Definition and Concept Heart failure is understood as a pathological condition in which organic and/or functional abnormalities occur in the heart, causing a breakdown in the compensatory mechanism of the cardiac pump function, resulting in elevated ventricular end-diastolic pressure and insufficient perfusion to major organs, resulting in the appearance or worsening of symptoms and signs (Izumi et al., 2011). There are a wide variety of diseases that cause heart failure, including cases where myocardial tissue is directly damaged, such as in myocardial infarction and cardiomyopathy, cases where long-term mechanical load is applied to myocardial tissue due to valvular disease and hypertension, and cases where rhythm abnormalities such as tachycardia and bradycardia lead to deterioration of hemodynamics (Table 5-3-1). There are also non-cardiac causes, such as myocardial damage caused by systemic endocrine and metabolic diseases, inflammatory diseases, storage diseases, nutritional disorders, and external factors such as drugs and chemicals. However, in actual clinical practice, ischemic heart disease and hypertension are the most common, followed by dilated cardiomyopathy and valvular disease. Classification 1) Acute heart failure and chronic heart failure: Acute heart failure is classified into six pathological conditions: 1) acute decompensated heart failure (new onset heart failure and acute exacerbation of chronic heart failure), 2) hypertensive acute heart failure, 3) acute cardiogenic pulmonary edema, 4) cardiogenic shock, 5) high-output heart failure, and 6) acute right heart failure. Chronic heart failure is defined as "a condition in which the pumping function of the heart is reduced due to chronic myocardial damage, and the heart is absolutely or relatively unable to pump out a volume of blood sufficient to meet the oxygen demand of the major peripheral organs, causing congestion in the pulmonary or systemic venous system or both, resulting in impairment of daily life" (Matsuzaki et al., 2010). 2) Left heart failure and right heart failure: In left-sided heart failure, damage is seen in the left heart system, and organ congestion is seen primarily in the pulmonary circulatory system. On the other hand, in right-sided heart failure, damage is seen in the right heart system, and congestion is seen primarily in the systemic circulatory system. When both occur simultaneously, it is called both-sided heart failure. 3) Systolic and diastolic dysfunction: In most cases of heart failure, the decline in the pumping function of the heart is due to a decline in myocardial contractile function, known as systolic heart failure. Therefore, the evaluation of cardiac function in heart failure has traditionally focused on left ventricular systolic function, and the left ventricular ejection fraction (LVEF) is the most widely used index of systolic function. However, it has been reported that systolic function as assessed by the left ventricular ejection fraction is preserved in 30-40% of patients with heart failure, and it has become clear that impairment of both systolic and diastolic function contributes to the emergence of heart failure symptoms. In general, heart failure with reduced systolic function is classified as systolic failure, and heart failure without reduced systolic function is classified as diastolic heart failure. However, in clinical heart failure, both systolic and diastolic function are often reduced, making it difficult to clearly distinguish between systolic and diastolic function. Recently, "systolic dysfunction" has come to be called "heart failure with reduced ejection fraction (HFrEF)" and "diastolic dysfunction" has come to be called "heart failure with preserved ejection fraction (HFpEF or HFPEF)." The cutoff value for the diagnosis of "normal left ventricular ejection fraction" is generally set at 40-50%. The basic pathology of "heart failure with preserved ejection fraction" is diastolic dysfunction, which includes increased myocardial stiffness and incomplete relaxation. Such patients are more common among elderly women, and often have hypertension, diabetes, and atrial fibrillation (Table 5-3-2). The reasons why diastolic dysfunction is considered important clinically include the fact that it is on the rise compared to systolic dysfunction due to the aging of the population, the prognosis is by no means good, and the prognosis has not improved sufficiently despite advances in treatment. 4) High-output heart failure and low-output heart failure: In most cases of heart failure, low output heart failure occurs when cardiac output is reduced, but in high output heart failure, cardiac output is greater than normal. Heart failure occurs when the balance between supply and demand cannot be maintained due to increased oxygen demand in peripheral tissues, and is seen in conditions such as hyperthyroidism, anemia, and arteriovenous fistulas. Epidemiology The average age of patients with heart failure is about 70 years old. The number of patients with chronic heart failure is steadily increasing due to the aging of the population, the increase in ischemic heart disease due to the Westernization of lifestyle habits, and the spread and improvement of acute treatment for acute coronary syndromes, and this number is expected to continue to increase in the future. In the United States, about 5 million patients suffer from heart failure, and 500,000 new cases are diagnosed with heart failure each year. In addition, 300,000 people die from heart failure, and the number of deaths is increasing every year. According to the Framingham study of general community residents, the prevalence of chronic heart failure by age is reported to be 800 in the 50s, 2300 in the 60s, 4900 in the 70s, and 9100 for those 80 years or older (per 100,000 population). The prevalence of heart failure in Japan has not been reported, but it is estimated that there are about 1 million patients with chronic heart failure. In Japan, as in Europe and the United States, the number of heart failure patients is increasing, and this trend is expected to become even stronger in the future. Pathophysiology: Myocardial contractile dysfunction, activation of neurohumoral factors, and myocardial remodeling play important roles in the pathogenesis of heart failure. When myocardial damage occurs, the myocardium hypertrophies to increase contraction as a compensatory mechanism for the decline in contractile function, while neurohumoral factors such as the sympathetic nervous system and the renin-angiotensin-aldosterone (RAA) system are activated. In addition, inflammatory cytokines and oxidative stress, which is a state of excess of active oxygen, are also activated. Excessive activation of neurohumoral factors induces myocardial remodeling, which further promotes myocardial damage and reduced cardiac pump function, forming a vicious cycle. This vicious cycle plays a central role in the pathogenesis and progression of heart failure (Figure 5-3-5). 1) Myocardial contractile dysfunction: The main pathology of heart failure is myocardial contractile dysfunction. Myocardial contractile dysfunction is due to a decrease in contractile function at the level of myocardial cells. The contractile ability of myocardial cells is determined by the amount of Ca2 + supplied to contractile proteins and the Ca2 + sensitivity of contractile proteins. Therefore, the causes of contractile dysfunction are a decrease in the amount of Ca2 + supplied to contractile proteins, a decrease in the Ca2 + sensitivity of contractile proteins, or both. The intracellular Ca2 + concentration of myocardial cells is regulated by Ca2 + regulatory proteins such as the Ca2+ release channel (ryanodine receptor) in the sarcoplasmic reticulum, Ca2 + -ATPase, and phospholamban. In failing myocardium, there is a decrease in the activity of sarcoplasmic reticulum Ca2 + -ATPase. If the amount of Ca2 + held in the sarcoplasmic reticulum decreases, the peak of the intracellular Ca2 + transient decreases, so it is easy to understand the importance of sarcoplasmic reticulum Ca2 + -ATPase as a mechanism for contractile dysfunction. Recently, it has been revealed that Ca 2+ leak caused by dissociation of FKBP12.6, a regulatory protein of the ryanodine receptor, a Ca 2+ release channel , is involved in the onset of heart failure, and its significance is attracting attention. 2) Activation of neurohumoral factors: The RAA system is a representative neurohumoral factor that is activated by myocardial damage and is involved in the formation and progression of myocardial remodeling and heart failure (Figure 5-3-5). In heart failure, not only the RAA system in the blood, which has been known for some time, but also the tissue RAA system in the myocardium and local blood vessels is activated. Activation of the RAA system in the early stages of heart failure is thought to be a compensatory mechanism to maintain circulatory dynamics. However, its sustained enhancement leads to a worsening of the pathology of heart failure. In other words, activation of the tissue RAA system causes myocardial cells to hypertrophy, which at the same time increases myocardial oxygen demand. On the other hand, interstitial fibrosis around intramyocardial blood vessels due to proliferation of smooth muscle in the intima and media of the vascular wall, proliferation of fibroblasts, and promotion of collagen synthesis leads to a decrease in coronary reserve, both of which promote myocardial ischemia. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are hormones produced by the heart. When the RAA system is activated locally in the heart, angiotensin II is produced in the myocardial tissue, which directly or indirectly enhances the expression of the BNP gene in myocardial cells, resulting in an increase in blood BNP concentrations. BNP, along with ANP, acts in a cardioprotective manner and is therefore thought to antagonize the activation of the RAA system. Furthermore, since BNP is produced almost entirely in the heart, and more than 80% of the time in the ventricles, it is widely used in clinical settings as a biomarker for heart failure not only for diagnosis but also as a prognostic factor. 3) Myocardial remodeling: Pressure overload, a physical and mechanical factor, is the most important factor in myocardial cell hypertrophy. Mechanical stimuli such as hemodynamic load are sensed by baroreceptors in the cell membrane and transmitted to the cell. Cells adhere to the extracellular matrix via actin and integrins at focal adhesions. Therefore, activation of integrins may play an important role in transmitting signals of mechanical stimuli, but the detailed mechanism is unknown. In hypertrophied hearts, interstitial fibrosis occurs due to the proliferation of extracellular matrix such as collagen. Collagen is produced by interstitial fibroblasts. Angiotensin II also plays an important role as a signal to promote collagen production. Angiotensin II induces the proliferation of fibroblasts and further increases the production of type I and type III collagen. Angiotensin II also induces the secretion of endothelin and TGF-β from fibroblasts. These factors act on fibroblasts themselves in an autocrine and paracrine manner, promoting myocardial fibrosis. Aldosterone also increases collagen production by fibroblasts, resulting in myocardial fibrosis. Interstitial fibrosis is thought to reduce compliance and promote diastolic dysfunction. Clinical manifestations 1) Symptoms: Symptoms of heart failure can be broadly divided into those caused by organ congestion, such as dyspnea and edema, and those caused by reduced cardiac output, such as general fatigue and easy fatigability (Table 5-3-3). a) Dyspnea: Dyspnea in heart failure begins with shortness of breath on exertion, but in severe cases, dyspnea can occur even with very mild exertion or at rest. Differentiation from dyspnea caused by respiratory diseases such as COPD is possible based on medical history, other symptoms, and physical examination findings, but is often difficult. When pulmonary congestion becomes severe, dyspnea appears within 1-2 minutes of lying down, making it impossible for the patient to lie horizontally and resulting in orthopnea. This is due to increased venous return and elevation of the diaphragm caused by lying down. Furthermore, paroxysmal nocturnal dyspnea (PND) is severe dyspnea that occurs several hours after going to bed at night, and may be accompanied by pink foamy sputum and wheezing (cardiac asthma). In addition to the same mechanism as orthopnea, this is also related to the shift of interstitial fluid into the veins of the lower limbs and abdomen, a decrease in sympathetic tone during sleep, and a decrease in the sensitivity of the respiratory center. The NYHA Cardiac Function Classification is used to evaluate the severity of subjective symptoms, including dyspnea (Table 5-3-4). The NYHA Cardiac Function Classification is simple and is the most widely used not only in actual clinical practice but also in the selection criteria for patients in large-scale clinical trials, but it is only an indicator of the patient's subjective symptoms and has limitations in that it lacks objectivity and quantification. b) Peripheral edema: Edema is often seen on the back of the feet and lower legs, and is accompanied by weight gain. In patients who have been bedridden for a long time, it appears in the sacrum and back. If edema persists for a long period of time, the skin will become shiny and hard, accompanied by red swelling and pigmentation. c) Digestive symptoms: Symptoms caused by congestion in organs such as the intestines, liver, and pancreas include loss of appetite and nausea, and if intestinal edema is severe, diarrhea and vomiting may occur. In cases of right-sided heart failure, right hypochondrium or epigastric pain may occur due to liver congestion. d) General fatigue and easy fatigability: This is caused by reduced blood flow to skeletal muscles due to reduced cardiac output. e) Decreased urinary volume and nocturnal polyuria: Decreased renal blood flow causes a decrease in urinary volume. When the patient is upright and active during the day, renal blood flow decreases, but when the patient rests in a recumbent position at night, renal blood flow increases, resulting in nocturnal polyuria. 2) Physical examination findings: a) Cardiac enlargement: Cardiac enlargement can be roughly estimated by inspection, palpation, and percussion, but a chest X-ray or echocardiogram is required for quantitative assessment. b) Third heart sound: The third heart sound is heard at the apex of the heart. It is also called a gallop rhythm and is one of the important signs of heart failure. It is heard because the left ventricular volume increases with heart failure, causing rapid blood flow from the atrium to the ventricle during early ventricular diastole. c) Abnormal breath sounds (adventitious murmurs, lung noises, rales): These appear along with dyspnea as a subjective symptom of pulmonary congestion and findings of pulmonary congestion on chest X-rays. When inhaling, fine crackles are initially heard at the base of the lungs, but as heart failure progresses, they can be heard throughout the entire lung field as coarse crackles during both inhalation and exhalation. When interstitial edema causes bronchiolar edema and narrows the airways, wheezing can be heard. d) Jugular venous distension: The jugular vein is distended and sometimes pulsates. The patient is placed in a semi-sitting position at 45 degrees from horizontal, and central venous pressure is estimated from the vertical difference between the height of the right atrium and the top of the distended jugular vein. If the increase in jugular venous pressure is not clear, hepato-jugular reflux is useful. Have the patient breathe quietly, and while sitting at a 45-degree angle, gently press the liver under the right hypochondrium with the palm of the hand for approximately one minute until the pulsatile distension of the jugular vein becomes evident. Jugular venous distension is observed as an increase in right ventricular diastolic pressure, which is observed as an increase in right atrial pressure and peripheral venous pressure. It is a typical sign of right-sided heart failure, but can also be seen in left-sided heart failure. This is due to an increase in circulating blood volume due to sodium and water retention, and an increase in pulmonary venous tone due to increased sympathetic nerve activity as a compensatory mechanism for heart failure. e) Hepatomegaly and jaundice: Hepatomegaly can occur in a variety of diseases, not just right heart failure, but hepatomegaly due to congestive liver is one of the characteristic signs of right heart failure and is often accompanied by tenderness and right hypochondriac pain during movement. Jaundice is caused by impaired liver function due to congestive liver, as well as increased bilirubin production due to the destruction of red blood cells associated with repeated embolism in the lungs, spleen, kidneys, etc. In any case, jaundice seen in heart failure is a sign of poor prognosis. f) Pleural effusion and ascites: In right-sided heart failure, filtrate accumulates in the serous cavity and is seen as pleural effusion, ascites, pericardial effusion, etc. Pleural effusion is seen on chest X-rays as a small amount of pleural effusion in the interlobular pleura or costophrenic angle. In diseases that cause severe hepatomegaly, such as tricuspid regurgitation and constrictive pericarditis, severe ascites may be seen even if peripheral edema is not very prominent. Test results 1) Urine and blood tests: When chronic heart failure is suspected based on symptoms and physical findings, urine and blood tests are useful for verifying the validity of the diagnosis and for ruling out other diseases. Plasma ANP and BNP concentrations correlate well with hemodynamics, but BNP reflects left ventricular end-diastolic pressure better and has superior sensitivity and specificity. BNP is particularly useful as an auxiliary diagnostic method for heart failure in diagnosing the presence, severity, and prognosis of heart failure. Diagnosis of chronic heart failure, especially compensated heart failure, and heart failure in primary care is not always easy, and in systolic failure, a BNP cutoff value of 100 pg/mL is useful for differentiating it from respiratory diseases. Plasma BNP concentrations also rise in parallel with the NYHA classification. Furthermore, it correlates with prognosis, and the lower the BNP value at the time of discharge, the lower the incidence of cardiac events, with 200-250 pg/mL being a predictive index. However, when using BNP to diagnose heart failure and evaluate its severity, it is necessary to take into account the influences of age, sex, renal function, etc. In Japan, BNP is mainly used, but in Europe and the United States, the BNP precursor NT-proBNP is also commonly used. Differences between NT-proBNP include the lack of physiological activity, a long half-life, and susceptibility to the effects of renal function. 2) Electrocardiogram : An electrocardiogram is essential for diagnosing underlying heart failure, arrhythmias such as atrial fibrillation and ventricular arrhythmia, and measuring QRS width. 3) Chest X-ray: Chest X-rays are used to evaluate pulmonary congestion, pleural effusion, cardiac shadows, etc. As heart failure becomes severe, it progresses to enhanced pulmonary vein shadows, interstitial edema, and intra-alveolar edema (Figure 5-3-6). Initially, the pulmonary veins, which have expanded due to increased pulmonary venous pressure, are seen as enhanced deer antler-shaped shadows, and at the same time, the course of the pulmonary blood vessels becomes unclear and is enhanced due to interstitial edema around the pulmonary blood vessels. Furthermore, images of congestion in the interlobular lymphatic vessels or lobular septa are seen as linear shadows 1 to 2 cm long that run perpendicular to the pleura in the lower lung fields and above the diaphragm (Kerley B line). Intra-alveolar edema is seen as an accumulation of small patchy shadows. 4) Echocardiogram: Echocardiography is the most widely used method to evaluate cardiac function in heart failure, but echocardiography can also be used to diagnose underlying diseases and observe valves and left ventricular morphology [⇨5-5-3]. a) Systolic function: The left ventricular ejection fraction is the most widely used index of systolic function. However, the left ventricular ejection fraction is affected not only by left ventricular systolic function but also by heart rate, blood pressure, left ventricular volume, etc., so caution is required in interpreting it. It is particularly prone to overestimation in patients with mitral regurgitation, hypertensive heart disease, and left ventricular wall thickening, such as hypertrophic cardiomyopathy. In ischemic heart disease, evaluation of regional wall motion is also necessary. In addition, the presence and degree of asynchronous contraction (dyssynchrony) is evaluated to consider the suitability of cardiac resynchronization therapy. Rest alone is insufficient for evaluating contractile reserve and myocardial viability, so dobutamine stress or exercise stress echocardiography is useful. Functional or ischemic mitral regurgitation is observed in more than half of heart failure cases. This regurgitation occurs when the left ventricle expands and the papillary muscles are displaced outward, pulling (tethering) the mitral valve leaflets abnormally strongly, causing the closing position of the valve leaflets to shift towards the left ventricular apex, resulting in insufficient closure of the valve leaflets. b) Diastolic function: Left ventricular expansion and inflow are restricted not only by disorders of the myocardial diastolic function itself, but also by pressure due to right ventricular enlargement, constrictive pericarditis, cardiac tamponade, etc. Currently, non-invasive indicators of diastolic function that are widely used are not direct indicators of left ventricular diastolic function, but rather left atrial pressure and morphological changes that occur secondarily due to diastolic dysfunction. i) When the left ventricular ejection fraction is reduced: Using the pulsed Doppler method, the dynamics of blood inflow from the left atrium to the left ventricle, i.e., the early diastolic inflow blood flow velocity waveform E wave and the atrial systolic inflow blood flow velocity waveform A wave, are measured. The ratio of the peak blood flow velocity of these two waves, E/A, decreases, and the deceleration time (DT) of the E wave is prolonged, resulting in a "relaxation impaired type" that first appears in the early stages of diastolic dysfunction. As diastolic dysfunction progresses and the left atrial pressure rises, the E/A increases and the DT shortens, resulting in a "pseudo-normal type" that resembles a normal waveform. As diastolic dysfunction progresses and the left atrial pressure rises further, the E/A increases further and the DT shortens further, resulting in a "restrictive type" (Figure 5-3-7). In cases with reduced left ventricular ejection fraction, the higher the E/A and the shorter the DT, the higher the left atrial pressure. However, caution is required as the E/A decreases and the DT prolongs with age. Evaluation of diastolic function in systolic failure is useful not only for understanding the pathology but also for predicting prognosis. In other words, a high E/A or low DT after adequate treatment is an indicator of poor prognosis, along with a low left ventricular ejection fraction, advanced left ventricular enlargement and hypertrophy, high blood BNP levels, and pulmonary hypertension. ii) When left ventricular ejection fraction is preserved: When left ventricular ejection fraction is preserved, E/A and DT do not correlate with left atrial pressure or left ventricular end-diastolic pressure, making it difficult to evaluate diastolic function using only the left ventricular inflow velocity waveform. The ratio E/e' of the early diastolic e' wave, measured using tissue Doppler to observe mitral annular movement, and the left ventricular inflow velocity waveform E wave, is useful for diagnosing heart failure because it correlates with left atrial pressure without being affected by left ventricular ejection fraction (Figure 5-3-7). 5) CT, MRI, and Nuclear Medicine: In recent years, there have been remarkable advances in cardiovascular imaging diagnostics, including CT, MRI, and nuclear medicine, and these imaging techniques are now being used to diagnose underlying diseases and observe left ventricular morphology. Left ventricular ejection fraction can also be measured by left ventriculography, but this requires cardiac catheterization and is not common these days. However, left ventricular ejection fraction can also be measured and left ventricular morphology observed by CT, MRI, and nuclear medicine. 6) Cardiac catheterization: Although cardiac catheterization remains an essential test for the diagnosis of heart failure, to assess hemodynamics and coronary artery disease, as well as for myocardial biopsy, advances in non-invasive testing, such as echocardiography, CT, MRI, and nuclear medicine, are increasingly replacing these procedures. 7) Exercise tolerance: Methods for assessing exercise tolerance include the 6-minute walking test and the measurement of maximum oxygen uptake by exercise stress testing. The 6-minute walking test measures the walking distance at maximum effort for 6 minutes, is a simple method that does not require special equipment, and can estimate approximate exercise capacity. The 6-minute walking distance is related to height, weight, and age, and the normal range (m) for Japanese people is [454-0.87 x age (years)-0.66 x weight (kg)] ± 82 (2 standard deviations) multiplied by height (m). The standard method for quantitatively assessing exercise tolerance is dynamic exercise stress testing using a symptom-limited incremental load method using a treadmill or bicycle ergometer. It is evaluated by the exercise time, power at maximum exercise, and maximum oxygen uptake according to a standardized protocol, but it is necessarily limited to patients who are able to exercise. Maximum oxygen uptake is a first approximation of maximum cardiac output and reflects the maximum oxygen transport capacity of the cardiovascular system and the maximum oxygen utilization capacity of the peripheral blood vessels. Furthermore, the anaerobic threshold (AT), which indicates the breakdown of the oxygen supply-demand balance during exercise, is a quantitative index with excellent objectivity and reproducibility. However, in patients with heart failure, the AT may be reached at a low load, and detection of the AT may be difficult due to oscillatory ventilation. It is useful for distinguishing whether exercise limitations due to dyspnea or fatigue are due to heart failure or other reasons. Diagnosis and Differential Diagnosis In acute heart failure, the patient's condition may deteriorate in a very short time, so it is important to keep in mind the importance of an early and rapid diagnosis (diagnosis of severity and cause) and triage (priority) for initial treatment. In addition to observing the patient's overall condition, vital signs should be checked, an intravenous line should be established, and arterial blood gas analysis, blood tests (myocardial damage markers, liver and kidney function, electrolytes, CRP, etc.), 12-lead electrocardiogram, and portable chest X-ray should be performed in a short period of time. The Killip classification is used to evaluate the severity of the condition (Table 5-3-5). In addition, there is the Forrester classification using a Swan-Ganz catheter, but this is not recommended for routine use, and the Nohria-Stevenson classification, a non-invasive evaluation method, is more useful (Figure 5-3-8). Diagnosis of chronic heart failure also begins with symptoms and physical examination (Figure 5-3-9). The main symptoms of chronic heart failure are dyspnea, edema, and fatigue. However, these may also be seen in other organ diseases such as respiratory disease, renal failure, and anemia, and differential diagnosis is required. Physical examination should check for the presence of heart murmurs, galloping third heart sound, rales, and jugular venous distension. An electrocardiogram and chest X-ray are essential tests, but measuring plasma BNP is also useful. If BNP is 100 pg/mL or higher or NT-proBNP is 400 pg/mL or higher, testing should be carried out assuming heart failure. Using echocardiography to diagnose whether a patient has heart failure with reduced or preserved left ventricular ejection fraction is useful not only for understanding the pathology but also for selecting a treatment method. If a patient is diagnosed with heart failure, tests will be performed to diagnose the underlying disease and determine the treatment method, as well as to evaluate the effectiveness of treatment and severity. If heart failure with preserved left ventricular ejection fraction (HFPEF) is suspected, valvular disease and other conditions will be ruled out using echocardiography, and if signs of diastolic dysfunction are found, a diagnosis of heart failure will be made. Course and prognosis: In Japan, the one-year mortality rate after discharge for patients hospitalized with worsening chronic heart failure is 11%, while the readmission rate due to worsening heart failure is 26%, which is higher than the death rate. The prognosis for patients with diastolic heart failure is also poor, with no difference from that for systolic heart failure. Furthermore, according to a study by the Mayo Clinic that looked at changes over time in survival rates for patients with systolic and diastolic heart failure from 1987 to 2001, there was an improvement in survival rates for patients with systolic heart failure, but not for those with diastolic heart failure. Thus, the long-term prognosis for chronic heart failure is extremely poor, regardless of whether the patient has systolic or diastolic heart failure. Treatment (treatment for acute heart failure is 【⇨3-2】 Emergency treatment) The goal of treating chronic heart failure is not only to improve symptoms and quality of life by improving hemodynamics, but also to prevent hospitalization due to exacerbation and improve life prognosis. When treatment of the underlying disease is possible, the first fundamental treatment is to correct the underlying disease. In ischemic heart disease accompanied by heart failure, it is expected that left ventricular function will improve through coronary revascularization. In valvular disease and congenital heart disease, cardiac function can be restored through surgical repair, but it is important not to miss the timing of surgery before myocardial failure progresses to irreversible damage. 1) Drug therapy for systolic failure (Figure 5-3-10): Angiotensin converting enzyme (ACE) inhibitors are administered to a wide range of patients, from asymptomatic (NYHA stage I) to severe (NYHA stage IV). When ACE inhibitors cannot be used, angiotensin II receptor blockers (ARBs) are used. In patients with NYHA stage II or higher, β-blockers are administered in addition to ACE inhibitors or ARBs. Loop diuretics and thiazide diuretics are used to treat fluid retention. In addition, antialdosterone drugs and digitalis are used in combination. In patients with NYHA stage IV, hospitalization is usually required. Diuretics, nitrates, PDE III inhibitors, catecholamines, hANP, etc. are administered parenterally to stabilize the condition. a) ACE inhibitors: ACE inhibitors have been proven to improve prognosis in numerous large-scale clinical trials, and are positioned as the first-line drug for the treatment of heart failure. Therefore, ACE inhibitors should be administered to all patients with systolic failure, regardless of the severity of heart failure. Higher doses of ACE inhibitors have been reported to be more effective, and should be increased as much as the patient can tolerate. Dry cough may occur within 2-3 weeks of administration, the most common side effect, but disappears when the drug is discontinued. b) ARB: になったんです。 English: The first thing you can do is to find the best one to do.になったんです。 English: The first thing you can do is to find the best one to do.になったんです。 English: The first thing you can do is to find the best one to do. Therefore, digitalis controls ventricular rates and improves exercise tolerance in patients with chronic heart failure associated with atrial fibrillation. However, caution is required as older age, kidney damage, and electrolyte abnormalities (hypokalemia, hypomagnesemia) can induce digitalis poisoning. Also, be careful when using drugs with interactions that affect blood concentrations. f) Oral cardiac intestinal drugs: The effectiveness of oral cardiac intensive drugs has been denied by large-scale clinical trials, and oral cardiac intensive drugs is not recommended as a treatment for chronic heart failure in the United States. However, if we believe that only improvement in life prognosis is not the ultimate goal of treatment, we also have the position that its clinical utility should be re-evaluated. In particular, there are patients who are effective when improving quality of life, withdrawal from parenteral cardiac intensive drugs, and introducing beta-blockers. However, due to the fact that it has a pro-arrhythmic effect, it is necessary to take great care. 2) Drug treatment for diastolic failure (Figure 5-3-11): While many large-scale clinical trials have established drug therapy for systolic failure, drug therapy for dilation failure has not been established. Diuretics are the most effective in reducing congestion. However, since excessive reduction in left ventricular filling pressure due to diuretics can reduce cardiac output and lead to hypotension, it is important to adjust the dose. Due to the high frequency of hypertension, blood pressure management, rate control of atrial fibrillation, and even improve ischemia. While ACE inhibitors and ARBs have established an effectiveness in improving the prognosis of systolic failure, only hospitalization due to heart failure has decreased, and no clear effect on improving the prognosis of systolic failure has been proven. Beta-blockers and Ca antagonists are expected to improve diastolic functions, but their clinical utility has not been proven. 3) Non-drug therapy: If drug therapy is not sufficiently controlled, the application of non-pharmacotherapy is considered. With the difficulties in developing new drug therapy, there are remarkable advances in non-pharmacotherapy. a) Implantable cardiac defibrillator (ICD): Sudden death is a cause of death in patients with heart failure, especially in NYHA II-II levels, which amounts to 50-60%. 80-90% of sudden deaths are caused by fatal arrhythmias, i.e. sustained ventricular tachycardia or ventricular fibrillation. Implantation of ICD is useful for such fatal arrhythmias, and large-scale clinical trials have proven effective in improving prognosis. b) Cardiac resynchronization therapy (CRT): In NYHA III or IV, in which heart failure with left ventricular conduction delays in the left bundle branch block, correcting the asynchronous contraction of left ventricular contraction (dyssynchrony) by biventricular pacing of CRT, and CRT with ICD function (CRT-D) is effective, improving not only subjective symptoms, exercise tolerance and cardiac function, but also prognosis. Furthermore, recently it has proven effective in mild cases of NYHA II, and the indications have been expanded. c) Exercise therapy: Exercise therapy not only reduces exercise tolerance and quality of life (QOL) in patients with stable chronic heart failure, but also reduces cardiovascular death and cardiovascular readmission. Prevention and Disease Management When treating heart failure, it is also important to prevent the onset and progression of hypertension, diabetes, dyslipidemia, etc., which are underlying diseases of heart failure, and to thoroughly manage it. になったんです。 English: The first thing you can do is to find the best one to do. In particular, if symptoms of heart failure exacerbation are observed, hospitalization can be avoided by increasing the amount of diuretics and promptly visiting the clinic if necessary. [Tsutsui Hiroyuki] ■References <br /> Izumi Toru, et al.: Guidelines for Treatment of Acute Heart Failure, 2011 revised edition, Japanese Society of Circulation, 2011. http://www.j-circ.or.jp/guideline/pdf/JCS2011_izumi_h.pdf Matsuzaki Masutoku, et al.: Guidelines for Treatment of Chronic Heart Failure, 2010 revised edition, Japanese Society of Circulation, 2010. http://www.j-circ.or.jp/guideline/pdf/JCS2010_matsuzaki_h.pdf Tsutsui Hiroyuki, et al.: Challenging heart failure and saving patients. Bunkodo, Tokyo, 2005. Diseases Caused by Heart Failure "> Table 5-3-1 Systolic and dilatation failure "> Table 5-3-2 Heart failure symptoms "> Table 5-3-3 NYHA Cardiac Function Classification "> Table 5-3-4 Evaluation of severity of acute heart failure by Killip classification "> Table 5-3-5 Myocardial remodeling, formation and development of heart failure "> Figure 5-3-5 Findings of heart failure in chest X photographs "> Figure 5-3-6 Evaluation of dilated functions using echocardiography "> Figure 5-3-7 Severity Classification of Acute Heart Failure: a.Forrester Classification b.Nohria-Stevenson Classification "> Figure 5-3-8 Diagnosis flow chart for chronic heart failure "> Figure 5-3-9 Treatment guidelines for chronic heart failure (systolic failure) "> Figure 5-3-10 Treatment flow chart for chronic heart failure (systolic failure) "> Figure 5-3-11 Heart failure (Nervous system disorders associated with heart and lung disease)Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information |
定義・概念 心不全とは心臓に器質的および/あるいは機能的異常が生じて心ポンプ機能の代償機転が破綻し,心室拡張末期圧の上昇や主要臓器への灌流不全をきたし,それに基づく症状や徴候が出現,あるいは悪化した病態ととらえられている(和泉ら,2011). 原因 心不全の原因疾患は幅広く,心筋梗塞や心筋症のように心筋組織が直接的に障害を受ける場合,弁膜症や高血圧などにより長期的な機械的負荷が心筋組織に加わり機能障害により発症する場合,頻脈や徐脈などのリズム異常により血行動態の悪化を招く場合がある(表5-3-1).また,全身性の内分泌・代謝疾患,炎症性疾患,蓄積疾患や栄養障害や薬剤・化学物質などの外的因子による心筋障害から発症する場合など心臓以外の原因もある.ただし,実際の診療では虚血性心疾患と高血圧が最も多く,それに拡張型心筋症,弁膜症が続く. 分類 1)急性心不全と慢性心不全: 急性心不全(acute heart failure)は,①急性非代償性心不全(新規発症心不全と慢性心不全の急性増悪),②高血圧性急性心不全,③急性心原性肺水腫,④心原性ショック,⑤高拍出性心不全,⑥急性右心不全の6つの病態に分類される. 慢性心不全(chronic heart failure)とは,「慢性の心筋障害により心臓のポンプ機能が低下し,末梢主要臓器の酸素需要に見合うだけの血液量を絶対的また相対的に拍出できない状態であり,肺・体静脈系または両系にうっ血をきたし日常生活に障害を生じた病態」と定義される(松﨑ら,2010). 2)左心不全と右心不全: 左心不全(left-sided heart failure)では左心系に障害を認め,主として肺循環系に臓器うっ血をみる.一方,右心不全(right-sided heart failure)では右心系に障害を認め,主として体循環系にうっ血が現れる.両者が同時に出現する場合を両心不全(both-sided heart failure)という. 3)収縮不全と拡張不全: 心不全の多くは,心臓のポンプ機能の低下が心筋の収縮機能低下に基づく「収縮不全(systolic heart failure)」である.したがって,心不全における心機能評価は,従来より左室収縮機能に重点がおかれ,収縮機能の指標として左室駆出率(left ventricular ejection fraction:LVEF)が最も広く用いられている.しかしながら,心不全患者の30~40%では左室駆出率で評価される収縮機能は保持されていることが報告され,心不全症状の出現には収縮機能と拡張機能の両者の障害が寄与していることが明らかとなってきた.一般には収縮機能が低下した心不全を「収縮不全」,収縮機能が低下していない心不全を「拡張不全(diastolic heart failure)」と分類するが,臨床的な心不全では収縮機能も拡張機能もともに低下していることが多く,「収縮不全」と「拡張不全」を明確に区別することは容易ではない. そこで, 最近では「収縮不全」を「左室駆出率が低下した心不全heart failure with reduced ejection fraction(HFrEF)」,「拡張不全」を「左室駆出率が保持された心不全heart failure with preserved ejection fraction (HFpEFまたはHFPEF)」とよぶようになっている.「正常な左室駆出率」の診断は,一般的には40〜50%をカットオフ値とすることが多い. 「左室駆出率が保持された心不全」の基本病態は,心筋stiffness(硬さ)の増大と不完全弛緩を含む拡張不全である.このような患者は,高齢者の女性に多く,高血圧,糖尿病や心房細動を認めることが多い(表5-3-2).臨床的に拡張不全が重要視される理由には,人口の高齢化により,収縮不全に比し増加傾向にあること,決して予後が良好ではないこと,さらに治療の進歩にもかかわらず予後の改善が十分でないことがある. 4)高心拍出量性心不全と低心拍出量性心不全: 通常心不全では,心拍出量が低下している低心拍出量性心不全(low output heart failure)が多いが,高心拍出量性心不全(high output heart failure)では心拍出量は正常よりも増大している.末梢組織での酸素需要が増すために需要と供給のバランスが維持できず心不全をきたすもので,甲状腺機能亢進症や貧血,動静脈瘻などで認められる. 疫学 心不全患者の平均年齢は約70歳と高齢である.人口の高齢化,生活習慣の欧米化に伴う虚血性心疾患の増加,急性冠症候群に対する急性期治療の普及・成績の向上などにより慢性心不全患者は増加の一途をたどっているが,今後もさらに増加していくと予想される.米国では約500万人の患者が心不全に罹患し,毎年50万人が新たに心不全と診断されている.また,30万人が心不全を原因として死亡し,死亡者数は年々増加している.一般地域住民を対象としたFramingham研究によると,年齢ごとの慢性心不全の有病率は,50歳代800,60歳代2300,70歳代4900,80歳以上で9100(人口10万対)と報告されている.わが国における心不全の有病率は報告されていないが,100万人前後の慢性心不全患者がいると推測されている.わが国でも,欧米同様に心不全患者が増加しており,今後この傾向はさらに強まると予想される. 病態生理 心不全の病態形成には,心筋収縮不全,神経体液性因子の活性化および心筋リモデリングが重要な役割を果たしている.心筋に障害が加わると,収縮機能の低下に対する代償機転として心筋が肥大を形成して収縮を増加させる一方,交感神経やレニン-アンジオテンシン-アルドステロン(renin-angiotensin-aldosterone:RAA)系などの神経体液性因子の活性化が引き起こされる.また,炎症性サイトカインや活性酸素の過剰状態である酸化ストレスなども活性化される.神経体液性因子の過剰な活性化は,心筋リモデリングを引き起こし,さらに心筋障害や心ポンプ機能低下を助長させ,悪循環サイクルを形成する.このような悪循環サイクルが,心不全の病態の形成・進展において中心的な役割を担っている(図5-3-5). 1)心筋収縮不全: 心不全の主たる病態は心筋の収縮不全である.心筋の収縮不全は,心筋細胞レベルでの収縮機能の低下による.心筋細胞の収縮能は,収縮蛋白へのCa2+供給量と収縮蛋白のCa2+感受性とで規定される.したがって,収縮不全の成因としては,収縮蛋白へのCa2+供給量の低下または収縮蛋白のCa2+感受性の低下,もしくはその両者が重要な役割を果たしている.心筋細胞の細胞内Ca2+濃度は,筋小胞体のCa遊離チャネル(リアノジン受容体),Ca2+-ATPase,ホスホランバンなどのCa2+制御蛋白によって調節されている.不全心筋では筋小胞体Ca2+-ATPaseの活性の低下が認められる.筋小胞体のCa2+保持量が減少すれば,細胞内Ca2+トランジエントのピークが低下することから,収縮不全の発生機序として筋小胞体Ca2+-ATPaseの重要性は理解しやすい.最近,Ca2+放出チャネルであるリアノジン受容体の調節蛋白であるFKBP12.6の解離によるCa2+リークが心不全の発症に関与することが明らかにされ,その意義が注目されている. 2)神経体液性因子の活性化: 心筋障害によって活性化され,心筋リモデリング・心不全の形成・進展に関与する神経体液性因子の代表はRAA系である(図5-3-5).心不全では,従来から知られている血中のRAA系のみならず,心筋や血管局所における組織RAA系が活性化される.心不全の初期におけるRAA系の活性化は循環動態を維持するための代償機転と考えられる.しかしながら,その持続的な亢進は心不全の病態の悪化をもたらす.すなわち,組織RAA系の活性化は心筋細胞を肥大させ,同時に心筋酸素需要の増大をもたらす.一方,血管壁内膜・中膜平滑筋の増殖や線維芽細胞の増殖・コラーゲン合成促進による心筋内血管周囲の間質線維化は冠予備能の低下をもたらし,ともに心筋虚血を助長する. 心房性ナトリウム利尿ペプチド(atrial natriuretic peptide:ANP),脳性ナトリウム利尿ペプチド(brain natriuretic peptide:BNP)は心臓から産生されるホルモンである.心臓局所でRAA系が活性化されると心筋組織でアンジオテンシンⅡが産生され,それが直接あるいは間接に心筋細胞におけるBNP遺伝子の発現を亢進させ,その結果として血中BNP濃度が上昇する.BNPはANPとともに心保護的に作用することから,RAA系の亢進に拮抗するものと考えられる.さらに,BNPは産生臓器がほぼ100%心臓であり,そのなかでも80%以上が心室であることから,心不全のバイオマーカーとして診断のみならず,予後の予知因子として臨床の現場で広く用いられている. 3)心筋リモデリング: 心筋細胞肥大には,圧負荷という物理的・機械的因子が最も重要である.血行力学的負荷といった機械的刺激は,細胞膜の圧受容体で感知され,細胞内に伝えられる.細胞は,接着斑でアクチン・インテグリンを介して細胞外マトリックスに接着している.したがって,インテグリンの活性化が,機械的刺激のシグナルの伝達に重要な役割を果たしている可能性があるが,その詳細な機序は不明である.肥大心では,コラーゲンなど細胞外マトリックスの増生により間質の線維化が生じる.コラーゲンは間質の線維芽細胞において産生される.コラーゲン産生を促進するシグナルとしても,アンジオテンシンⅡが重要な役割を果たしている.アンジオテンシンⅡは線維芽細胞の増殖を引き起こし,さらにⅠ型やⅢ型コラーゲンの生成を増加させる.また,アンジオテンシンⅡは線維芽細胞からエンドセリンやTGF-βなどの分泌を誘導する.これらの因子は,線維芽細胞自体にオートクライン・パラクライン的に作用し,心筋線維化を助長する.また,アルドステロンも,線維芽細胞のコラーゲン産生を増加させ心筋線維化をきたす.間質の線維化は,コンプライアンスを低下させ,拡張機能障害を助長すると考えられる. 臨床症状 1)自覚症状: 心不全における症状は,呼吸困難や浮腫など臓器うっ血による症状と全身倦怠感,易疲労感など心拍出量低下に基づく症状とに大別される(表5-3-3). a)呼吸困難(dyspnea):心不全における呼吸困難は,労作時の息切れ(shortness of breath)から始まるが,重症になるとごく軽度の労作や安静時にも呼吸困難を生じるようになる.COPDなどの呼吸器疾患による呼吸困難との鑑別は病歴やほかの症状や身体所見から可能であるが,困難なことも少なくない.肺うっ血が高度になると,呼吸困難が臥位1〜2分で出現するため,患者は水平に寝ることができなくなり,起坐呼吸(orthopnea)を呈する.これには,臥位による静脈還流の増加や横隔膜の挙上が関与する.さらに,発作性夜間呼吸困難(paroxysmal nocturnal dyspnea:PND)は,夜間就寝数時間後に発症する高度の呼吸困難であり,ピンク色泡沫状痰や喘鳴を伴うこともある(心臓喘息,cardiac asthma).これには,起坐呼吸と同様の機序に加えて下肢・腹部の間質水分の静脈内への移行,就寝中の交感神経緊張の低下や呼吸中枢の感度の低下が関与する. 呼吸困難を含む自覚症状の重症度評価にはNYHA心機能分類が用いられる(表5-3-4).NYHA心機能分類は,簡便であり,実際の臨床ばかりでなく大規模臨床試験の患者の選択基準なども含め最も広く用いられているが,あくまで患者の自覚症状の指標であり,客観性・定量性に欠けるという限界がある. b)末梢浮腫(peripheral edema):浮腫は足背や下腿に認めることが多く,体重増加を伴う.長期臥床例では仙骨部や背部に出現する.浮腫が長期間持続すると皮膚は光沢を帯びて硬化し,赤色の腫脹や色素沈着を伴ってくる. c)消化器症状:腸管,肝,膵などの臓器うっ血による症状として,食欲不振,悪心などがみられ,腸管の浮腫が著しいと下痢や嘔吐をみる.右心不全では,肝うっ血による右季肋部ないし心窩部痛が出現することがある. d)全身倦怠感・易疲労感:心拍出量の低下に基づき骨格筋への血流が低下することによる. e)尿量減少・夜間多尿:腎血流の低下は,尿量減少を引き起こす.昼間立位で活動しているときは,腎血流が低下するが,夜間臥位をとり安静にすると腎血流が増加するため,夜間多尿が生ずる. 2)身体所見: a)心拡大:心拡大は,視診・触診・打診によっておおよその見当がつくが,定量的に評価するには胸部X線や心エコー図が必要である. b)Ⅲ音:Ⅲ音は,心尖部で聴取される.奔馬調律(Ⅲ音ギャロップ,gallop)ともよばれ,心不全の重要徴候の1つである.これは,心不全で左室容積が増加することによって,心室拡張早期に心房から心室へ急速に血液流入が生ずるために聞かれる. c)異常呼吸音(副雑音,肺雑音,ラ音):肺うっ血の自覚症状としての呼吸困難および胸部X線での肺うっ血所見に伴って出現する.吸気時に捻髪音 (fine crackles)として,当初は肺底部に聴取するが,心不全の進行につれて全肺野で水泡音(coarse crackle)として吸気・呼気時ともに聴取される.間質性浮腫によって細気管支浮腫が生じ気道が狭くなると,喘鳴(wheeze)を聴取する. d)頸静脈怒張(jugular venous distension):頸静脈が怒張し,ときに拍動も観察される.患者の体位を水平より45度の半座位とし,右心房の高さと頸静脈怒張の最上部との垂直高差から中心静脈圧を推測する.頸静脈圧上昇が明らかでない場合には,肝・頸静脈逆流が有用である.患者に静かに呼吸を行わせ,45度起坐位で右季肋下の肝を手掌で約1分間静かに圧迫し,頸静脈の拍動性怒張が明瞭化となるのを観察する.頸静脈怒張は,右室拡張期圧の上昇が右房圧,末梢静脈圧上昇として観察されるもので,右心不全の代表的な徴候であるが,左心不全でも認められる.これには,Na・水貯留による循環血液量の増加,心不全の代償機序としての交感神経活動性亢進による肺静脈緊張増加などが関与する. e)肝腫大・黄疸:肝腫大は右心不全に限らず種々の疾患で起こるが,うっ血肝による肝腫大は右心不全の特徴的徴候の1つであり,しばしば圧痛や体動時の右季肋部痛を伴う.黄疸はうっ血肝による肝機能の障害のほか,肺,脾,腎などでの反復塞栓に伴う赤血球の破壊によるビリルビン生成の亢進が関与する.いずれにせよ,心不全でみられる黄疸は予後不良の徴候である. f)胸水・腹水:右心不全では,濾出液として漿膜腔内に貯留し,胸水,腹水,心膜液などとして認められる.胸水は,葉間胸膜や肋骨横隔膜角に少量の胸水貯留像として胸部X線上で認められる.三尖弁閉鎖不全や収縮性心膜炎など高度の肝腫大をきたす疾患では,末梢浮腫があまり顕著でなくても高度の腹水貯留をみることがある. 検査成績 1)検尿・血液検査: 検尿・血液検査は,症状・身体所見から慢性心不全が疑われた場合に,その診断の妥当性の検討および他疾患の除外診断に有用である.血漿ANPやBNP濃度は血行動態とよく相関するが,BNPのほうが左室拡張末期圧をよく反映し,感度,特異度ともすぐれている.BNPが心不全の補助診断法として特にすぐれているのは,心不全の存在,重症度,予後の診断である.慢性心不全,特に代償期心不全や,プライマリーケアにおける心不全の診断は必ずしも容易ではなく,収縮不全ではBNPのカットオフ値を100 pg/mLとすると,呼吸器疾患などとの鑑別に有用である.また,血漿BNP濃度はNYHA分類に並行して上昇する.さらに,予後とも相関し,退院時のBNP値が低いほど心事故の発生が低率であり,200~250 pg/mLが予測指標になる.ただし,BNPを利用した心不全診断と重症度評価では,年齢,性別,腎機能などの影響を考慮しておく必要がある.わが国ではおもにBNPが用いられているが,欧米ではBNP前駆体のNT-proBNPもよく使用されており,NT-proBNPには生理活性がないこと,半減期が長いこと,腎機能の影響を受けやすいなどの違いがある. 2)心電図 : 心電図は,心不全の基礎疾患の診断や心房細動,心室性不整脈など不整脈の診断,さらにはQRS幅の測定に必須である. 3)胸部X線写真: 胸部X線写真では,肺うっ血・胸水・心陰影などを評価する.心不全が重症になると,肺静脈陰影の増強,間質性浮腫,肺胞内水腫と進行する(図5-3-6).当初,肺静脈圧上昇によって拡張した肺静脈が,鹿の角状の陰影増強として認められ,同時に肺血管周囲の組織間浮腫によって肺血管の走行が不明瞭となり,かつ増強する.また小葉間リンパ管ないし小葉隔壁のうっ血像が,下肺野と横隔膜上方に,胸膜に直角方向に走行する長さ1~2 cmの線状陰影として認められる(Kerley B line).肺胞内水腫では,小斑状陰影の集積像として認められる. 4)心エコー: 心不全における心機能評価には心エコーが最も広く用いられるが,心エコーでは同時に原因疾患の診断,弁や左室形態の観察なども合わせて行うことができる【⇨5-5-3】. a)収縮機能:収縮機能の指標として,最も広く用いられるのは左室駆出率である.しかしながら,左室駆出率は,左室収縮機能ばかりでなく心拍数,血圧,左室容積などの影響も受けるため,その解釈には注意が必要である.特に僧帽弁閉鎖不全や高血圧性心疾患, 肥大型心筋症など左室壁肥厚を有する場合に過大評価されやすい.虚血性心疾患では,局所壁運動の評価も必要である.また,心臓再同期療法の適応を検討するためには非同期収縮(dyssynchrony)の有無と程度を評価する.収縮予備能や心筋バイアビリティの評価には安静時のみでは不十分であり,ドブタミン負荷あるいは運動負荷心エコーが有用である.心不全例の半数以上において,機能性・虚血性僧帽弁逆流を認める.この逆流は,左室が拡大し乳頭筋が外側へ変位し僧帽弁尖を異常に強く牽引 (テザリング)するために弁尖の閉鎖位置が左室心尖方向へ変位することによって弁尖の閉鎖が不十分となり生ずる. b)拡張機能:心筋の拡張機能自体の障害ばかりでなく,右室拡大,収縮性心膜炎,心タンポナーデなどに基づく圧迫によっても左室拡張・流入が制限される. 現在,拡張機能として広く用いられる非侵襲的指標は,直接的な左室拡張機能指標ではなく拡張機能障害のために二次的に生じた左房圧や形態変化などである. ⅰ)左室駆出率が低下している場合:パルスドプラ法を用いて左房から左室への血液の流入動態,すなわち拡張早期流入血流速波形E波,心房収縮期流入血流速波形A波を測定する.この両波のピーク血流速の比E/Aが低下し,E波の減速時間(deceleration time: DT)が延長した「弛緩障害型」がまず拡張機能障害初期に現れる.拡張機能障害が進行し左房圧が上昇するとE/Aが増加しDTが短縮し,正常波形と類似した「偽正常型」となり,さらに拡張機能障害が進行し左房圧がより上昇するとE/Aのさらなる増高とDTのさらなる短縮により「拘束型」となる(図5-3-7).左室駆出率が低下している症例ではE/Aが高値でありDTが短縮しているほど左房圧が上昇している.ただし,加齢とともにE/Aは低下しDTは延長するため注意が必要である. 収縮不全における拡張機能評価は,病態把握ばかりでなく予後予測にも有用である.すなわち,十分な治療を行った後におけるE/A高値あるいはDT低値は,左室駆出率の低値,進行した左室拡大と左室肥大,血中BNP高値,肺高血圧などとともに予後不良の指標である. ⅱ)左室駆出率が保持されている場合:左室駆出率が保持されている場合,E/AやDTは左房圧や左室拡張末期圧と相関せず,左室流入血流速波形のみによる拡張機能評価は困難である.組織ドプラ法を用いて測定した僧帽弁弁輪部運動を観察した拡張早期のe′波と左室流入血流速波形E波の比E/e′は,左室駆出率の影響を受けず左房圧と相関することから心不全の診断に有用である(図5-3-7). 5)CT,MRI,核医学: 近年CT,MRI,核医学などの循環器画像診断の進歩は著しく,原因疾患の診断や左室形態の観察に用いられるようになっている.左室駆出率は左室造影でも測定可能であるが,心臓カテーテル検査が必要であり,最近は一般的ではない.左室駆出率の測定や左室形態の観察はCT,MRI,核医学でも可能である. 6)心臓カテーテル検査: 血行動態や冠動脈病変の評価,さらに心筋生検のために心臓カテーテル検査が心不全の診断においていまなお必要な検査であることは間違いないが,心エコー,CT,MRI,核医学など非侵襲的検査の進歩により,これらに取って代わられることが多くなりつつある. 7)運動耐容能(exercise tolerance): 運動耐容能の評価法には,6分間歩行試験と運動負荷試験による最大酸素摂取量の測定がある.6分間歩行試験は,6分間の最大努力による歩行距離を測定するものであり,特殊な設備が不要で簡便な方法であり,およその運動能力を推定し得る.6分間歩行距離は身長と体重および年齢に関連しており,日本人の正常域(m)は[454-0.87×年齢(歳)-0.66×体重(kg)]±82(2標準偏差)に身長(m)を乗じたものとされる. 運動耐容能を定量的に評価する標準的方法は,トレッドミルや自転車エルゴメータを用いた症候限界性漸増負荷法による動的運動負荷試験である.標準化したプロトコールによる運動時間,最大運動時の仕事率と最大酸素摂取量により評価されるが,必然的に運動可能な患者に対象が限定される.最大酸素摂取量は最大心拍出量の第一次近似であり,心血管系の最大酸素輸送能および末梢の最大酸素利用能を反映する.さらに,嫌気性代謝閾値(anaerobic threshold:AT)は,運動時の酸素需給バランスの破綻を示すポイントであるが,客観性,再現性にすぐれた定量的指標である.しかしながら,心不全患者では低い負荷量でATに到達したり,oscillatory ventilationのためATの検出が容易でないことがある.呼吸困難や易疲労による運動制限が心不全によるものか,それ以外によるものかを鑑別するのに有用である. 診断・鑑別診断 急性心不全ではきわめて短時間のうちに患者の容態が悪化するおそれがあり,初期の迅速な診断(重症度と原因診断)と初期治療のためのトリアージ(優先順位)を念頭におく.全身状態の観察とともに,バイタルサインのチェック・静脈ラインの確保,動脈血ガス分析・採血検査(心筋障害マーカー,肝・腎機能,電解質,CRPなど)・12誘導心電図・ポータブル胸部X線撮影を短時間に並行して行う. 重症度評価には,Killip分類が用いられる(表5-3-5).さらに,Swan-GanzカテーテルによるForrester分類があるが,ルーチンには推奨されず,非侵襲的評価方法であるNohria-Stevenson分類が有用である(図5-3-8). 慢性心不全の診断も症状・身体所見に始まる(図5-3-9).慢性心不全の主たる症状は,呼吸困難,浮腫や易疲労感である.ただし,これらは呼吸器疾患,腎不全,貧血など他臓器疾患でも認められることがあり鑑別を要する.身体所見では,心雑音やⅢ音奔馬調律,ラ音や頸静脈怒張がないか確認する.心電図と胸部X線は必須の検査であるが,血漿BNPの測定も有用である.BNP 100 pg/mLあるいはNT-proBNP 400 pg/mL以上であれば心不全を想定して検査を進める. 心エコーを用いて左室駆出率が低下した心不全か,左室駆出率が保持された心不全かを診断することは,病態の理解ばかりでなく,治療法の選択においても有用である.心不全と診断されれば,基礎疾患の診断,治療法の決定に必要な検査,さらに治療効果判定・重症度評価を進める.左室駆出率が保持された心不全(HFPEF)が疑われる場合,心エコーで弁膜症などを除外し,拡張機能障害の所見を認める場合,心不全と診断する. 経過・予後 わが国の慢性心不全の増悪による入院患者の退院後1 年死亡率が11%であるのに対し,心不全増悪による再入院率は26%と死亡以上に高率である.拡張不全の生命予後も不良であり収縮不全と差を認めない.さらに,収縮不全と拡張不全の生存率の経年的変化を1987年から2001年にわたって観察したMayo Clinicの研究によると,収縮不全では生存率の改善がみられたが,拡張不全では認めなかった.このように慢性心不全の長期予後は,収縮不全と拡張不全とにかかわらずきわめて不良である. 治療 (急性心不全の治療は【⇨3-2】救急治療) 慢性心不全の治療目標は,血行動態の改善により自覚症状およびQOLを改善するばかりでなく,増悪による入院を抑制し,生命予後を改善することである.基礎疾患に対する治療が可能な場合は,まず基礎疾患の是正が根本的治療となる.心不全を伴う虚血性心疾患では冠血行再建により左室機能が改善することが期待できる.弁膜症や先天性心疾患では外科的修復により心機能の回復が得られるが,心筋不全が不可逆的障害に陥る前に手術時期を逸しないことが必要である. 1)収縮不全に対する薬物治療 (図5-3-10): 無症状(NYHAⅠ度)から重症(NYHA Ⅳ度)までの幅広い患者に対してアンジオテンシン変換酵素(angiotensin converting enzyme:ACE)阻害薬を投与する.ACE阻害薬が使用できない場合,アンジオテンシンⅡ受容体拮抗薬(angiotensin Ⅱ receptor blocker:ARB)を用いる.NYHAⅡ度以上の患者では,ACE阻害薬またはARBに加えてβ遮断薬を投与する.体液貯留に対してループ利尿薬,サイアザイド系利尿薬を用いる.さらに,抗アルドステロン薬やジギタリスを併用する.NYHA Ⅳ度では,通常入院治療が必要である.利尿薬,硝酸薬,PDEⅢ阻害薬,カテコールアミン,hANPなどの非経口投与を行い状態の安定化をはかる. a)ACE阻害薬:ACE阻害薬は,数多くの大規模臨床試験により生命予後に対する改善効果が証明されており,心不全治療の第一選択薬に位置づけられている.したがって,ACE阻害薬は,心不全の重症度にかかわらずすべての収縮不全の患者に投与すべきである.ACE阻害薬は高用量のほうがより効果が大きいことが報告されており,患者が耐えうる限り増量する.投与後2~3週間以内に空咳が生じることがあり,最も頻度の高い副作用であるが,薬剤を中止することで消失する. b)ARB: ARBはACE阻害薬と同等の臨床的有用性を有すると考えられており,空咳などのためにACE阻害薬が投与できない場合はARBを用いる.ARBも高用量のほうがより効果が大きい.さらに,ACE阻害薬とARBの併用の有効性も証明されているが,実際に併用療法の対象となるのは重症例である. 心不全に対してRA系抑制薬を投与する際には,特に低血圧,腎機能低下,高カリウム血症に注意が必要である.心不全では,このような副作用が高血圧に用いるときよりも起こりやすい.血圧低下は,投与後2~3日で起こりやすく,利尿薬併用によって助長される.RA系抑制薬は,予後の改善を期待して投与しているため,収縮期血圧が80 mmHg台であっても,ふらつきなどの症状がなければ,そのまま継続する.また,開始後は,血清クレアチニンや血清Kを2週間~1カ月以内に測定し,その後もモニターを継続する.血清クレアチニンの上昇が,前値の30%までか1 mg/dLまでなら,そのまま投与を継続する.ただし,血清Kが5.5 mEq/L以上に上昇すると不整脈を誘発することがあり,Kの補正とともに投与を見合わせる. c)β遮断薬:β遮断薬はその陰性変力作用により心不全患者への投与は禁忌であると考えられていた.しかし,数多くの大規模臨床試験によって,幅広い重症度の患者の生命予後を改善することが明らかにされており必須の薬剤である. β遮断薬投与の対象となる患者は,収縮機能障害による慢性心不全患者である.NYHA Ⅱ~Ⅲ度を対象とするが,Ⅰ度,Ⅳ度の患者も対象となり得る.ACE阻害薬を含む標準的治療を受けていること,著明な臓器うっ血所見がなく比較的安定していることが必要である.少量から導入し,患者の状態をみながら徐々に増量していくが,導入時期は特に心不全の増悪,低血圧,徐脈の出現に注意する.心不全増悪の際には,できるだけβ遮断薬を中止せず利尿薬を中心とした心不全治療を強化する.心不全が改善しない場合や血圧低下を伴う場合は強心薬としてPDEⅢ阻害薬を投与する.β遮断薬の中断は,心不全改善後に再導入が必要となり,再導入を行わないと心不全増悪さらには死亡リスクを高めることになり,できるだけ行わないようにする. d)利尿薬:利尿薬は,臓器うっ血を軽減するために最も有効な薬剤であり,おもにループ利尿薬を使用する.ただし,低カリウム血症や低マグネシウム血症などの電解質異常は,ジギタリス中毒ばかりでなく致死性不整脈を誘発することがあり注意を要する.うっ血が消失したら,減量・中止やサイアザイド系利尿薬への切り替えを行う.抗アルドステロン薬は,NYHA Ⅱも含む幅広い重症度の慢性心不全患者の生命予後を改善することが示されており,K保持を兼ねて併用される. e)ジギタリス:ジギタリスは,心筋細胞膜におけるNa-K-ATPaseを阻害し陽性変力作用を示す.また迷走神経活性を亢進させ,房室結節の不応期を延長させて,心室レートを低下させる.したがって,ジギタリスは心房細動を伴う慢性心不全患者において心室レートをコントロールし運動耐容能を改善する.しかしながら,高齢,腎障害,電解質異常(低カリウム血症,低マグネシウム血症)などはジギタリス中毒の誘因となるので注意を要する.また,血中濃度に影響を与えるような相互作用を有する薬剤の併用にも注意する. f)経口強心薬:経口強心薬の予後改善効果は大規模臨床試験によってことごとく否定され,米国では経口強心薬は慢性心不全治療薬としては推奨されていない.しかし生命予後の改善のみが治療の最終目的ではないとの見解に立てば,その臨床的有用性についても再考慮すべきであるという立場もある.特に,QOLの改善,非経口強心薬からの離脱,β遮断薬導入などの際に経口強心薬が有効な患者が存在する.ただし,催不整脈作用があるため細心の注意が必要である. 2)拡張不全に対する薬物治療(図5-3-11): 数多くの大規模臨床試験によって収縮不全に対する薬物治療が確立されてきたのに対し,拡張不全に対する薬物治療は確立していない.うっ血の軽減には利尿薬が最も有効である.ただし,利尿薬による左室充満圧の過度の低下は,心拍出量を減少させ低血圧を引き起こす危険性があるため,投与量を調節することが重要である.高血圧の頻度が高いことから血圧の管理,心房細動のレートコントロール,さらに虚血の改善も重要である.ACE阻害薬やARBは,収縮不全における生命予後の改善効果は確立している一方で,拡張不全の予後に対する有効性については心不全による入院が減少したにとどまっており,あきらかな生命予後の改善効果は証明されていない.β遮断薬やCa拮抗薬は拡張機能を改善すると期待されるが,その臨床的有用性は確実には証明されていない. 3)非薬物療法: 薬物治療で十分なコントロールができない場合,非薬物療法の適用が考慮される.新規の薬物療法の開発が難渋している中で,非薬物療法の進歩には目覚しいものがある. a)植え込み型除細動器(implantable cardiac defibrillator:ICD):心不全患者の死因の約40%は突然死であり,特にNYHA Ⅱ〜Ⅲ度では50〜60%に上る.突然死の80〜90%は致死性不整脈すなわち持続性心室頻拍や心室細動による.このような致死性不整脈に対してはICDの植え込みが有用であり,大規模臨床試験で予後改善効果が証明されている. b)心臓再同期療法(cardiac resynchronization therapy:CRT):NYHAⅢまたはⅣで左脚ブロック主体の左室内伝導遅延を伴う心不全では,CRTの両心室ペーシングによる左室収縮の非同期収縮(dyssynchrony)の是正,さらにICD機能付きCRT(CRT-D)が有効であり,自覚症状・運動耐容能や心機能ばかりでなく予後を改善する.さらに,最近ではNYHAⅡの軽症例でも有効であることが証明され適応が拡大している. c)運動療法:運動療法は安定した慢性心不全患者の運動耐容能や生活の質(QOL)ばかりでなく,心血管死や再入院を含む心事故を減少させる. 予防・疾患管理 心不全の治療にあたっては,心不全の基礎疾患となる高血圧・糖尿病・脂質異常症などの管理を徹底することにより,その発症・進展を予防することも重要である. 慢性心不全患者は高齢者が多く,その生命予後が不良であるばかりでなく,心不全増悪による再入院を反復する.心不全増悪には誘因(増悪因子)が存在する場合が多く,感染症,不整脈,高血圧,虚血,貧血などの医学的要因があるが,塩分制限の不徹底,活動制限の不徹底,内服薬の中断など予防可能な因子も多い.したがって,心不全増悪の防止には,予防可能な誘因の除去も必要である.慢性心不全に対する薬物治療の効果を最大限引き出し,再入院を減少させ,症状・QOLを改善するには,疾患管理(disease management)が必要である.心不全の病態や治療内容に関する知識に加えて,治療薬を規則的に服用し,自己判断で中止しないように指導する.塩分,水分制限とともに,体重を定期的に測定し心不全の早期発見に努める.症状のモニタリングについては,呼吸困難や浮腫などの主要症状とともに,増悪時の症状とその対処方法を十分に説明しておく必要がある.特に,心不全増悪の症状を認めた場合,利尿薬の増量,さらに必要に応じて速やかに受診することにより入院を回避することができる.[筒井裕之] ■文献 和泉 徹,他:急性心不全治療ガイドライン,2011年改訂版,日本循環器学会,2011.http://www.j-circ.or.jp/guideline/pdf/JCS2011_izumi_h.pdf松﨑益德,他:慢性心不全治療ガイドライン,2010年改訂版,日本循環器学会,2010.http://www.j-circ.or.jp/guideline/pdf/JCS2010_matsuzaki_h.pdf筒井裕之他編:心不全に挑む・患者を救う.文光堂,東京,2005. 心不全の原因疾患"> 表5-3-1 収縮不全と拡張不全"> 表5-3-2 心不全の症状"> 表5-3-3 NYHA 心機能分類"> 表5-3-4 Killip 分類による急性心不全の重症度評価"> 表5-3-5 心筋リモデリング・心不全の形成・進展"> 図5-3-5 胸部X写真における心不全の所見"> 図5-3-6 心エコーによる拡張機能評価"> 図5-3-7 急性心不全の重症度分類:a.Forrester の分類 b.Nohria-Stevensonの分類"> 図5-3-8 慢性心不全の診断フローチャート"> 図5-3-9 慢性心不全(収縮不全)の治療指針"> 図5-3-10 慢性心不全(収縮不全)の治療フローチャート"> 図5-3-11 心不全(心・肺疾患に伴う神経系障害)心拍出量低下によるショック状態で脳循環不全や,低酸素血症(脳症)をきたした場合に種々の程度の意識障害をきたす.脳波で徐波化がみられる.診断は意識障害,脳局所症状の有無と血圧,血液ガス,画像診断による.上矢状静脈洞血栓症などと鑑別する.ショックが改善すれば通常回復する.神経細胞は低酸素に感受性が高く,無酸素状態が数分続くと非可逆的となり,心臓が停止した場合には4~6分以内に心蘇生術を施す必要がある.蘇生直後に瞳孔反応のみられない症例では植物状態となる可能性が高い.[高 昌星] 出典 内科学 第10版内科学 第10版について 情報 |
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