PATHOPHYSIOLOGY OF CARDIOVASCULAR SYSTEM

PATHOPHYSIOLOGY OF CARDIOVASCULAR SYSTEM

PATHOPHYSIOLOGY OF VASCULAR TONE

 

Arterial hypertension is the leading cause of death in the world and the most common cause for an outpatient visit to a physician; it is the most easily recognized treatable risk factor for stroke, myocardial infarction, heart failure, peripheral vascular disease, aortic dissection, atrial fibrillation, and end-stage kidney disease. Despite this knowledge and unequivocal scientific proof that treatment of hypertension can prevent many of its life-altering complications, hypertension remains untreated or undertreated in the majority of affected individuals in all countries, including those with the most advanced systems of medical care. Inadequate treatment of hypertension is a major factor contributing to some of the adverse secular trends since the early 1990s, including an increased incidence of stroke, heart failure, and kidney failure plus a leveling off of the decline in coronary heart disease mortality.

The World Health Organisation (WHO) has proposed the following values for all age groups (mmHg/7.5 = kPa):

 

Arterial hypertension, defined as a systolic blood pressure (SBP) in excess of 140 mm Hg and/or diastolic blood pressure (DBP) in excess of 90 mm Hg, has long been identified as an independent risk factor for cardiovascular disease. Traditionally, emphasis has been placed on elevated DBP as a risk factor for the development of target organ damage. However, as early as 1971, the Framingham study showed that, although DBP was a major determinant of cardiovascular risk in men under 45 years of age, SBP was the stronger risk factor in older men and in women of all ages. Since then, several observational studies have suggested that the pulse pressure (PP) may be a better predictor of cardiovascular complications than SBP or mean arterial pressure.

 

Hypertension commonly is divided into the categories of primary and secondary hypertension. In primary, or essential, hypertension, which accounts for 90% to 95% of all hypertension, the chronic elevation in blood pressure occurs without evidence of other disease. In secondary hypertension, the elevation of blood pressure results from some other disorder, such as kidney disease. Malignant hypertension, as the name implies, is an accelerated form of hypertension.

Etiology and pathogenesis of essential arterial hypertension

Several factors, including hemodynamic, neural, humoral, and renal mechanisms, are thought to interact in producing long-term elevations in blood pressure. As with other disease conditions, it is probable that there is not a single cause of essential hypertension or that the condition is a single disease. Because arterial blood pressure is the product of cardiac output and peripheral vascular resistance, all forms of hypertension involve hemodynamic mechanisms—an increase in either cardiac output or peripheral vascular resistance, or a combination of the two. Other factors, such as sympathetic nervous system activity, kidney function in terms of salt and water retention, the electrolyte composition of the intracellular and extracellular fluids, and humoral influences such as the renin-angiotensin-aldosterone mechanism, play an active or permissive role in regulating the hemodynamic mechanisms that control blood pressure.

Mechanisms of the development of Hypertension

 

The product of cardiac output (= stroke volume [SV] · heart rate) and total peripheral resistance (TPR) determines blood pressure (Ohm’s law). H. thus develops after an increase in cardiac output or TPR, or both. In the former case one speaks of hyperdynamic H. or cardiac output H., with the increase in P_S being much greater than that in P_D. In resistance H., P_S and P_D are either both increased by the same amount or (more frequently) P_D more than P_S. The latter is the case when the increased TPR delays ejection of the stroke volume. The increase of cardiac output in hyperdynamic hypertension is due to an increase in either heart rate or extracellular volume, leading to an increased venous return and thus an increased stroke volume (Frank–Starling mechanism). Similarly, an increase in sympathetic activity of central nervous system origin and/or raised responsiveness to catecholamines (e.g., caused by cortisol or thyroid hormone) can cause an increase in cardiac output.

Resistance hypertension is caused mainly by abnormally high peripheral vasoconstriction (arterioles) or some other narrowing of peripheral vessels, but may also be due to an increased blood viscosity (increased hematocrit). Vasoconstriction mainly results from increased sympathetic activity (of nervous or adrenal medullary origin), raised responsiveness to catecholamines, or an increased concentration of angiotensin II. Autoregulatory mechanisms also include vasoconstriction. If, for example, blood pressure is increased by a rise in cardiac output, various organs (e.g., kidneys, gastrointestinal tract) “protect” themselves against this high pressure. This is responsible for the frequently present vasoconstrictor component in hyperdynamic H. that may then be transformed into resistance H. Additionally, there will be hypertrophy of the vasoconstrictor musculature. Finally, H. will cause vascular damage that will increase TPR (fixation of the H.).

Some of the causes of hypertension are known (e.g., renal or hormonal abnormalities), but these forms make up only about 5 – 10 % of all cases. In all others the diagnosis by exclusion is primary or essential hypertension. Apart from a genetic component, more women than men and more urbanites than country dwellers are affected by primary H.

In addition, chronic psychological stress, be it job-related (pilot, bus driver) or personality-based (e.g., “frustrated fighter” type), can induce hypertension. Especially in “salt-sensitive” people (ca.1 ⁄ 3 of patients with primary H.; increased incidence when there is a family history) the high NaCl intake (ca. 10 –15 g/d= 170– 250 mmol/d) in the western industrialized countries might play an important role. While the organism is well protected against Na+ loss (or diminished extracellular volume) through an increase in aldosterone, those with an increased salt sensitivity are apparently relatively unprotected against a high NaCl intake. In these patients, aldosterone release is so strongly inhibited even at “normal” Na⁺ intake (> 100 mmol/d) that it cannot be lowered any further. A diet with low NaCl intake would in this case bring NaCl balance into the aldosterone regulatory range.

The actual connection between NaCl sensitivity and primary H. has not been fully elucidated, but the possibility is being considered that responsiveness to catecholamines is raised in people sensitive to NaCl. This results, for example, on psychological stress, in a greater thaormal rise in blood pressure, on the one hand, due directly to the effect of increased cardiac stimulation and, on the other hand, indirectly as a result of increased renal absorption and thus retention of Na+ (rise in extracellular volume leads to hyperdynamic H.). The increased blood pressure leads to pressure diuresis with increased Na+ excretion, restoring Na+ balance (Guyton). This mechanism also exists in healthy people, but the pressure increase required for excretion of large amounts of NaCl is much lower. In primary H. (as in disorders of renal function) the NaCl-dependent increase in blood pressure is greater thaormal. A diet that is low in Na+ can thus lower (not yet fixed) H. in these cases. A simultaneously elevated K⁺ supply accentuates this effect for unknown reasons. The cellular mechanism of salt sensitivity still awaits clarification. It is possible that changes in cellular Na+ transport are important. In fact cellular Na+ concentration is raised in primary H., which decreases the driving force for the 3 Na⁺/Ca²⁺ exchange carrier in the cell membrane, as a result of which the intracellular Ca²⁺ concentration rises, which in turn increases the tone of the vasoconstrictor muscles (Blaustein). It is possible that digitalis like inhibitors of Na⁺-K⁺-ATPase are involved. They may be present in larger amounts, or there may be a special sensitivity to them in primary H. Atriopeptin (= atrial natriuretic peptide [ANP]), which has vasodilator and natriuretic effects, is probably not involved in the development of primary H. Although the concentration of renin is not elevated in primary H., blood pressure can be reduced even in primary H. by inhibiting the angiotensin-converting enzyme (ACE inhibitors; see below) or angiotensin receptor antagonists.

The various forms of secondary hypertension make up only 5 –10% of all hypertensive cases, but contrary to primary H. their cause can usually be treated. Because of the late consequences of H., such treatment must be initiated as early as possible. Renal hypertension, the most common form of secondary H., can have the following, often partly overlapping, causes: Every renal ischemia, for example, resulting from aortic coarctation or renal artery stenosis, but also from narrowing of the renal arterioles and capillaries (glomerulonephritis, hypertension-induced atherosclerosis), leads to the release of renin in the kidneys. It splits the dekapeptide angiotensin I from angiotensinogen in plasma. A peptidase (angiotensin–converting enzyme, ACE), highly concentrated especially in the lungs, removes two aminoacids to form angiotensin II. This octapeptide has a strong vasoconstrictor action (TPR rises) and also releases aldosterone from the adrenal cortex (Na+ retention and increase in cardiac output), both these actions raising the blood pressure.

In kidney disease with a significant reduction of the functioning renal mass, Na+ retention can therefore occur even during normal Na+ supply. The renal function curve is steeper thaormal, so that Na+ balance is restored only at hypertensive blood pressure levels. Glomerulonephritis, renal failure, and nephropathy of pregnancy are some of the causes of the primarily hypervolemic form of renal H. Renal H. can also be caused by a renin-producing tumor or (for unknown reasons) by a polycystic kidney.

Ischemia of kidneys as a reason of secondary hypertension

 

The kidney is also central to other forms of hypertension that do not primarily originate from it (primary H., hyperaldosteronism, adrenogenital syndrome, Cushing’s syndrome). Furthermore, in every case of chronic H. secondary changes will occur sooner or later (vascular wall hypertrophy, atherosclerosis): they fix the H. even with effective treatment of the primary cause. If unilateral renal artery stenosis is repaired surgically rather late, for example, the other kidney, damaged in the meantime by the hypertension, will maintain the H.

Causes of Hypertension

 

Hormonal hypertension can have several causes:

In the adrenogenital syndrome cortisol formation in the adrenal cortex is blocked, and thus adrenocorticotropic hormone (ACTH) release is not inhibited. As a result excessive amounts of mineralocorticoid active precursors of cortisol and aldosterone, for example, 11-deoxycorticosterone (DOC), are produced and released. This leads to Na⁺ retention, hence to an increase in extracellular volume (ECV) and thus to cardiac output H. Primary hyperaldosteronism (Conn’s syndrome). In this condition an adrenal cortical tumor releases large amounts of aldosterone without regulation. Also in this case Na+ retention in the kidney leads to cardiac output H. Cushing’s syndrome. Inadequate ACTH release (neurogenic cause; hypophyseal tumor) or an autonomous adrenal cortical tumor increase plasma glucocorticoid concentration, resulting ina raised catecholamine effect (cardiac output increased), and the mineralocorticoid action of high levels of cortisol (Na⁺ retention) lead to H. A similar effect occurs from eating large amounts of liquorice, because the glycyrrhizinic acid contained in it inhibits renal 11β-hydroxysteroid dehydrogenase. As a result, cortisolin the kidneys is not metabolized to cortison but rather has its full effect on the renal mineralcorticoid receptor. Pheochromocytoma is an adrenomedullary tumor that produces catecholamines, resulting in uncontrolled high epinephrine and norepinephrine levels and thus both cardiac output hypertension and resistance hypertension. Contraceptive pills can cause Na⁺ retention and thus cardiac output hypertension.

Increased secretion of aldosterone as a reason of secondary hypertension

 

Neurogenic hypertension. Encephalitis, cerebral edemas or hemorrhage, and brain tumors may lead to a massive rise in blood pressure via central nervous stimulation of the sympathetic nervous system. An abnormally high central stimulation of cardiac action as part of the hyperkinetic heart syndrome may also cause H. The consequences of hypertension most importantly result from atherosclerotic damage in arterial vessels, which can be observed well by means of fundoscopy. Because of the resulting increase in flow resistance, every form of hypertension ultimately creates a vicious circle. Vascular damage finally leads to ischemia of various organs and tissues (myocardium, brain, kidneys, mesenteric vessels, legs), renal ischemia accelerating the vicious circle. Damage to the vascular walls together with hypertension can, for example, lead to brain hemorrhage (stroke) and in the large arteries (e.g., aorta) to the formation of aneurysms and ultimately their rupture. Life expectancy is therefore markedly reduced. American life insurance companies, monitoring the fate of 1 million men whose blood pressure had been normal, slightly, or moderately elevated when aged 45 years, found that of those men who definitely had normal blood pressure (ca. 132/85 mm Hg) nearly 80% were still alive 20 years later, while of those with initially raised blood pressure (ca. 162/100 mm Hg) fewer than 50% had survived.

Consequences of Hypertension

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MYOCARDIAL INFARCTION

Acute myocardial infarction (MI), also known as a heart attack, is characterized by the ischemic death of myocardial tissue associated with atherosclerotic disease of the coronary arteries.

Risk factors.

1. Stress. Emotional or physical stress stimulates sympathetic link of the vegetative nervous system and hypothalamus-hypophysis-suprarenal system. Adrenalin stimulates β-adrenoreceptor-mediated functions of the sympathetic nervous system. Heart work, its metabolism and O₂ need increase. But atherosclerotical plaque results vessel diameter narrowing and reduces the coronary arteries ability to dilate. All these cause acute blood flow insufficiency and ischemia.

2. Age.  Most often myocardial infarction happened in person 40-59 years old.

3. Mail sex. Men are ill myocardial infarction in 2-3 time frequently then women and die in 3-4 time more often. It difference is the result of many factors. Atherosclerosis develops in men earlier then in women because after birth men have thicker intima then women. Women are more adapted to hypoxia; it is the result of periodic menstrual blood loss. Men have trunk type of heart arteries anatomy, but women have ramified vessels and many anastomoses. Estrogens have protective properties as antioxidants.

4. Arterial hypertension. The high arterial pressure causes the increase of heart work and O₂ requirement, besides it accelerates the atherosclerosis development and violation of the heart blood perfusion. Arterial hypertension causes myocardium hypertrophy, which decreases of the vessels number in volume unit. It leads to blood flow insufficiency and hypoxia. Hypertonic crisis (sharp arterial hypertension) is very dangerous because it very increases peripheral vessel resistance, cardiac output, heart work and especially O₂ need (remind about vessel diameter narrowing and reduces the coronary arteries ability to dilate) and acute ischemia.

5.  Diabetes mellitus is complicated by atherosclerosis (so-called macroangiopathy). It results from hyperlipoproteinemia.

 

Causes. If the myocardial ischemia lasts for some time (even at rest [unstable angina]), tissue necrosis, i.e., myocardial infarction (MI), occurs within about an hour. In 85 % of cases this is due to acute thrombus formation in the region of the atherosclerotic coronary stenosis. This development is promoted by

– turbulence, and

– atheroma rupture with collagen exposure.

Both events

– activate thrombocytes (aggregation, adhesion, and vasoconstriction by release of thromboxan). Thrombosis is also encouraged through

– abnormal functions of the endothelium, thus its vasodilators (NO, prostacyclin) and antithrombotic substances are not present (tissue plasminogen activator [t-PA], antithrombin III, heparin sulfate, protein C, thrombomodulin, and prostacyclin).

Rare causes of MI are inflammatory vascular diseases, embolism (endocarditis; valve prosthesis), severe coronary spasm (e.g., after taking cocaine), increased blood viscosity as well as a markedly raised O₂ demand at rest (e.g., inaortic stenosis)

Acute Ischemia in Coronary Atherosclerosis

 

Atherosclerosis of Coronary Arteries

 

Pathogenesis of myocardial infarction

All mechanisms of myocardial infarction beginning can be divided in two groups: first group mechanisms (start mechanisms) provoke acute myocardial ischemia in the result of blood flow violation and second group includes mechanisms of myocardium necrosis.

 Mechanisms of acute myocardial ischemia. Growing up of atherosclerotical plaque decreases coronary artery diameter, violates blood flow through same area of the heart, especially in left ventricle, complicates myocardium nutrition and may cause development so-called critical stenosis and necrosogenic ATP deficiency. Atherosclerotical injury of vessel strengthens its sensitivity to vasospastic influences. It results from violation of NO (vasodilation agent) synthesis by endotoliocytes because NO-synthase activity in such vessel is very decreased. Atherosclerotical vessel injury reduces anticoagulative blood properties because heparin concentration is decreased. This substance is used for lipoproteinlipase activation in hyperlipoproteinemia condition (it is the main risk factor of atherosclerosis), besides injured vessel has reduced antithrombotic potential (antithrombin III deficit), unmasked collagen fibers and fibronectin cause thrombocytes activation, their adhesion, aggregation and then thrombin formation. It is the resultant thrombus that interrupts blood flow. All these mechanisms lead to development of acute myocardial ischemia and onset the mechanisms of myocardiocytes necrosis.

Pathogenesis of Myocardial Infarction

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Mechanisms of myocardium necrosis. Acute ischemia causes deficiency of the energy substances supply (adenosinthreephosphate, creatinphosphate). It results from the decrease of cytochromoxydase activity. Electrons transposition violates and it very reduces Crebs cycle activity. Cardiomyocytes use adenosinthreephosphate and creatinphosphate but restoring of their concentration is inadequate. ADP, AMP, adenosine and inorganic phosphate are accumulated in cardiomyocytes. Energy deficit leads to oppression of Na,K-ATPase and Ca-ATPase activity. Insufficiency of Na, K-ATPase activity causes violation  of  repolarization, Na+ accumulates in the myocardiocytes, myocardium becomes electrically unstabilized and inhomogeneous. These changes contribute to cardiac fatal arrhythmias and sudden death, usually as the result of ventricular fibrillation. During the period of impaired blood flow, injured and ischemic cells revert to anaerobic metabolism, with accumulation of organic acids (especially lactic), much of which is released into the local extracelullar fluid. The necrotic cells become electrically inactive, and their membranes become disrupted, such that their intracellular contents, including potassium, are released into the surrounding extracellular fluid. This causes local areas of hyperkalemia, which can affect the membrane potentials of functioning myocardial cells. As a result of membrane injury and local changes in extracellular potassium and pH levels, some parts of the infracted myocardium are unable to conduct or generate impulses, other areas are more difficult to excite, and still others are overly excitable. These different levels of membrane excitability in the necrotic, injured, and ischemic zones of the infracted area set the stage for development of dysrhythmias and conduction defects after myocardial infarction. Each of these zones in the infracted area conducts impulses differently. Typical ECG changes associated with death of myocardial tissue include prolongation of Q wave, elevation of the ST segment, and inversion of the T wave. Ca²⁺ accumulation results from Ca-ATPase activity oppression, it contributes to cardiomyocytes contracture (cardiomyocytes caot relax), and mitochondriaes damage (Ca2+ excess can be accumulated in mitochondriaes) that make worse energy deficit. Because many enzymes are blocked, Crebs cycle violation leads to accumulation of acetylcoensim A and fat acids. Fat acids oxidation in the β-cycle is impossible because this cycle needs ATP, so concentration of fat acids in cardiomyocytes increases. These substances have ability to dissolve membrane lipids and contribute to damage membrane ion channels. The principal biochemical consequence of acute myocardial infarction is the onset of anaerobic metabolism with inadequate production of energy to sustaiormal myocardial function. As a result, a striking loss of contractile function occurs within 60 seconds of acute myocardial infarction onset. It results from H+ ions accumulation (metabolic acidosis develops). Lactic and piruvate acids accumulation causes depress of creatinkinase activity, this enzyme controls phosphates delivery to myofibrils. Besides, H+ ions obstruct Ca2+-troponin interaction, so actin-myosin interaction is impossible in this condition, all these depress of myocardiocytes contractile function. Phosphates accumulation, which results from macroergic substances breakup, causes insoluble calcium phosphate salt forming and then calcium ions concentration decrease in myocardiocytes.

Some time “reperfusion syndrome” (term reperfusion refers to reestablishment of blood flow in ischemic area) results from the primary decrease of calcium ions concentration. This phenomenon is characterized by the repeat damage of myocardiocytes in the result of rapid come in myocardiocytes Ca2+ ions because big gradient concentration of calcium between blood and heart tissue in zone of ischemia. This paradox arises at stress, during surgical treatment of coronary artery occlusion or thrombolytic therapy. Calcium and catecholanimes cause phospholipases activation; ischemia stimulates lipid peroxidation and exhausts antioxidation system of the membrane protection. All these impair membranes, violates membrane ion channels. Lysosomal membrane damage leads to development myocardiocytes autolysis (it is necrosis which results from action own cell enzymes). Myocardial cells necrosis causes release of different myocardiocytes components that appear in the blood and are the diagnostic markers (myoglobin, creatine kinase, lactate dehydrogenase, troponin).

Early reperfusion (within 15 to 20 minutes) after onset of ischemia can prevent necrosis. Reperfusion after a longer interval can salvage some of the myocardial cells that would have died owing to longer periods of ischemia. It may also prevent microvascular injury that occurs over a longer period. Although much of the viable myocardium existing at the time of reflow ultimately recovers, critical abnormalities in biochemical function may persist, causing impaired ventricular function. The recovering area of the heart is often referred to as stunned myocardium. Because myocardial function is lost before cell death occurs, a stunned myocardium may not be capable of sustaining life, and persons with large areas of dysfunctional myocardium may require life support until the stunned regions regain their function.

A myocardial infarct may involve the endocardium, myocardium, epicardium, or a combination of these. Acute myocardial infarction can be divided into two major types: transmural and subendocardial infarcts. Transmural infarcts involve the full thickness of the ventricular wall and most commonly occur when there is obstruction of a single artery. Subendocardial infarcts involve the inner one third to one half of the ventricular wall and occur more frequently in the presence of severely narrowed but still patent arteries.

Although gross tissue changes are not apparent for hours after onset of an acute myocardial infarction, the ischemic area ceases to function within a matter of minutes, and irreversible damage to cell occurs in about 40 minutes. The principal biochemical consequence of acute myocardial infarction is the onset of anaerobic metabolism with inadequate production of energy to sustaiormal myocardial function. As the result, a striking loss of contractile function occurs within 60 seconds of acute myocardial infarction onset. Changes in cell structure (glycogen depletion and mitochondrial swelling) develop within several minutes. These early changes are reversible if blood flow is restored. Irreversible myocardial cell death occurs after 20 to 40 minutes of severe ischemia. Microvascular injury occurs in about 1 hour and follows irreversible cell injury. If blood flow can be restored within this 20- to 40-minute timeframe, loss of cell viability does not occur or is minimal. The progression of ischemic necrosis usually begins in the subendocardial area of the heart and extends through the myocardium to involve progressively more of the transmural thickness of the ischemic zone. The extent of the infarct depends on the location, rapidity of development, severity of coronary vessel occlusion and vasospasm, amount of heart tissue supplied by the vessel, duration of the occlusion, metabolic needs of the affected tissue, extent of collateral circulation, and other factors such as heart rate, blood pressure.

Myocardial Infarction

 

ECG. A prominent characteristic of transmural infarction (tmI) is an abnormal Q wave of > 0.04 seconds and a voltage that is > 25 % of overall QRS voltage. It occurs within one day and is due to the necrotic myocardium not providing any electrical signal, so that when this myocardial segment should be depolarized (within the first 0.04 s), the excitation vector of the opposite, normal portion of the heart dominates the summated vector. This “0.04 vector” therefore “points away” from the site of infarction so that, for example, in anterior-wall infarction, it is registered particularly in leads V5, V6, I, and aVL as a large Q wave (and small R). (In a transmural infarction of the posterior wall such Q wave changes caot be registered with the conventional leads). Abnormal Q waves will still be present years later, i.e., they are not diagnostic of an acute infarction. An infarction that is not transmural usually causes no Q changes.

ST segment elevation in the ECG is a sign of ischemic but not (yet) dead myocardial tissue. It occurs

– during an anginal attack (see above)

– iontransmural infarction

– at the very beginning of transmural infarction

– at the margin of a transmural infarction that occurred hours to days before

The ST segment returns to normal one to two days after an MI, but for the next few weeks the T wave will be inverted

ECG in Coronary Infarction

 

If sizeable portions of the myocardium die, enzymes are released from the myocardial cells into the bloodstream. It is not so much the level of enzyme concentrations as the temporal course of their maxima that is important in the diagnosis of MI. Myocardial creatine kinase (CK-MB [MB=muscle, brain]) reaches its peak on day 1, aspartate aminotransferase (ASAT) on day 2, and myocardial lactate dehydrogenase (LDH1) on days three to five.

Possible consequences of MI depend on site, extent, and scarring of the infarct. In addition to various arrhythmias, among them acutely life-threatening ventricular fibrillation, there is a risk of a number of morphological/mechanical complications:

– Tearing of the chordae tendineae resulting in acute mitral regurgitation;

– Perforation of the interventricular septum with left-to-right shunting;

– Fall in cardiac output that, together with

– stiffened parts of the ventricular wall (akinesia) due to scarring,

– will result in a high end-diastolic pressure. Still more harmful than a stiff infarct scar is

– a stretchable infarct area, because it will bulge outward during systole (dyskinesia), which will therefore—at comparably large scar area—be more likely to reduce cardiac output to dangerous levels (cardiogenic shock) than a stiff scar will;

–       Finally, the ventricular wall at the site of the infarct can rupture to the outside so that acutely life-threatening pericardial tamponade occurs.

Consequences of MI

 

HEART FAILURE

Heart insufficiency develops at loading disparity on heart of it ability to execute the work, which determines by amount of blood, which comes to the heart, but by resistance to banishment of blood in aorta and pulmonary trunk. So, heart insufficiency arises, when a heart with available resistance can’t pump into artery all blood, which comes by veins.

 

There are three pathophysiologic heart insufficiency variants:

1.     Heart insufficiency because of overload. The main causes are high resistance to cardiac out put, for example generall or pulmonary hypertension, heart apertures stenosis; and big diastolic blood inflow, for example atriovenous fistulas, heart values insufficiency, heavy physical work.

2.     Heart insufficiency because of myocardium damage.

3.     All causes are divided into four groups, as following: 

a) infectional and toxic damages (different etiology myocarditis, alcohol myocardiopathy);

b) total or local hypoxia (coronary heart disease, pneumonia, obstructive bronchitis, bronchial asthma;

c) different metabolism disorders (metabolism of vitamins, carbohydrate, protein, urine acid and others), in such cases insufficiency develops even at normal or diminished heart load;

d) neurotrophical and hormone abnormal influences on the heart (continuous emotional or physical stress, hyperthyreosis, hyperfunction of suprarenal glands).

4.            Mixed heart insufficiency variant. It arises at combination of myocardium damage and its overload, for example at rheumatism, when of inflammatory myocardium damage and valvular heart violations are combined.

 

 

 

Causes and Pathogenesis of Left Ventricular Failure

Stages of heart failure development

Heart failure has three stages of development:

·        the first – emergency condition

·        the second- stable adaptation (bouth these stages display the compensation)

·       the third – exhaustion (decompensation).

If the organism or some organs need more nutritious substances and O2 the heart work is increased iorm. At myocardium damage when the normally working cardiomyocites amount is decreased and, as the result, is increased of each cardiomyocites load or in heart overflow condition heart work is provided by the alarm cardiac and extracardiac mechanisms (first stage).

Compensatory mechanisms

Compensatory mechanisms that are activated in heart failure include: increased ventricular preload, or the Frank-Starling mechanism, by ventricular dilatation and volume expansion; peripheral vasoconstriction, which initially maintains perfusion to vital organs; myocardial hypertrophy to preserve wall stress as the heart dilates; renal sodium and water retention to enhance ventricular preload; and initiation of the adrenergic nervous system, which raises heart rate and contractile function. These processes are controlled mainly by activation of various neurohormonal vasoconstrictor systems, including RAAS, the adrenergic nervous system, and non-osmotic release of arginine-vasopressin. These and other mechanisms contribute to the symptoms, signs, and poor natural history of heart failure. In particular, an increase in wall stress along with neurohormonal activation facilitates pathological ventricular remodelling; this process has been closely linked to heart failure disease progression. Management of chronic heart failure targets these mechanisms and, in some instances, results in reverse remodelling of the failing heart.

Myocardium hypertrophy

So, in such condition another (long-time) compensatory mechanism is stimulated. The myocardium hypertrophy develops, which is characterised by  heart mass increase and  reinforces heart function (second stage). Long time cardiac muscle loading leads to increase of cardiomyocite functional units loading, therefore muscular and connective cells genes are activated.  Consequently, in experimental animal over a little hours after constriction of aorta in heart cells appear the reinforcing signs of nuclear function,  RNA synthesis augmentations and amount of ribosomes. This indicates on that albumens synthesis  in myocardium cells mainly regulates by loading level.  Also this process is controled by mechanisms of nevro-humoral regulation.

Myocardium hypertrophy – adaptive phenomenon, directed on execution of raised work without essential loading rise of myocardium units mass. This is perfect adaptation. Consequently, sportsmen’s myocardium hypertrophy  allows heart to execute great work. Nervous heart regulation also changes, that considerably broadens a diapason of its adaptation and possibility to be tolerance to long time loadings. But also at the pathological processes in the heart hypertrophy can compensate the long timeviolations.

An hypertrophic heart differs from normal by some changed functions and structural signs, which display possibilities to overcome raised loading for a long time, and preconditions presence for beginnings of pathological changes.  The heart mass increase is the result of each muscle fibre thickening, that is attended with change of intracellular structures correlation.

Myocardium hypertrophy

 

Volume of cell augments in proportion to cub of linear dimensions, and surface – in square proportion to them, it results in cellular surface and cell mass unit proportion decrease.  It’s known, that cell surface plays key role in process of cells metabolism  – oxygen and nutrients using, evacuation of metabolism products, metabolism of water and electrolytes. Aggravation of myocardiocytes metabolism causes the inadequate heart muscle nutrition, especially its central departments.

A cell membrane is the place of membrane charge conduction for all tubular system and sarcoplasmatic net. Because growth of these formations at hypertrophy of muscle fibre also falls behind, thus preconditions for violation of contraction and weakening of cardiomyocytes arises. Retardation of calcium ions and their accumulation in sarcoplasma results in worse contraction. Aggravation of calcium   ions come back causes inadequate cardiomiocytes relaxation.  Sometimes local contracture of cardiomyocytes can arise. In case of hypertrophy cell volume increases more thauclear volume.  In such case, only the linear nuclear size is increased because chromosomes count and DNA level is rised.  As the nuclear   role is controle of protein synthesis, and intracellular structures renewal, thus relative nuclear size reduction can cause protein synthesis violation and aggravation of cardiomiocytes nutrition. At first mitochondria mass increases more quickly, than mass of contractive proteins at hypertrophy. It causes the conditions for adequate energy provision and compensation of heart function. But then mitochondria mass begins fall down and cytoplasm mass begins increases. Mitochondria begins suffer on maximum loading, it results in their destructive changes, and their function effectiveness decrease, for example oxidative phosphorilation disturbs. This causes energy provision aggravation of hypertrophied cells. Cardiomiocytes mass increase often does not attended with adequate augmentation of capillary net, especially in cases of fast heart hypertrophy development.  Big coronal arteries are also have no ability to be conformed to necessary adaptive growth. That’s why provision of hypertrophied myocardium becomes worse vascular at loading time.  Disturbed structure of insertive disks and Z-lines in hypertrophied heart is broken, so electric myocardium activity changes,  heart coordination contraction  becomes worse in general.

A heart nervous structures is pulled in process of myocardium hypertrophy. Reinforced activity of intra- and extracardial nervous elements is observed. However, growth of nervous elements is tardier than a growth of contractive myocardium elements.  Exhaustion of nervous cells takes place; trophic influences disturb, a contents of norepinephrine in myocardium diminishes, it results in aggravation of contractive properties and myocardium reserves mobilization. So, a regulation of the heart functions disturbs too. A hypertrophied heart due to big mass of contractive and energy provider elements can to work adequate more time, than healthy heart, which is provided by normal metabolism. But adaptation abilities to the changes of loading and   adaptative possibilities measuresof hypertrophied heart are limited because functional reserve is decreased. Intracellular and extracellular structures are not balanced, it results in greater impressionability of hypertrophied heart in case of inauspicious factors influence. Long time overloading of cardiac muscles causes of functions. The main reason is contractive function disorder in the result of insufficient energy synthesis by mitochondrias and also violation of energy using by contractive fibres.

One of these pathological variants can prevail at different heart insufficiency types, for example, violation of using energy is main in case of long time heart hyperfunction. At the same time can appear contractive function depression common aggravation of muscle fibre relaxation, it results in local muscle contractures, and then dystrophy and death of cardimyocytes arises. Overloading distributes unevenly between different groups of muscle fibres: muscle fibres, which are more intensive worked, become weak quickly, die and substitute for connective tissue. In such case other myocardiocytes are overloaded.

Connective tissue cells squeare of nearby cells, mechanical heart properties changed cause of nutrition disturbance.  It is believed  that normal work is impossible  when replacement by connecting tissue 20-З0 % of heart mass is really. Dilatation of heart cavities can arises at distrophy of myocardium, it causes further decrease of cardiac contraction force (myogenic dilatation). In this case diastolic blood volume increases  in heart cavities,  and it causes the veins overflow.

Raised blood pressure in right atria cavity and in cava veins straightly (by influence on sino-atria ganglia) and reflexly (Beinbrige’s reflex) causes tachycardia, which complicates violation of myocardium metabolism. That’s why heart cavities dilatation and tachycardia are the dangerous symptoms of decompensation development.

Valuing biological myocardium hypertrophy sense,  turn mind to internal discrepancy of given phenomenon. On one hand, this is a prettily perfect adaptative mechanism, which provides for a long time execution of raised work by heart in normal  and  pathological  conditions,  on  another – structure  peculiarities  and  functions  of  hypertrophied  heart  are  by precondition for development of pathology. Dominance first or second in each concrete case determines peculiarities of pathological process.

According to metabolism, structures and myocardium functions disorders in phase of compensative heart hyperfunction there are three stages.

1. Emergency stage develops directly after heart overload, it characterizes by combination of pathological changes in myocardium (disappearance of glycogen, decrease of creatinphosphate, intracellular potassium concentration decrease and sodium one increase, stimulation of glycolysis and lactate accumulation). This stage is characterized by the fast heart mass increase (during weeks) due to protein synthesis and increase of  muscle fibres thickness.

2. Stage of completed hypertrophy and steady hyperfunction. In this stage myocardium mass is increased on 100 – 120 % and couldn’t longer increases. Metabolism and structures of myocardium  is normal; oxygen consumption, energy synthezise, macroergic substances contents does not differ from norm, blod flow is normalized. A hypertrophic heart is adaptated to new loading conditions.

3. Stage of gradual exhaustion of the heart and progressing of cardiosclerosis is characterized by deep disorder of metabolism and structures in power-creating and contractive elements of myocardium. Part of myocardiocytes dies and replaces by connective tissue. Heart regularly apparatus is disturbed. Progressing of compensatory mechanisms exhaustion leads to chronic heart insufficiency development, and then to the blood circulation insufficiency.

 

Chronic heart insufficiency

Chronic heart insufficiency develops gradually, mainly by reason of metabolic violations in myocardium at long time heart hyperfunction or at different kinds of myocardium injury appearances. Because heart output is decreased, blood supply of organs, which are localized on heart outflow ways, diminishes.  At the same time by reason of heart inability to pump all blood, that comes to it, stagnation on blood inflow ways develops (in veins). As volume of venous channel approximately in 10 time exceeds an arterial channel volume, a considerable amount of blood nuddle together in veins. Blood insufficiency acquires some specific signs in case of work violation mainly some heart ventricle circulation and is called by insufficiency of left-ventricle type or right-ventricle one. In first case blood stagnation is observed in veins of small blood circulation, that can to be reason of lungs edema, in second case – in veins of big blood circulation, in such case liver is enlarged, the edema of legs and  ascites appears. Violation of contractive myocardium function does not at once causes development of the blood circulation insufficiency.

As adaptive mechanism at first peripheral arterioles resistance of big blood circulation reflexly decreases, that relieves a blood flow to majority of organs. Arterioles of small blood circulation reflexly narrow, thus to left atria blood inflow diminishes and at the same time pressure in system of pulmonary capillaries decreases. Last mechanism is the pulmonary capillaries protection from  overflow of the  blood and it prevents of lungs edema development.  There is typical some function discord sequence of different heart departments. Consequently, decompensation of strong left ventricle functions quickly causes violation of left atria function, blood stagnation in small blood circulation and constriction of pulmonary аrteriole. But then a less stronger right ventricle is overloaden, that leads to its decompensation and development of the right-ventricle type insufficiency.

Hemodynamic indexes of chronic heart insufficiency change like so:  heart volume per minute decreases (from 5-5,5 to 3-4 l/min); speed of blood stream decreases in 2-4 times; arterial pressure changes a little; venous pressure rises; the capillaries and postcapillares vein are dilated; a blood stream slows; pressure rises.  The pathological changes of other organs, which arise later, are the result of  prescribed changes.

Retardation of blood stream in big blood circulation system and violation of the lung blood circulationin  causes increase  of renewed hemoglobin amount in blood. Skin and mucous membranes have a typical blue colour (cyanosys). Tissues have no adequate quantity of oxygen. Hypoxia is characterized by accumulation of organic acids and CO₂ that leads to acidosis development. Acidosis and hypoxia results in violation of breathing regulation and causes dyspnoea. Erythropoiesis is stimulated, general volume of circulatory blood and relative contents of blood cells is increased too, all these changes display of hypoxia compensation, but in same time are the reasen of blood viscosity increase and violation of blood hemodinamic properties.

 By reason of high pressure in capillaries and tissue acidosis  an edema develops, which, into its turn, reinforces hypoxia, because diffuse way from capillary to cell is increased. The general violations of water and electrolytes metabolism (sodium and water accumulation) streingthen stagnant edema. This is one more proof of internal compensation mechanisms contradictions during pathological process. Mechanisms, which evolutional happened for guaranteeing of salts and liquid sufficient contentsfin organism in case of  water loss and blood loss complicates of patient condition in case of  heart insufficiency. Surplus of common used in patients blood, which have heart insufficiency,  does not excret by kidneys like in healthy man, and accumulates in organism together with equivalent water volume.

Violation of tissues nutrition at long time  of the blood supply insufficiency causes deep and inconvertible disorder of intracellular metabolism. It results in violation of protein synthesis, especially ensime of respiratory metabolism ways, in development of histotoxic type of hypoxia. These phenomena are typical for terminal phase of circulatory insufficiency. Blood flow insufficiency in digestive tract  causes terrible exhaustion of the organism, so – called cardiac cachexia.

Pathophysiological mechanism of heart insufficiency another origin is a cardiomyocites damage. It can be result of inflammation or dystrophy, genetic defects, infection, intoxication or immunopathological processes, illnesses, which cause myocardium hypoxia or metabolism violations (protein, lipid, mineral and vitamin). Uneffective ATP synthezise or ATP using by cardiomyocytes can be really. Processes of uneffective ATP synthezise arises in case of oxygen in come insufficient to the cardiomyocyte, O₂  concentration decrease or ischemia, and also at violation of oxidative substances in come, uneffective mitochondrias functions, creatinekinase – creatinephosphate system system violation. Uneffective ATP using arises in case of myofibril proteins and sarcoplasmal net damage and at disorder of calcium ions, potassium, and sodium metabolism. Violation of cardiomyocytes membrane structures by lipid peroxides, by free radicals and hydroperoxyde can be one of damage mechanisms. Free radical oxidation can be result of oxidative metabolism violation cardiomyocyte or antioxidant systems insufficiency. First functions of specific membrane pumps (Na⁺, К⁺–АТP-ase, Са⁺⁺–АТP-ase) disturb, than gradually membrane penetrability and membrane phospholipid damage arises. Violation of membrane results in change of sodium, potassium, chlorine ions and water stream. It causes swelling of cell, and calcium ions accumulation and development of  calcium toxic effects. It is possible the increase of α– and  β– adrenoreceptors amount and free catecholamine concentration, that deepens a primary damage. In case of metabolism violations, which turned in extremely long ways, death of cardiomyocytes is possible. The number of working cardiomyocytes decreases and it leads to their overload, thus mechanisms of compensations are the same as earlier prescribed.

 

Heart Failure: Pathogenesis of Syndroms

 

Metabolic demands of the heart are increased with everyday activities such as mental stress, exercises, and exposure to cold. In certain disease states, such as thyrotoxicosis, the metabolic demands may be so excessive that blood supply is inadequate despite normal coronary arteries. In other situations, such as aortic stenosis, the coronary arteries may not be diseased, but the perfusion pressure may be insufficient to provide adequate blood flow. Symptomatic myocardial ischemia (angina pectoris) and silent, or painless, myocardial ischemia are important functional indicators of active CHD and increased risk of myocardial infarction or sudden death. The term angina pectoris is derived from a Latin word meaning to choke. Angina pectoris (stenocardia) is a symptomatic paroxysmal chest pain or pressure sensation associated with transient myocardial ischemia. The pain typically is described as constricting, squeezing, or suffocating. It usually is steady, increasing in intensity only at the onset and end of the attack. The pain of angina commonly is located in the precordial or substernal area of the chest; it is similar to myocardial infarction in that it may radiate to the left shoulder, jaw, arm, or other areas of the chest (in some persons may be epigastric pain).

 

CLINICAL PATHOPHYSIOLOGY OF PULMONARY SYSTEM

Breathing through the lungs has two functions: firstly, to supply O₂ to the blood and, secondly, to regulate the acid–base balance via the CO₂ concentration in the blood. The mechanics of breathing serve to ventilate the alveoli, through whose walls O₂ can diffuse into the blood and CO₂ can diffuse out. Respiratory gases in the blood are largely transported in bound form. The amount transported depends, among other factors, on the concentration in blood and on pulmonary blood flow (perfusion). It is the task of respiratory regulation to adapt ventilation to the specific requirements.

A number of disorders can affect breathing in such a manner that ultimately sufficient O₂ uptake and CO₂ release cao longer be guaranteed.

In obstructive lung disease flow resistance in the respiratory tract is raised and ventilation of the alveoli is thus impaired. The primary consequence is hypoventilation in some alveoli (abnormal distribution) or of all alveoli (global hypoventilation). If alveolar ventilation ceases completely, a functional arteriovenous shunt occurs. However, hypoxia leads to constriction of the supplying vessels, thus diminishing blood flow to the under ventilated alveoli.

In restrictive lung disease the loss of functioning lung tissue reduces the area of diffusion and in this way impairs gaseous exchange. There is also a reduced area of diffusion in emphysema, a condition characterized by alveoli that have a large lumen but are also diminished iumber. Disorders of diffusion canal so be caused by an increased distance between alveoli and blood capillaries. If alveoli and capillaries are completely separated from one another, this results in both a functional dead space (nonperfused alveoli) and an arteriovenous shunt.

Restrictive and obstructive lung disease as well as cardiovascular disease may affect lung perfusion. Decreased perfusion results in a reduced amount of gases being transported in blood, despite adequate O₂ saturation and CO₂ removal in the alveoli. If flow resistance is increased, severe consequences for the circulation are possible, because the entire cardiac output (CO) must pass through the lungs. Breathing is also impaired in dysfunction of the respiratory neurons as well as of the motoneurons, nerves, and muscles that are controlled by them. The changes in breathing movement that occur when the breathing regulation is abnormal do not, however, necessarily lead to corresponding changes of alveolar ventilation.

Consequences of inadequate breathing can be hypoxemia, hypercapnia or hypocapnia (increased or decreased CO₂ content, respectively) in arterialized blood. The supply of O₂ to the cells as well as the removal of CO₂ from the periphery do not only depend on adequate respiration but also on unimpaired oxygen transport in the blood and on intact circulation.

Pathophysiology of Respiration

 

Ventilation, Perfusion Abnormalities

To reach the alveoli, inspired air must pass through those respiratory pathways in which no gaseous exchange takes place (dead space), i.e., normally the mouth, pharynx and larynx, trachea, bronchi and bronchioles. On its way the air will be warmed, saturated with water vapor, and cleansed.

The tidal volume (V_T) contains, in addition to the volume of air that reaches the alveoli (V_A), the volume of air that remains in the dead space (V_D). If tidal volume is less than V_D (normally ca. 150 ml), the alveoli are not ventilated with fresh air. When tidal volume is greater than V_D, the proportion of alveolar ventilation rises with increasing V_T. Alveolar ventilation may even be reduced during hyperpnea, if the depth of each breath, i.e., V_T, is low and mainly fills the dead space.

Increased ventilation can occur as a result of either physiologically (e.g., during work) or pathophysiologically (e.g., in metabolic acidosis) increased demand, or due to an inappropriate hyperactivity of the respiratory neurons.

Decreased ventilation can occur not only when the demand is reduced, but also when the respiratory cells are damaged, or wheeural or neuromuscular transmission is abnormal. Further causes include diseases of the respiratory muscles, decreased thoracic mobility (e.g., deformity, inflammation of the joints), enlargement of the pleural space by pleural effusion or pneumothorax as well as restrictive or obstructive lung disease.

Changes in alveolar ventilation do not have the same effect on O₂ uptake into the blood and CO₂ release into the alveoli. Because of the sigmoid shape of the O₂ dissociation curve, O₂ uptake in the lungs is largely independent of alveolar partial pressure (PA_O2). If there is only minor hypoventilation, the partial pressure of O₂ in the alveoli and thus in blood is reduced, but the O₂ dissociation is at the flat part of the curve, so that the degree of hemoglobin saturation and thus O₂ uptake in blood is practically unchanged. On the other hand, the simultaneous increase in CO₂ partial pressure in the alveoli and blood leads to a noticeable impairment of CO₂ release.

Massive hypoventilation lowers the O₂ partial pressure in the alveoli and blood, so that oxygen is at the steep part of the O₂ binding curve of hemoglobin and O₂ uptake is therefore impaired much more than CO₂ release is. Hyperventilation increases the O₂ partial pressure in the alveoli and blood, but cannot significantly raise the level of O₂ uptake into the blood because the hemoglobin is already saturated. However, hyperventilation boosts CO₂ release.

Lung perfusion is increased, for example, during physical work. It can be reduced by heart or circulatory failure, or by constriction or occlusion of pulmonary vessels.

A moderate increase in lung perfusion while ventilation remains unchanged increases O₂ uptake virtually in proportion to the amount of blood flow. Even though the alveolar O₂ partial pressure falls slightly because of the increased O₂ uptake from the alveoli into the blood, this has little influence on O₂ saturation in the blood. It is only when the alveolar partial pressure of O₂ falls into the steep part of the O₂ dissociation curve that a decrease of alveolar O₂ partial pressure significantly affects O₂ uptake into blood. At those O₂ partial pressures a further increase in lung perfusion only slightly increases O₂ uptake. Furthermore, at very high lung perfusion flow, the contact time in the alveoli is not sufficient to guarantee that partial O₂ pressure in blood approaches that in the alveoli. If lung perfusion is reduced, O₂ uptake is proportionally decreased.

CO₂ removal from blood is dependent on lung perfusion to a lesser extent than O₂ uptake. In case of reduced lung perfusion (but constant ventilation and venous CO₂ concentration) the CO₂ partial pressure in the alveoli falls and thus favors the removal of CO₂ from the blood. This, in turn, attenuates the effect of the reduction in perfusion. At raised lung perfusion an increase of alveolar CO₂ concentration prevents a proportional rise in CO₂  release.

Ventilation, Perfusion of the lungs

 

Diffusion Abnormalities

O₂  has to diffuse from the alveoli to hemoglobin in the erythrocytes, and CO₂ from the erythrocytes into the alveoli. The amount of gas (M) that diffuses across the diffusion barrier between alveoli and blood per unit time is proportional to the diffusion area (F) and the difference in partial pressure between alveolar gas (PA) and blood (Pblood), and inversely proportional to the length of the diffusion pathway (d): M = K х F (P_A – Pblood)/d

Krogh’s diffusion coefficient K is about 20 times greater for CO₂ than for O₂. The diffusion capacity D (= K х F/d) is about 230 mL х min^–1 х kPa^–1 (1.75 L х min^–1 х mmHg^–1) in a healthy person.

A diffusion abnormality exists when the ratio of diffusion capacity to lung perfusion (or cardiac output) is reduced.

The diffusion capacity may be reduced by increased distance. When a pulmonary edema occurs, raised intravascular pressure means plasma water is exuded into the interstitial pulmonary tissue or into the alveoli, and thus increases the diffusion distance. Inflammation causes a widening of the space between alveoli and blood capillaries as a result of еdema and the formation of connective tissue. In interstitial lung fibrosis, the connective tissue forces alveoli and blood capillaries apart. It is the distance between hemoglobin and alveolar gas which matters. Thus, the distance can also be slightly increased by vessel dilation (inflammation) or anemia.

A diminished diffusion capacity may also be caused by a reduction of the diffusion area, as after unilateral lung resection, loss of alveolar septa (pulmonary emphysema), or in loss of alveoli in pneumonia, pulmonary tuberculosis, or pulmonary fibrosis. The diffusion area can also be reduced by alveolar collapse (atelectasis), pulmonary edema, or pulmonary infarction.

Diffusion abnormalities become obvious when cardiac output is large, blood flows rapidly through the lungs, and the contact time of blood in the alveoli is thus quite brief. In effect, diminution of the diffusion area (e.g., after unilateral lung resection) also means a shorter contact time in the remaining lung tissue, because the same amount of blood will now pass through a reduced amount of lung tissue per unit of time. An increased O₂ demand during physical exercise forces an increase in cardiac output and can thus reveal a diffusion abnormality.

Abnormal diffusion primarily affects O₂ transport. In order for the same amount of gas to diffuse per time, the O₂ gradient must be twenty times greater than the CO₂ gradient. Should the diffusion capacity in an alveolus be diminished while ventilation remains constant, O₂ partial pressure will fall in the blood leaving the alveolus. If all alveoli are similarly affected, O₂ partial pressure will fall in the pulmonary venous (and thus systemic arterial) blood. If O₂ consumption remains constant, O₂ partial pressure will necessarily be lower also in deoxygenated (systemic venous) blood. For this reason patients with a diffusion abnormality get blue lips on physical exertion (central cyanosis). The primary effects of abnormal diffusion on CO₂ transport and acid–base metabolism are much less marked. Hypoxia stimulates the respiratory neurons, and the resulting increase in ventilation can produce hypocapnia. However, the hypoxemia due to abnormal diffusion can only be slightly improved by hyperventilation. In the example given, doubling of the alveolar ventilation at unchanged O₂ consumption increases alveolar O₂ partial pressure by only 4 kPa to 17 kPa (30 mmHg to 129 mmHg), but the increased O₂ gradient does not normalize the O₂ saturation of the blood. At the same time, respiratory alkalosis develops, despite the abnormal diffusion, because of the increased CO₂ removal. Hypoxemia due to abnormal diffusion can be neutralized with O₂ -enriched inspiratory air. The degree of hypoxemia can be lessened by decreasing O₂ consumption.

Diffusion Abnormalities

 

Restrictive Lung Disease

Restrictive lung disease is a term given to an anatomical or functional loss of gaseous exchange area.

An anatomical loss occurs after removal (resection) or displacement (e.g., by a tumor) of lung tissue. Atelectasis may also lead to a decrease in diffusion area.

A functional decrease in exchange area occurs is if plasma water is exuded into alveoli, for example, in pulmonary edema or in inflammation (increased vascular permeability, e.g., in pneumonia). In pulmonary fibrosis proliferating connective tissue displaces intact pulmonary parenchyma (decrease in diffusion area), infiltrates between capillaries and alveoli (increase in distance), and prevents the normal expansion of the lung (impairment of alveolar air exchange). Pulmonary fibrosis can be caused by inflammatory reaction against connective tissue (so-called collagen disease) or by inhalation of dust which contains silicate or asbestos. Sometimes no cause is found (idiopathic pulmonary fibrosis [Hamman–Rich syndrome]). Local or generalized impairment of lung expansion can also occur in thoracic deformities, diaphragmatic paralysis, or adhesion of both pleural layers (as a result of inflammation [pleural fibrosis]).

Pneumothorax is also a restrictive lung disease. If there is an open connection between the pleural space and outside air (thoracic injury) or the alveoli (torn alveolar wall due to over distension), air enters and the ipsilateral lung collapses. Breathing is also impaired in the other lung, because the pleural pressure on the healthy side falls on inspiration and as a result the mediastinum is displaced to the healthy side. On expiration the pressure rises and the mediastinum moves toward the collapsed side. This mediastinal flutter reduces the breathing excursion (V_T) of the healthy lung. If a valve-like mechanism develops on the injured side, allowing air into the pleural space but not out of it, tension pneumothorax develops. It is especially the burst alveoli that often act like valves: the collapsed lung expands on inspiration, allowing air to enter the pleural space through the damaged alveolus, but when lung and alveolus collapse during expiration the escape of air is prevented. The mediastinum is massively displaced by the increasing pressure toward the healthy side and breathing correspondingly impaired. The increase in intrathoracic pressure also reduces the venous return and thus right ventricular filling, as a consequence of which cardiac output falls.

In whole-body plethysmography the air in the pleura is indistinguishable from that in the alveoli, because both are equally reduced on expiration. However, inspired test gas is distributed only throughout the lung. In pneumothorax, the intrathoracic volume measured by whole-body plethysmography is thus greater than the alveolar volume obtained with a test gas.

Restrictive pulmonary disease causes a fall in compliance (C), vital capacity (VC), functional residual capacity (FRC), and diffusion capacity. The latter leads to diffusion abnormality and thus to hypoxemia (SO₂ = oxygen saturation of blood). Maximum breathing capacity (V_max) and forced expiration volume in 1 second (FEV1) are usually reduced, but relative forced expiration volume (normally 80 % of VC) is generally normal. To inspire a certain volume, greater negative pressure thaormal is required in the pleural space and more energy thus has to be expended during breathing (increased work of breathing; V ˙ = ventilation flow). Reduction of the vascular bed by removing lung tissue or by compressing blood vessels increases vascular resistance. Greater pressure is required to pump the blood through the pulmonary vascular bed, pressure which must be generated by the right heart. The consequence is a raised load on the right ventricle (cor pulmonale).

Causes and Effects of Restrictive Lung Diseases

 

Obstructive Lung Disease

In order to reach the alveoli air must pass through the respiratory tract or airways, which present a resistance to the flow. This resistance is determined by the lumen in the tract. In particular the narrow lumen of the bronchioles can be further narrowed by mucus and the contraction of the bronchial musculature. Mucus is secreted in order to trap pathogens and dirt particles. It is transported toward the mouth by the cilia of the lining epithelium and then swallowed. As the cilia cannot propel very sticky mucus, an electrolyte solution is usually secreted that lifts the mucus from the cilia, so that mucus moves toward the mouth on a thin fluid layer. The lumen can be narrowed by the action of the bronchial muscles, which increases the likelihood of pathogens being caught in the mucus. The disadvantage, however, is that narrowing raises flow resistance. Obstructive lung diseases are characterized by an increased flow resistance.

Intrathoracic increase in resistance is usually due to a narrowing or obstruction of the bronchi, by either external compression, contraction of bronchial muscles, thickening of the lining mucus layer, or obstruction of the lumen by mucus. Most of these changes are the result of asthma or chronic bronchitis. In asthma there is an allergy to inhaled antigens (e.g., pollen). These antigens cause an inflammation of the bronchial mucosa leading to the release of histamine and leukotrienes (called slow reacting substances in anaphylaxis [SRSA]). The bronchial muscles contract and mucus secretion as well as vessel permeability (mucosal edema) are increased under the influence of these mediators. In addition to the inhaled antigens, microorganisms in the mucosa may also act as antigens (infectious–allergic asthma). Here there is no clear cut distinction between asthma and bronchitis. Obstructive lung disease can also be the result of cysticfibrosis (CF). As the result of an autosomal recessive genetic defect of the CF transmembrane regulator (CFTR) there is decreased secretion and hyperreabsorption of fluid, and mucus cao longer be cleared from the airways. The result is obstructive lung disease. The lung’s reduced ability to retract (flaccid lung) can also lead to obstructive lung disease, because reduced elastic recoil (increased compliance) of the lung requires an increase in pressure during expiration, resulting in compression of the intrathoracic air ways (see below).

Extrathoracic increase in resistance occurs, for example, in paralysis of the vocal chords, edema of the glottis, and external tracheal compression (e.g., by tumor or goitre). In tracheomalacia the tracheal wall is softened and collapses on inspiration.

The effect of obstructive lung disease is reduced ventilation. If extrathoracic obstruction occurs, it is mainly inspiration that is affected (inspiratory stridor), because during expiration the pressure rise in the prestenotic lumen widens the narrowed portion. Intrathoracic obstruction mainly impairs expiration, because the falling intrathoracic pressure during inspiration widens the airways. The ratio of the duration of expiration to that of inspiration is increased. Obstructed expiration distends the alveolar ductules (centrilobular emphysema), lung recoil decreases (compliance increases), and the midposition of breathing is shifted toward inspiration (barrel chest). This raises the functional residual capacity. Greater intrathoracic pressure is necessary for expiration because compliance and resistance are increased. This causes compression of the bronchioles so that the airway pressure increases further. While the effort required to overcome the elastic lung resistance is normal or actually decreased, the effort required to overcome the viscous lung resistance and thus the total effort of breathing is greatly increased. The obstruction reduces maximum breathing capacity (V ˙max) and FEV₁, and the differing ventilation of various alveoli results in abnormal distribution. The hypoxia of under ventilated alveoli leads to vasoconstriction, increased pulmonary vascular resistance, pulmonary hypertension, and an increased right ventricular load (cor pulmonale).

Obstructive Lung Diseases

 

Pulmonary Emphysema

Emphysema is characterized by an increase in the volume of the airways distal to the bronchioles. Centrilobular emphysema, with predominant distension of the alveolar ducts and respiratory bronchioles, is distinguished from panlobular emphysema, in which the terminal alveoli in particular are distended. In flaccid lung there is merely a loss of elastic recoil. The disease can affect a circumscribed area (local emphysema), or the entire lung (generalized emphysema). Emphysema is one of the most frequent causes of death.

Emphysema

 

Centrilobular emphysema is caused mainly by obstructive lung disease: in flaccid lung there is a loss of connective tissue of unknown cause; inpanlobular emphysema there is additional loss of alveolar septa. In the elderly an increase in alveolar volume in relation to alveolar surface regularly occurs. In some patients (ca. 2 %) there is a deficiency in α1-proteinase inhibitor (α1-antitrypsin), which normally inhibits the action of proteinases (e.g., leukocyte elastase). This enzyme is produced in the liver; its mutation can affect its secretion and/or function. In either case decreased inhibition of the proteinases leads to a breakdown and thus a loss of lung tissue elasticity. If secretion is disturbed, the accumulation of the defective protein in the liver cells can additionally lead to liver damage. Finally, a lack of proteinase inhibition can also affect other tissues, for example, renal glomeruli and the pancreas may be damaged. α1-antitrypsin is oxidized and thus inhibited by smoking, which thus promotes the development of emphysema even in some one without a genetic predisposition.

In addition to a lack of inhibitors, increased elastase production may be a cause of emphysema (e.g., of a serine elastase from granulocytes, a metalloelastase from alveolar macrophages, and various proteinases from pathogens). The excess of elastases in chronic inflammatory disease leads, for example, to a breakdown of elastic fibers in the lung.

When considering the effects of pulmonary emphysema, the consequences of reduced elastic recoil are important. In the end the lung’s elastic recoil generates the positive pressure in the alveoli in comparison to ambient air necessary for normal expiration. Although positive pressure in the alveoli can also be produced by external compression, i.e., by contraction of the expiratory muscles, this will also compress the bronchioles and thus bring about a massive increase in flow resistance. Maximal expiratory flow rate (V˙max) is thus a function of the ratio between elastic recoil (K) and resistance (RL). Reduced elastic recoil can thus have the same effect as obstructive lung disease. Elastic recoil can be raised by increasing the inspiratory volume, eventually leading to a shift in the resting position toward inspiration (barrel chest). If tidal volume remains constant, both the functional residual capacity and the residual volume are increased, sometimes also the dead space. However, vital capacity is diminished because of the reduced expiratory volume. The loss of alveolar walls leads to a diminished diffusion area; the loss of pulmonary capillaries to an increase in functional dead space as well as increased pulmonary artery pressure and vascular resistance with the development of cor pulmonale. In centrilobular, but not panlobular, emphysema a distribution abnormality develops, because of differing resistances in different bronchioles. The abnormal distribution results in hypoxemia. Patients with centrilobular emphysema due to obstructive lung disease are called “blue bloaters”. In contrast, patients with panlobular emphysema at rest are called “pink puffers”, because enlargement of the functional dead space forces them to breathe more deeply. It is only when diffusion capacity is greatly reduced or oxygen consumption is increased (e.g., during physical work) that diffusion abnormality will result in hypoxemia.

Emphysema