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36ОРИГИНАЛЬНЫЕ СТАТЬИ | ORIGINAL PAPERS
УДК 6.13-004.6;612.13]:615.849.19
ДИАГНОСТИКА ЗАБОЛЕВАНИЙ СИСТЕМЫ ДЫХАНИЯ И ЕЕ ПАТОФИЗИОЛОГИЧЕСКИЕ ОСНОВЫ. III. COR PULMONALE - ЛЕГОЧНОЕ СЕРДЦЕ
© Юрий Иванович Строев, Леонид Павлович Чурилов
Санкт-Петербургский государственный университет, медицинский факультет. 199034, Санкт-Петербург, Университетская наб., д. 7-9
Контактная информация: Леонид Павлович Чурилов — заведующий кафедрой патологии медицинского факультета, зам. руководителя лаборатории мозаики аутоиммунитета, действительный член Международной академии наук (Здоровье и экология). E-mail: elpach@mail.ru
Резюме: Эта публикация продолжает серию работ, посвященных сердечно-легочным заболеваниям и их патофизиологии. В статье сравниваются достижения и традиции российской терапевтической школы с принципами внутренней медицины, сложившимися в практике зарубежного медицинского образования. Статья посвящена этиологии, патогенезу, клиническим проявлениям, формам, диагностике и основным принципам лечения и профилактики синдрома легочного сердца. Особое внимание уделено легочному сердцу как осложнению COVID-19. В статье анализируются механизмы и феноменология симптомов, важных для дифференциальной диагностики cor pulmonale, а также оригинальные авторские наблюдения и история медицинских исследований в этой области (8 рисунков, библиография — 58 источников).
Ключевые слова: Бронхолегочные заболевания; Коронавирусная инфекция; Сердечная недостаточность; Рефлекс Эйлера-Лильестранда; Синдром Хаммена-Рича; Легочное сердце; Легочная гипертензия, Острый респираторный дистресс-синдром; Тромбоэмболия легочной артерии.
DIAGNOSIS OF THE DISEASES OF RESPIRATORY SYSTEM AND ITS
PATHOPHYSIOLOGICAL BASIS:
III. COR PULMONALE - PULMONARY HEART DISEASE
© Yuri I. Stroev, Leonid P. Churilov
St. Petersburg State University, Faculty of Medicine. 199034, St. Petersburg, Universitetskaya nab., d. 7-9
Contact information: Leonid P. Churilov — M. D., Ph. D., Full Member of the International Academy of Sciences (Health and Ecology), Chairman of Pathology Dept., Faculty of Medicine, Deputy-Head of the Laboratory of Mosaic of Autoimmunity. E-mail: elpach@mail.ru
Summary: This publication continues a series of papers devoted to cardiopulmonary diseases and their pathophysiologic basis. The article compares the achievements and traditions of Russian therapeutic school with the principles of Internal Medicine that have evolved in the practice of foreign medical education. The article is devoted to etiology, pathogenesis, clinical manifestations, forms, diagnosis and basic principles of treatment and prevention of the cor pulmonale (pulmonary heart) syndrome. Special attention is paied to pulmonary heart as a complication of COVID-19. The article analyzes the mechanisms and phenomenology of the symptoms important for its differential diagnosis along with original author's observations and history of medical studies in this field (8 figs, bibliography — 58 refs).
Keywords: Acute respiratory distress syndrome, Cor pulmonale; COVID-19; Hamman — Rich syndrome; Heart failure; Hypoxic pulmonary vasoconstriction; Respiratory diseases; Pulmonary heart; Pulmonary hypertension; Lung thromboembolism.
In the previous articles [1-7] we have analyzed methodology of interviewing and visual as well as touching examination in diagnosis of cardiovascular and bronchopulmonary diseases. The continuation of the topic is devoted to diagnosis of pulmonary heart syndrome, integrating both cardiological and pulmonologi-cal aspects of physical diagnostics and its pathophysiological bases.
COR PuLMONALE: DEFINITION AND HISTORY
In broad sense of the term, pulmonary heart disease (PH, in Latin: Cor pulmonale) is a syndrome (pathological process) characteristic of hypertrophy and (or) dilation of the right ventricle of the heart due to pulmonary arterial hypertension caused by primary lesions of bronchopulmonary apparatus, pulmonary vessels, or by disorders of thorax and phrenic muscle. The term PH itself
fig. 1. Post stamp of uSA with a portrait of Dr. P.D. White [10]
was introduced by the classic of American Cardiology Paul Dudley White (1886-1973) in 1935 [8] (fig. 1).
But even much earlier the pathologists already have reported the connection of asthma and other chronic lung diseases with right side heart hypertrophy, dilatation and heart failure, beginning from works by Thomas Willis (1621-1675) and especially the founder of
Cardiology, French royal physician Jean-Baptiste de Sénac (1693— 1770) , who precisely explored cardiac hypertrophy, [9] (fig. 2).
Fig. 2. J.-B. de Sénac by unknown painter
The first systematic review of heart status in lung diseases belonged to a Scottish pathologist W.T. Gairdner (1853), who correctly suspected that the mechanical overload of right ventricle in lung pathology may be responsible for pathogenesis of this condition [10]. New level of comprehension in Clinical Pathophysiology of the heart was achieved in second half of 20th century due to technique of catetherization of heart chambers and pulmonary artery. It was introduced into clinical practice by three physicians, Nobel Prize winners. A French-American clinical pathophysiologist André Frédéric Cournand (1895-1988) and an American clinical pathophysiologist Dickinson Woodruff Richards, Jr. (1895-1973) elaborated this technique between 1941 and early 1950ies. But, one must remember the fact that it was a young German surgeon (to that moment just graduated from medical school) Werner Theodor Otto Forssmann (19041979) [fig. 3] who originally suggested and performed the first catheterization of the human heart and pulmonary artery in vivo in 1929 at the clinic of Eberswalde, near Berlin.
Dr. Forssmann was assisted by a nurse Gerda Ditzen (who heroically offered herself for the experiment, but was deceived
fig. 3. Right to left: A.F Cournand; D.W. Richards, Jr.; W.T.O. forssmann talking to S. fissberg at Nobel Committee. W.T.O. forssmann and G. Ditzen looking on historical X-ray picture many years after their heroic self-experiment [24]
by kind doctor, which did prepare her arm for manipulation, but instead performed catheterization on himself). He has personally imbued a catheter into his own ulnar vein under local anesthesia for 60 cm and they both went downstairs to X-ray ward, where continued manipulation under roentgenoscopic control. Because a fresh graduate just started to specialize in Urology, the catheter he used was a urological one. Having conducted it through the right atrium and ventricle, Dr. Forssmann then entered the pulmonary artery and his friend, an X-ray specialist made a control rhoentgenogram [fig. 4], certifying that the goal was achieved. Although the chief physician of Eberswalde's Auguste Viktoria-Heim clinic initially was annoyed with brave initiative of the young surgeon, but nevertheless he permitted Dr. Forssmann to repeat the experiment few days later on a hopelessly ill female patient in order to deliver medicines directly into her heart.
Fig. 4. Forssmann's original chest X-ray picture with a catheter installed [12]
The second Forssmann's experiment also was successful, and even gave a provisional improvement in the patient's status [11]. Unfortunately, later on an outstanding coryphaeus of German thoracic surgery Ernst Ferdinand Sauerbruch (1875-1951) who supervised Forssmann's thoracic specialization, did not appreciate the importance of Dr. Forssmann's innovations and kicked young colleague out of his clinic for violation of its charter and experimentations without chief's approval. The small paper published by Dr. Forssmann in 1929 remained a single written result of his breakthrough in Thoracic Medicine, but later played very important role in his life [12]. He stopped any scientific career and swapped for urological practice, married and begot 6 children, joined in 1932 Nazi party and during World War II fought as a battle surgeon. In the end of the war being in the ranks of defeated German troops he was captured by Americans and sent to prisoners-of-war (POW) camp. And by lucky occasion, among the Americans who contacted to him in POW were his American colleagues A.F. Cournand and D.W. Richards
(former artillery officer), who have read his old pioneering publication of 1929! Dr. Forssmann was liberated and returned to his practice and later — to his studies and in 1956 shared with his followers the Nobel prize.
The technique by these authors revolutionized the field of PH studies, because it gave the option to characterize objectively the presence and degree of the pulmonary hypertension, a key link in pathogenesis of PH (see below). It is used for the measurement of blood pressure within the pulmonary artery. The systolic pressure there is normally 8 to 28 mm Hg, whereas the diastolic one is 2 to 12 mm Hg; anyway the blood pressure within the pulmonary artery normally does not exceed 30/15 mm Hg.
CLASSIFICATION OF PULMONARY HEART DISEASE
Cor pulmonale was classified by the WHO experts, and their consensus approved by WHO in 1961 [13]; it has been revised since then, but on the same basis.
The aetiological classification includes following 3 groups of PH cases:
• PH as a result of an ailment primarily affecting the passage of air through bronchi and alveoli;
• PH as a result of ailments primarily affecting pulmonary blood vessels;
• PH as a result of ailments primarily affecting the excursions of the thoracic cavity walls.
Next goes the clinical-pathogenetic classification of PH. According it, PH can proceed along acute, sub-acute or chronic course.
ACUTE AND SUB-ACUTE COR PULMONALE
The acute PH may be caused:
• By thromboembolism, (or much more seldom — fat, gaseous, neoplastic or exclusively — by parasitic embolism) of the pulmonary artery and its branches;
• By spontaneous (particularly valve-type) pneumothorax;
• By bronchial asthmatic status;
• By acute respiratory distress syndrome (ARDS) — for which PH is quite typical, including that of shock lung and that provoked by severe COVID-19 infection.
The sub-acute PH can result from the following reasons:
• Massive or repetitive microembolism of the small branches of pulmonary artery;
• Pulmonary vasculitides and primary pulmonary arterial hypertension in lesions of pulmonary blood vessels;
• Mediastinal tumors, lymphogenous pulmonary carcino-matosis (miliar metastases of malignant tumors of different locations and origin, e.g., gastric, prostatic, renal, etc);
• Bronchial asthma (severe cases);
• Alveolar hypoventilation caused by botulism, poliomyelitis, generalized myasthenia (myasthenia gravis).
оригинальные статьи
7
COR PULMONALE IN HAMMAN - RICH SYNDROME: STRIKING SIMILARITIES TO COVID-19
The Hamman — Rich1 syndrome (HRS — idiopathic acute interstitial pneumonia resulting in ARDS and in sub-acute phase giving idiopathic diffuse pneumofibrosis) regularly is complicating by PH [14].
Hans Selye once has noted, that clinicians always try to find difference between the diseases, but for pathologist the most interesting thing is why various diseases are so similar. In regards to HRS, we shall mention here one correlation which seems to us quite important. Comparing early and advanced clinical manifestations, lung pathomorphology and outcomes, as well as typical sub-acute complications of HRS [14-16] with all that facets of severe COVID-19 [17-19], we noticed strikingly close resemblance of these two entities.
ñ
Fig. 5. Left — L.V. Hamman (photo with autograph), right — A.R. Rich
Indeed, in our opinion the severe COVID-19 with its fever and dry non-productive cough and coming later interstitial pneumonia with diffuse alveolar damage and ARDS, as well as with its outcome to diffuse pneumofibrosis — looks very much like acquired phenocopy of HRS, although HRS apparently never was considered to be a contagious disease, rather listed into group of genetically based ones.
One may guess, either the sporadic cases of HRS were related to unrecognized type of coronavirus having small contagiousness; or, which looks much more probable, both entities, having different (infectious and non-infectious, presumably, genetic) aetiologies, address to similar or identical weak point of immune system, making its autoinflammatory and autoagressive potential the crucial link of pathogenesis in both cases. Anyway, it seems to us quite possible that old well known disease of HRS [20] in closer analysis may contain a key for comprehension of the new
1 Hamman, Louis Virgil (1877-1946) — an American internist; Rich, Arnold Rice (1893-1968) — an American pathologist (fig. 5). The syndrome they described first in 1933 and detailed in 1935 [14]. Here and everywhere below biographical data are verified according: Enersen O.-D. (Ed.) Whonamedit? A Dictionary of Medical Eponyms. URL: http:// www.whonamedit.com/ (accessed 28.04.2020).
COVID-19. There was even an observation that pneumofibrosis in survivors of HRS can exacerbate into ARDS due to viral and even coronavirus infection, although last was reported only in one of 43 cases of such exacerbations [21-22]. To study precisely and compare the genetic and immunological features of those having severe COVID-19 and those suffered from HRS may offer a fruitful approach for prognostic purposes and mechanistically based interventions.
CHRONIC COR PULMONALE
Chronic course of PH may elicit in the following chronic diseases:
• Chronic obstructive pulmonary disease (COPD);
• Bronchial asthma;
• Pneumoconioses;
• Tuberculosis;
• Pulmonary polycystosis;
• Berilliosis;
• Sarcoidosis of the lungs;
• Idiopathic hemosiderosis;
• Chronic "idiopathic" diffuse interstitial fibrosis;
• Systemic autoimmune diseases with non-organ specific autoantibodies (systemic sclerosis etc). This and previous lines are akin because certain manifestations of autoimmunity (like, for example, autoantibodies against citrullinat-ed peptides) are common for both of them. In view of that currently some cases of "idiopathic" pneumofibrosis can be re-classified as autoimmune ones [23];
• Various limitations of thoracic wall excursions in kyphosco-liosis, post-thoracoplastics states, and pleural fibrosis;
• Different ailments of the thorax and diaphragm paresis;
• Pickwickian syndrome (obesity hypoventilation syndrome) (see: [2]);
• Finally, it may develop in post-operation period after pul-monectomy.
Periodization of PH includes compensation period (stage); decompensation period and finally — insufficiency stage or pulmonary-cardiac failure.
PATHOGENESIS OF COR PULMONALE
The key pathogenic link of PH is pulmonary arterial hypertension due to increased resistance to passage of blood through the lesser circulation cycle. The reasons for increased resistance to passage of blood are as follows:
• Functional vasoconstriction due to hypoxemia and hypox-ia;
• Altered rheological properties of blood (increased viscosity caused by polycytemia or/and polyglobulia, regional intrapulmonary or systemic disseminated intravascular coagulation in shock);
• Increase of per-minute heart output combined with extensive pulmonary failure;
• Anatomic changes in pulmonary blood vessels (thrombosis, embolism, obliteration, atrophy, sclerosis, etc);
• Hypoventilation of pulmonary alveoli causes alveolar hypoxia, which automatically provokes vasoconstriction at the zone of poorly ventilated alveoli. This phenomenon historically was known as von Euler — Lillestrand "refleX'2 [25].
P
I f
L
Fig. 6. Left: U.S. von Euler; right — G. Liljestrand
In fact the phenomenon discovered by these Swedish scholars later appeared to be of non-neural origin, because neither ganglion blockers nor lung denervation were unable to prevent it. Nevertheless, this is extremely important mechanism redistributing the blood supply in favor of well-ventilated lung portions in order to maintain ventilation/perfusion (V/P) matching. Very useful for optimization of regional V\P ratio, it should not disturb topical variance of this parameter. It can be detrimental if violates the topical regional border and involves both lungs in global hypoxia, for example, in high altitude disease and in PH. In such cases it provokes generalized vasoconstriction in lesser circulation, thus causing pulmonary hypertension. That is a bright example of the general pathology principle earlier coined by L.P. Churilov [26] and stating that the balance of local and systemic defensive mechanisms is health prerequisite, but their conflict due to trespassing of the borders limiting their spheres of action is always highly pathogenic.
The very mechanism of the hypoxic pulmonary vasoconstriction is still disputable, and there are several theories for it based on quite remarkable research achievements of last period. There are hypoxia-sensitive voltage-gated potassium channels in pulmonary artery smooth muscle cells, which cause in response to low local pO2 their depolarization, activation of calcium influx and vascular spasm [27]. Also, transient receptor potential canonical 6 (TRPC6) and vanilloid 4 (TRPV4) channels are involved in this direct reaction probably driven by local autacoids [28]. Also, there is an assumption that some electrical signal generated in capillary endothelial cells of lesser circulation is transmitted via intercellular gaps upstream to arteriole smooth muscle cells, thus rep-
2 von Euler Ulf Svante, 1905-1983 — Swedish physiologist and pharmacologist, Nobel prize winner of 1970; Liljestrand, Goran, 18861968 — Swedish physiologist and pharmacologist. They described phenomenon in 1946.
resenting non-neural "electric wire" and resulting in local spasm of arterioles. The antagonists of gap junction connexin-40 protein can stop this process and attenuate hypoxic vasoconstriction phenomenon [29]. The changes driven by hypoventilation and hypoxial pulmonary vasocinstriction are most conspicuous and diffuse during COPD:
• hypoxia per se causes some electrolyte abnormalities with increased extracellular potassium content, which may involve above mentioned channels causing vasoconstriction. Due to increased intracellular sodium with cell swelling in hypoxia swollen capillary endotheliocytes may hamper blood passage;
• disturbed ventilation biomechanics with increased tidal volume can increase intrathoracic transpulmonary pressure during exhale (positive end expiratory pressure — PEEP), thus causing involvement of expiratory muscles and in turn increasing of originally elevated minute heart output volume (mostly in case of obstructive bronchopulmonary diseases, e.g., in COPD, bronchial asthma, etc; "The end result of the above mechanisms is increased pulmonary arterial pressure and resistance" [30], which means increased afterload for right cardiac ventricle. The latter leads to its hyperfunction and hypertrophy driven by growth factors.
Hypertrophy and/or dilation of the right ventricle is caused by the following pathogenic factors: Pulmonary arterial hypertension (pressure load or afterload) and increased heart minute output (volume load or preload).
Because right ventricle is a thin-wall chamber, it sustains pressure load much worse than volume one. Progressive systolic pressure increase causes its dilatation, end-diastolic pressure elevation and finally its pump (overload) failure. Of equal meaning is the fact that right and left ventricles are originated by different progenitor cell clones, the former one — by those displaying lower potency for hypertrophy [31]. But, interaction of the lungs and heart in pathogenesis of PH seems to be more complicated in comparison with this classic key scheme. It has been recently reviewed elsewhere [32-33]. As it is shown by [33] and depicted in fig. 7 below, increase in end-diastolic pressure within right ventricle causes shift of interventricular septum to the left. Hence, the volume and output of left ventricle diminishes, which results in decrease of right ventricle perfusion via right coronary artery, making its working capacity low. It means a vicious circle (positive feedback) in the pathogenesis of PH.
Because of that, right ventricle failure in PH (if one will apply F.Z. Meerson's classification [34]), cannot be interpreted as purely and exclusively hemodynamic (overload-derived) one. It has typical evolution toward mixed type, because of secondary joined energodynamic component. In advanced cases on autopsy one may notice the features of hypoxic necrobiosis in tissue of right ventricle, most pronounced in severe cases accompanied by lung infections and water-electrolyte disorders.
Several factors and comorbid illnesses increasing the cardiac load or decreasing the efficiency of pump function — may contribute to decompensation of cor pulmonale. These are:
• Stress, emotional and physical strain;
Conditions:
- PEEP
- COPD (Pulmonary capillary loss)
- Hypoxic Pulmonary Vasoconstriction
- Acute Lung Injury
- Large Tidal Volume
fig. 7. Direct ventricular interaction during increased pulmonary vascular resistance (1 — PVR). Decrease in stroke volume (SV) of right ventricle (RV) via increased RV end-diastolic volume causes leftward septal shift and hence SV of left ventricle decreases, making coronary perfusion worse. Adapted from [33]. Other abbreviations in the text
• Adrenomimetics;
• Bioactive substances disturbing lung ventilation and bronchial conduction;
• Autoimmune (and infectious) myocarditides and cardyo-myopathies.
PATHOMORPHOLOGY OF COR PULMONALE
The pathomorphological changes typical for PH vary depending on its course and aetiology. Chronic and subacute PH cases display in compensated stage the following changes:
• Concentric hypertrophy of the right ventricle with its tono-genic (compensatory) dilatation; but in non-compensated stage — vice versa excentric hypertrophy or myogenic (passive) dilation of the right ventricle cavity with thinning of the ventricle wall can be observed;
• The most pronounced dilatation of the right ventricle causes relative insufficiency of tricuspid valve, which in its turn may result in hypertrophy and dilatation of the right atrium;
• Dilatation of pulmonary artery and its branches is often combined with relative insufficiency of pulmonary artery valves;
• Pathohistological study reveals small-droplet and large-droplet fatty degeneration of some cardiomyocytes with swelling and fragmentation of cardiac muscle fibers, particularly noticeable in subendocardial areas, also diffuse cardiosclerosis is observed;
• On autopsy pathomorphological changes in other organs, caused by right-ventricle-type heart failure are typical, e.g. chronic congestive hyperemia or «muscat» liver, cyanotic induration of kidney and spleen, ascites and anasarca, etc;
In acute cor pulmonale the picture is characteristic for:
• Myogenic (passive or congestive) dilatation of the right ventricle (without signs of myocardium hypertrophy);
• Pathohistological studies reveal multiple small foci of my-omalacia, with sites of clot-like decay of cardiac muscle cells, contractures of myocardial fibers, and disorders of microcirculation (foci of stasis and some hematomas).
According the differences of pathogenesis, the patterns of PH currently are clinically divided into 2 types — with predominance of bronchopulmonary either vascular primary processes [30-31].
CLINICAL MANIFESTATIONS OF COR PULMONALE IN ACUTE AND CHRONIC CASES
Clinical features of acute cor pulmonale very often are manifested in the typical picture of pulmonary artery thromboembolism (acute breathlesness, cyanosis, chest pain, acute phase response symptoms). Pulmonary thromboembolism is virtually its main acute reason, giving annually, for example, about 50 000 of lethal cases in USA [30]. The manifestations and management of this dangerous syndrome were recently described elsewhere [35-36].
Another new contributor into acute cor pulmonale problem currently is COVID-19 pandemic. That's why we shall concern below the latest data on PH in COVID-19. Acute PH may complicate severe cases of COVID-19, especially in ARDS and in those patients having hidden or overt cardiomyopathies [37-39].
There are several links of COVID-19 pathogenesis which may lead to acute PH.
Of course, first of all it is ARDS, which was noticed as PH provoking syndrome long before COVID-19 pandemic and requires prone positioning of pulmonary vasculature and right heart as well as protective ventilatory regime to avoid PH [40]. Besides ARDS which is a factor greatly increasing right ventricle afterload, there are ACE2 receptors (entrance gates of virus) in myocardium, which makes acute viral myocarditis frequent tile in mosaic of severe COVID with estimated prevalence 20-30 % of all heavy cases [39, 41], thus including decrease of myocardium pump efficiency as an additional mechanism in the pathogenesis of acute PH. Also, pulmonary thromboembolism is not rare in severe COVID-19 [42], which in turn is a prerequisite of acute PH. The connection of pulmonary thromboembolism and COVID-19 is not occasional. Pulmonary thromboembolism is a severe and common complication of autoimmune antiphospholipid syndrome, especially its fulminant type. COVID-19 has several features putting it close to autoimmune pathology and namely some similarities with antiphospholipid syndrome: Hyperferritinemia and possible immune cross-reactivity between viral and lung phospholipopro-tein surfactant peptides, which was first pointed out by Y. Shoen-feld and D. Kanduc Interestingly, Pneumocystis Carinii known as a germ provoking interstitial pneumoniae with PH complications also shares some peptides with lung surfactant [43-44]. Hence, lung and pulmonary vasculature catastrophic damge in COVID-19 from the point of view of PH genesis may be interpreted as a regional variety of catastrophic antiphospholipid syndrome.
I PVR
One of the most clinically important aspects of PH problem in context of COVID-19 pandemic is high probability of acute PH as a complication of ventilatory support in severe ARDS. As early as in 2016 A. Mekontso Dessap et al. [45] reported high incidence of acute PH (22 %) in a cohort consisted of 752 moderate to severe ARDS patients on protective ventilation with high mortality rate in ARDS-PH cases (57 %). The main criteria of acute PH on echocardiography were septal dyskinesia with a dilated RV and end-diastolic RV/left ventricle (LV) area ratio > 0.6 ( > 1 for severe dilatation). Presumably, the reason was excessive PEEM of ventilatory support, lack of proper prone positioning and late application of protective ventilation. One may suggest that acute PH can worsen the outcomes of ventilatory support in COVID-19 patients also, in lack of appropriate precautions.
Chronic cor pulmonale during stage of compensation is characterized by the prevail of the clinical symptoms of its main provoking primary disease, most frequently — COPD [30] of bronchial type or some other disorder causing PH. It is manifested in pulmonary arterial hypertension symptoms:
• Accentuated and split 2nd heart sound over pulmonary artery;
• Split 1st heart sound due to belated tricuspid component caused by pulmonary hypertension;
• Right heart hypertrophy signs which mostly are to be revealed by X-ray and have some electrocardiographic and ultrasonic manifestations as well.
Palpation, percussion and auscultation data are of small value, they just can reveal physical signs of main primary disease in cases of pronounced emphysema, pleurisy or hydrothorax, pleural adhesions and mediastinal dislocation.
If PH gets out of compensation state, the symptoms of overt cardiopulmonary insufficiency appear according the right heart failure pattern:
• Cardiac ache (pulmonary stenocardia or angina hypercy-anotica) is different from that characteristic of typical angina pectoris. In case of pulmonary stenocardia the aches are not associated with physical or emotional strain, can not be killed with nitroglycerin, on the other hand, the patients can get relief from oxygen therapy. The pathogenesis of angina hypercyanotica is related to left main coronary artery extrinsic compression from a dilated pulmonary artery in patients with pulmonary arterial hypertension, which recently has been proven by computed tomography [46]
• Diffuse cyanosis of central origin, due to lack of proper blood oxygenation in lesser circulation is often combined with acrocyanosis related to congestion and passive hy-peremia in peripheral areas (it gives purplish-blue coloring of nose, ears and lips), and may be accompanied by ortho-pnea — breath shortness occurring while lying flat;
• Dyspnea in this stage varies depending on the period of cardio-pulmonary failure, and can present in case of light physical strain or even during rest;
• Swelling of cervical veins, oedemata of limbs, and in most severe cases even ascites — all are common in PH.
• Hepatojugular reflux (or abdominojugular test), was first described by a scholar who was not medical doctor at all, although contributed greatly into building of scientific Medicine. That was French scientist Louis Pasteur (18221895). He suggested it in 1885 as a sign of tricuspid regurgitation. It is the distention of the jugular vein induced by applying manual pressure over the liver area if patient is placed in a semi-recumbent position with an elevation of the head of the bed to 30-45° angle. It is still very useful although sometimes neglected physical sign of chronic PH, but it can present in cases of other congestive heart failure also [47];
• Cardiac beat accelerated and resistant under fingers in the precardial or epigastric areas, witnessing for hypertrophy of the right ventricle;
• Significant dilatation of the right ventricle is associated with an expansion of heart width and even shifts upwards the upper border of the relative cardiac dullness on percussion. The expansion of the heart borders to the right from the sternum is caused by the dilatation of the right atrium [48];
• Systolic murmur getting louder during inspiration is frequently auscultated close to the base of xyphoid processus. This phenomenon is associated with the regurgitation of tricuspid valve [49];
• a delicate diastolic murmur (Graham Steell3 murmur) is frequently auscultated in the 2nd intercostal space to the left from the sternal margin. This phenomenon is produced by the relative insufficiency of the pulmonary artery valve [50];
Fig. 8. Graham Steell in young age [50]
• At the apex as well as over Botkin — Erb's4 point there is a split 1st sound, auscultated;
• Over the pulmonary artery — the 2nd sound is accentuated;
• The rhythm disturbances are mostly represented in PH by sinus tachycardia, fibrillation is possible in latest stages only, though seldom. The coryphaeus of domes-
3 Steell, Graham, 1851-1942 — an English internist (fig. 8 above), first reported this phenomenon in 1888, there is a witness that earlier it was noticed and used by his teacher, a Scottish physician George Balfour (1823-1893) [50]
4 Botkin, Sergei Petrovich, 1832-1889, a Russian internist; Erb, Wilhelm Heinrich, 1840-1921, a German neuropathologist. The point is located in 4th intercostal space, close to the sternum between left sternal and parasternal lines.
tic Internal Medicine and Biophysics, inventor of impedance plethysmography and alumnus of Leningrad State University, professor of Leningrad Paediatric Medical Institute Aleksei Alekseevich Kedrov (1906-2004) use to emphasize that PH never gives a ciliary arrhythmia and highly appreciated the differential diagnostic value of this feature;
• Arterial blood pressure in the gross circulation may also be elevated due to the effects of variety hormones and auta-coids produced in response to heart failure.
ADDITIONAL DIAGNOSTIC METHODS AND TECHNIQUES IN COR PULMONALE
At the initial stages of PH (in status of compensation) the following X-ray signs are typical:
• Relatively unchanged dimensions of the heart shadow, positioned closer to vertical due to low diaphragm position caused by lung emphysema;
• Bulging cone of the pulmonary artery in frontal and left side projections;
• Combined dilatation of the pulmonary artery trunk and major branches with narrowing of its small ramifications («root amputation» symptom). This phenomenon is particularly evident on tomograms;
At the late stages of cor pulmonale during obvious heart failure the picture is added with:
• Expanded heart shadow due to hypertrophy and dilatation of the right ventricle and the right atrium;
• The right ventricle may force the left one backwards, and in this case both the right and the left heart contours are formed by the shadow of right ventricle;
• Extreme dilatation of the right atrium causes major expansion of the heart shadow to the right.
At the initial stage of PH the following signs are revealed by electrocardiogram (ECG):
• Vertical or semi-vertical position of the heart; less often — a right-ward bias of its electric axis ( + 110° or more);
• Shift of the transition zone to the left due to clock-wise turn of the heart around the longitudinal axis with the right ventricle ahead;
• Backward bias of the apex due to a turn of the heart around the transverse axis;
• Decrease of the magnitude of the waves comprising the QRS complex due to lung emphysema;
• P-wave changes (known as "P-pulmonale" caused by right atrial enlargement): increase of magnitude (2 mm and more) in the 2nd , 3rd and AVF leads.
Also there are ECG signs of the right ventricle hypertrophy:
• dominant S-wave in V5 or V6 ( > 7mm deep or R/S ratio < 1) is more typical than dominant R wave in V1 (> 7mm tall or R/S ratio > 1);
• the signs of the right ventricle hypertrophy are combined with a complete or a partial block in the A-V bundle right branch;
• There are also intermediate ECG forms registered [48, 51-52]
Echocardiography, especially its ultrasound Doppler's version is of utmost importance for PH diagnosis (see above) and may reveal:
• Thickening of the anterior wall of the right ventricle and the interventricular septum;
• Increased magnitude of inter-ventricular septum excursions;
• Dilatation of the right ventricle with septum shift to the left;
• Regurgitation of tricuspid valve as well as the pulmonary artery valve — in the status of decompensation.
As it was mentioned above, the essential data are achieved by technique of the blood pressure measurement within pulmonary artery: Either by direct method with catheterization of the pulmonary artery, or indirectly, by means of impedance pletismoghaphy of lungs, Doppler's echocardiography or by other methods (which all are much less precise compared to direct measurement).
The measurement of the blood partial pressure of gases gives the following data:
• Patients with cor pulmonale out of compensation state have decreased oxygen partial pressure both in the venous and the arterial blood, at the same time their carbon dioxide partial pressure is increased (hypoxemia combined with hypercapnia is regarded in Pathophysiology as asphyxia).
Among the additional laboratory and instrumental data of some diagnostic value, it is worth to mention the following:
• Cardiac magnetic resonance imaging which does not use ionizing radiation and can help in evaluation of heart structure, remodeling, and function; some authors [30] insist that this modality is advantageous "in assessing pulmonary artery dimensions when compared to traditional echocardiography";
• Immunocompetitive (for example, ELISA) test for brain natriuretic peptide, which is produced in excess in response to heart overload and failure, particularly in pulmonary arterial hypertension, as a matter of compensation.
• Clinical blood analysis is taken and polycythemia may be expected as a result of chronic hypoxia, which is important as an additional reason for heart overload due to increased blood viscosity;
• Serum alphal-antitrypsin is worth to check in suspicion for hereditary basis of lung emphysema;
• The set of autoantibodies typical for lupus, systemic sclerosis, rheumatoid arthritis, antiphospholipid syndrome, systemic vasculitides — involving lung or pulmonary vas-culature or both, as well as autoantibodies against modified citrullinated vimentin (common for some kinds of diffuse idiopathic or autoimmune pneumofibrosis) should be determined.
• Coagulations studies to evaluate possible hypercoagulability states risky for pulmonary thromboembolism are advisable.
DIFFERENTIAL DIAGNOSIS OF COR PULMONALE
Differential diagnosis of PH with congenital and acquired heart disease is essential.
The major criteria for this distinguishing are the following:
• Decompensation of PH usually takes place after development of pronounced respiratory failure with decreased lung volumes and seriously disturbed ventilation;
• The signs of hypertrophy of the left heart part as a rule exist in the case of heart disease are not characteristic of PH;
• Unlike PH, most of congenital and acquired heart diseases (defects) have their distinctive auscultation melodies;
• Of certain aid are the instrumental methods such as echocardiography, computed tomography, ventriculography, and invasive catheterization of the heart. In some cases the results of the instrumental examination supply the decisive data;
• Anamnesis morbi (case history) also is of considerable importance, because it may contain earlier registered information about bronchopulmonary diseases, heart murmur audible since birth, prior rheumatic fever, etc;
Differentiation with ischaemic heart disease (IHD) is not always necessary, as well as with atherosclerotic cardiosclerosis, because many PH patients have these diseases as comorbid ones. Nevertheless, in case of necessity the following differential diagnostic criteria are useful:
• Cardiac pain in case of PH differs from typical angina pec-toris (see above), having character of cardialgia not prone to nitrates, while in case of IHD aches are of the typical stenocardia's patterns;
• Anamnesis morbi (case history): In case of PH there are usually data on existing bronchopulmonary ailments, disorders of pulmonary blood vessels, chest deformations, while in case of IHD — there may be prior myocardial infarctions and episodes of stenocardia;
• Hypertrophy and dilatation of the right heart chambers both are characteristic of PH, while IHD is associated with hypertrophy and dilatation of the left cardiac half;
• In case of PH decompensation develops on the background of very severe respiratory failure, and heart failure in PH is of right-ventricle type. On the contrary, in case of IHD it is the left-ventricle failure that develops initially, the right-ventricle one evolves only after the left-ventricle failure has matured [53];
• Polycytemia and polyglobulia are both characteristic of PH, particularly in its decompensation stage, but are not typical for IHD patients.
PRINCIPLES OF TREATMENT IN COR PULMONALE
Although the detailed treatment in various kinds of PH is not the subject of this article and is reviewed elsewhere [30, 32, 45, 48, 54-56], we shall mention here few basic statements.
In sub-acute and chronic PH the treatment is based upon a combination of two main principles: The first is the treatment
of the main underlying disorder, the second is the correction of hemodynamics. The treatment of the main disease takes into consideration the key links of pathogenesis. In COPD it will include antibacterial drugs in exacerbations; correction of immu-nological status and fighting the bronchial obstruction. Patient has to stop smoking and eliminate occupational hazards. Also methods stepping up anti-hypoxic resistance of the organism are recommended (special physical exercises, massage, climatic therapy, etc).
Hemodynamics and gas exchange correction in PH shall include oxygen therapy in case of decompensated PH, monitoring the acid-base balance and gas content of blood and as well as check of the subjective feelings of the patient. Hyperbaric oxygenation also proved to be effective. Peripheral vasodilatators and calcium channel blockers decrease pulmonary vascular resistance and the pressure in the pulmonary artery, enhance bronchial conductivity. They are effective at the early stages of PH, when it is functional vasoconstriction which plays the leading part in the pathogenesis of circulatory changes. Patients with overt congestive heart failure also should get treatment with calcium channels blockers, however, in this case the long acting nitrates are preferred, as well as other peripheral vasodilatators. This category of patients should get a lifelong treatment. Anticoagulant therapy is necessary in order to improve rheological properties of blood.
In case of decompensation of PH (particularly in case of congestive heart failure), the cardiac glycosides should be used. The starting doses should be administered intravenously. After that small supporting doses of glycosides should be administered per os. Diuretics are useful at the beginning of right-ventricle type heart failure. For example, aldosterone antagonists may be used. These drugs are notable for their moderate diuretic effect with potassium keeping up. Congestive heart failure would call for more powerful saluretics in combination with potassium medications. These diuretics should be used very carefully in strictly controlled way. Severe disturbances of saline homeostasis and heavy dehydration should be avoided.
Acute cor pulmonale treatment in case of most typical reason is a treatment of pulmonary thromboembolism, which was recently reviewed elsewhere [57]. Regarding the new aetiology of cor pulmonale resulted from severe COVID-19 infection, the medical community is just analyzing current experience and possible ways of treatment, with newest results just published elsewhere [37-39, 42, 58].
PROPHYLAXIS OF COR PULMONALE
First of all it should be based on early reveal, treatment and regular check-up of the patients with the primary illnesses underlying PH (COVID-19 among them!).
Generally, the following prophylactic measures should be used:
• Timely and effective treatment of any serious bronchopul-monary illness;
• Prevention of respiratory infections spread;
• Early complex treatment of pulmonary vascular diseases and thrombophilic disorders;
• Exclusion of various risk factors for pulmonological diseases, like hypothermia, exhaustion, smoking, excessive alcohol drinking, occupational hazards (dust particles, aerosols, harmful gases etc);
• Fighting for the clean and healthy environment, against air pollution;
• Moderate training and hardening for wellness;
• Special physical exercises for cardio-respiratory apparatus.
All of the aforementioned preventive methods shall be used in accordance with the main illness and the degrees of the impairment of the pulmonary and cardiovascular systems.
ACKNOWLEDGEMENT
Both authors contributed equally into this article and declare no conflict of interest. The authors are grateful to Assoc. Prof. Vladimir J, Utekhin M.D., Ph.D. for valuable recommendations given while this paper was prepared,
fUNDING
This work is supported by the grant of the Government of the Russian Federation for the state support of scientific research carried out under the supervision of leading scientists, agreement 14.W03.31.0009.
ЛИТЕРАТУРА
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оригинальные статьи
1б
2. Stroev Y.I., Churilov L.P. Physical methods of diagnosis in diseases of respiratory system and their pathophysiological basis. I. Interview and visual examination. Rus. Biomed. Res. 2019; 4(3): 3-16.
3. Stroev Y.I., Churilov L.P. Palpation in cardiovascular diseases. Rus. Biomed. Res. 2018; 3(2): 9-17.
4. Stroev Y.I., Churilov L.P. Percussion in cardiovascular diseases. Rus. Biomed. Res. 2018; 3(4): 3-7.
5. Stroev Y.I., Churilov L.P. Auscultation in cardiovascular diseases. Rus. Biomed. Res. 2018; 3(3): 3-13.
6. Stroev Y.I., Churilov L.P. Selected lectures in internal medicine for M.D. students. Part I. Introduction. patient interviewing and complaints. Rus. Biomed. Res. 2017; 2(4): 33-41.
7. Stroev Y.I., Churilov L.P. Visual examination in cardiovascular diseases. Rus. Biomed. Res. 2018; 3(1): 9-17.
8. White P.D. The clinical differentiation between cardiac and pulmonary diseases. Am. J. Surg. 1955; 89(1): 241-4.
9. de Sénac J.-B. Traité de la structure du coeur, de son action, et de ses maladies. Paris, 1749.
10. Gairdner W.T. Considerations on the Causes of Dilatation of the Heart, with an Analysis of Evidence Bearing on the Connexion of That Affection with Disease of the Lung. Br Foreign Med Chir Rev. 1853; 12(23): 209-25.
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