re- spiratory failure, ischemic heart diseases, chronic cor pulmonale, and intoxica- tion caused by the drugs they were taking. In recent papers,7)-9) it has been reported that arrhythmias were found in 80 to 94% of the patients with respiratory failure. With respect to the type of arrhythmias, both supraventricular premature beat and supraventricular tachycardia were found in 53% of patients by Hudson et al7) and in 66% by Sideris et al.9) and atrial flutter were both found in about 20% and ventricular arrhythmias in about 24% of the cases by both authors. Sinus tachycardia was found in 61% of the cases by Hudson et al7) and in 31% by Sideris et al,9) while sinus brady- cardia was found in only 4.4% and 3% of the cases respectively. Hudson et al7) investigated mortality from the standpoint of arrhythmias and they found that the major supraventricular arrhythmias, i.e. atrial tachy- cardia, atrial flutter, atrial fibrillation, multifocal , and A-V , and/or ventricular arrhythmias, i.e. ventricular bige- miny, A-V dissociation, idioventricular rhythm, , and , were present in 33 (47%) of 70 patients and during 2 and a half years of observation, 26 (79%) of these 33 patients died, including all of those with ventricular arrhythmias. The major supraventricular and ventricular arrhythmias reported by Hudson et al7) were found in only 6 (5.9%) of the 101PPH cases investigated by the authors, and of those cases, 5 died. In comparison with the mortality rate of 55.4% during our observation period, very few serious arrhythmias occurred in PPH. The reasons for the high incidence of arrhythmias in cases of chronic pulmonary diseases with dysventilation and especially during acute respiratory Vol.20 No.6 ARRHYTHMIAS IN PRIMARY PULMONARY HYPERTENSION 773 failure can be assumed to include the followings: (1) (PaO2<

50mmHg or PaO2≦40mmHg), (2) respiratory acidosis, (3) due to pulmonary hypertension, (4) pulmonary thromboembolism, (5) stretch- ing of the atrial wall or increased central venous pressure, (6) respiratory infection, (7) electrolyte imbalance, (8) effects of digitalis or , (9) stretch reflexes in the , trachea, bronchi, and pleura, (10) exercise, (11) occurrence of acute , and (12) the complication of coronary atherosclerosis with aging.5)-17) Conventionally, it is considered that atrial arrhythmias are apt to occur in the presence of enlargement of the right atrium. In the authors' study, it was shown that in cases of pure right atrial strain without any other con- ditions such as hypoxemia, severe atrial arrhythmias rarely occurred. However, James18) found in 3 autopsy cases that sinoatrial and A-V nodal arteriopathy were the causes of syncope and sudden death in PPH. Therefore, a vicious cycle occurs when the atrial arrhythmias and complete A-V block bring about a decrease in the effective coronary perfusion on ac- count of the extremely high pulmonary vascular resistance and the elevated right atrial pressure. This is assumed to result in a remarkable decrease in the cardiac output. Diener and Burrows19)reported that sudden death occurred in 8.1% of cases with chronic obstructive lung disease and that the cause of death was probably serious arrhythmias such as . Hudson et al7) and Holford et al8) observed that ventricular arrhythmias such as frequent ventricular premature beats, ventricular tachycarida, ventricular fibrillation, and second degree A-V block, and supraventricular arrhythmias such as sinus arrest, paroxysmal atrial tachycardia, chaotic atrial tachycardia and atrial fibrillation often occur in chronic obstructive lung diseases, especially in acute respiratory failure. In the authors' investigations, sinus bradycardia with a heart rate of 45 to 58/min was noted in 6 cases but most of these patients survived and there were no records of marked sinus bradycardia, sinoatrial. block, or sinus arrest. However, it is not clear whether or not the ECGs were recorded during a syncopal attack or chest pains and the method of detection of arrhythmias must be taken into consideration. Hudson et al7) performed long-term ECG monitoring for 72 hours and detected arrhythmia in 32 (89%) out of 35 patients with chronic obstructive pulmonary diseases; of these, 16 had acute respiratory failure. Among the cases with arrhythmias, treatment was required in 57% of the patients. Kleiger and Senior10)performed 10-hour ECG monitoring on 25 patients with chronic airway obstruction without acute respiratory failure, and found Jap. Heart J. N 774 KANEMOTO AND SASAMOTO ovember, 1979 arrhythmias in 84%, while arrhythmias could be detected in only 20% using the standard ECGs. Therefore, in the future investigation of such patients, it would be neces- sary to record ECGs using long-term monitoring, and to investigate patients with frequent syncopal episodes by means of the overdrive suppression test and His bundle ECGs.8),10),20)-22)

ACKNOWLEDGMENTS We gratefully acknowledge the invaluable aid of the following colleagues who graciously supplied ECG copies of their cases. Drs. Tatsumi, K., Amagasaki Hospital; Chino, M., Ashikaga Nisseki Hos- pital; Watanabe, S., Chiba University; Oosaki, G., Hokkaido University; Kita- mura, K., Juntendo Hospital; Katsu, M., Kawasaki City Hospital; Kishida, M., Kansai Rosai Hospital; Kashiwazaki, S., Kitasato University; Handa, S., Keio University; Tomomatsu, T., Kobe University; Kimura, N., Kurume University; Kanahisa, T., Kagoshima University; Mizutani, K., Meijo Hospital; Iwasaki, S., Nagasaki Chuo Hospital; Nakajima, K., Nakamichi Hospital; Hashiba, K. & Hara, K., Nagasaki University; Yo, S., Saiseikai Utsunomiya Hospital; Katayama, K., Saiseikai Chuo Hospital; Kusama, S., Shinshu University; Takishima, T., Tohoku University; Mori, H., Tokushima University; Moriyama, K., Yamaguchi Uni- versity; Yasumura, Yokohama City Hospital; Ohno, T. & Hoshino, T., Yokohama Hospital.

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