MINISTRY OF HEALTH REPUBLIC OF MOLDOVA STATE MEDICAL AND PHARMACEUTICAL UNIVERSITY “NICOLAE TESTEMIȚANU” Faculty of General Medicine Department of… [303609]

MINISTRY OF HEALTH REPUBLIC OF MOLDOVA

STATE MEDICAL AND PHARMACEUTICAL UNIVERSITY

“NICOLAE TESTEMIȚANU”

[anonimizat]: Amira Genem

6[anonimizat]:1049

Scientific Coordinator: M.D.,

conf., universitar,

Cristina Toma

Chișinău 2016

TABLE OF CONTENTS

CHAPTER I: Introduction

The WHO defines chronic obstructive pulmonary disease (COPD) as: "a lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible". (This is in contrast to the variable airways obstruction seen in asthma which can be reversed by drug treatment.) Cigarette smoking residue the major cause of COPD. [anonimizat] 80% of COPD cases. [anonimizat]. [anonimizat] -alpha-1 [anonimizat], irritants and fumes are also involved in the development of the illness.
COPD includes two other medical conditions chronic bronchitis and emphysema.[1]

Emphysema is a [anonimizat]-[anonimizat]- [anonimizat]. [anonimizat]-, [anonimizat], form in the injured areas. [anonimizat], and making breathing out more  hard .[anonimizat]. [anonimizat].

[anonimizat]. [anonimizat]: [anonimizat], which obstruct the airways and makes breathing difficult.

The mucus is cleared through coughing. Both persistent cough and inflammation can harm the bronchial tree. [anonimizat].

[anonimizat]. [anonimizat]. Measurement of lung function using spirometry confirms the diagnosis and helps to classify the severity of the disease. Spirometry is also useful to monitor the progress of the disease and the response to treatment.

[anonimizat], education, [anonimizat].[2]

[anonimizat], nutritional disturbances and abnormal skeletal muscle function. [anonimizat]-[anonimizat], which influence morbidity and mortality.[3]

Systemic inflammation is being considered as a risk factor for a number of different complications including atherosclerosis and is also play a role in the pathogenesis of cardiovascular disease (CVD). There is growing recognition that COPD is a systemic disease with multiple effects on end organs including organs in the cardiovascular system. The pathophysiology of how COPD increases cardiovascular risk is largely unknown. Several studies have shown that reduced lung function is related to an increase in a variety of systemic inflammatory markers.  conducted a systematic review of studies involving the relationship between COPD, forced expiratory volume in one second (FEV1), and levels of various systemic inflammatory markers. Compared to healthy controls, COPD patients were found to have significantly raised levels of C-reactive protein (CRP), fibrinogen, leucocytes, and tumor necrosis factor-alpha (TNF-α). All of which indicate persistent systemic inflammation. This finding may explain, at least in part, the high prevalence of systemic complications (including cardiovascular diseases) among patients with COPD.

C-reactive protein is an important serum marker of inflammation and an independent predictor of cardiovascular disease. CRP is increased in COPD patients and may be a systemic marker of the inflammatory process.[4]

The cardiovascular complication of chronic obstructive pulmonary disease have been known for decades . The spectrum of cardiovascular disease includes right ventricular (RV) dysfunction, pulmonary hypertension (PH), coronary artery disease (CAD), and arrhythmias . Pulmonary vascular disease correlating with COPD increases morbidity and worsens survival . Patients with COPD also have a high risk of mortality due to arrhythmia, myocardial infarction, or congestive heart failure in contrast with those who do not. The Lung Health Study showed that a  fundamental proportion of deaths in patients with mild COPD was the result of cardiovascular complications, and a recent large epidemiologic study detect increased cardiovascular mortality, specially in patients younger than 65 years with COPD. Because cardiac abnormalities  obviously contribute to the overall morbidity related to COPD, an understanding of their role and potential for treatment is vital.[5]

Obstructive Sleep Apnea (OSAS) consider an important syndrome as a differential diagnosis of COPD and as a complication.

Overlap syndrome between chronic obstructive pulmonary disease (COPD) and OSAS is related to greater hypoxaemia and hypercapnia in comparison with COPD or OSAS alone. Early diagnosis and appropriate therapy with CPAP can reduce morbidity and mortality of overlap syndrome .[1A]

CHAPTER III: Bibliographic analysis for theme

In recent studies indicates that chronic obstructive pulmonary disease (COPD) is a complex disease encompass more than airflow obstruction. Airflow obstruction has strong influence on cardiac work and gas exchange with systemic complications. In addition, as COPD results from inflammation and/or modification in repair mechanisms, the distribution of inflammatory mediators into the circulation may start substantial systemic manifestations of the disease, like skeletal muscle wasting and cachexia. Systemic inflammation may also start or worsen comorbid diseases, such as: ischemic heart disease- heart failure- osteoporosis- normocytic anemia- lung cancer- depression and diabetes. Comorbid diseases increase the morbidity of COPD, leading to increased hospitalizations, mortality and healthcare costs. Comorbidities may tangle the management of COPD and need to be predestined carefully.

Recent therapies for comorbid diseases, such as statins and peroxisome proliferator activated receptor agonists, may provide unforeseen advantage for COPD patients. Treatment of COPD inflammation may simultaneously treat systemic inflammation and associated comorbidities.[3]

The cardiovascular complication of chronic obstructive pulmonary disease have been known for decades . The spectrum of cardiovascular disease includes right ventricular (RV) dysfunction, pulmonary hypertension (PH), coronary artery disease (CAD), and arrhythmias . Pulmonary vascular disease correlating with COPD increases morbidity and worsens survival . Patients with COPD also have a high risk of mortality due to arrhythmia, myocardial infarction, or congestive heart failure in contrast with those who do not. The Lung Health Study showed that a  fundamental proportion of deaths in patients with mild COPD was the result of cardiovascular complications, and a recent large epidemiologic study detect increased cardiovascular mortality, specially in patients younger than 65 years with COPD. Because cardiac abnormalities  obviously contribute to the overall morbidity related to COPD, an understanding of their role and potential for treatment is vital.[5]

*Right Ventricular Dysfunction(Core Pulmonaly) and Pulmonary Hypertention:

Introduction:

The WHO defined cor pulmonale as ‘hypertrophy of the RV caused by diseases that influence on the function and, or structure of the lungs, except when these pulmonary modification are the result of diseases that primarily impact the left side of the heart, as in congenital heart disease’. COPD is the most common cause of chronic cor pulmonale in North America .In a study by Ben Jrad et al, COPD accounted for eighty four percent of their 100 cases of chronic cor pulmonale.

Pulmonary artery hypertension is the main cardiovascular complication occurring in COPD. PAH is characterized hemodynamically by a resting mean pulmonary artery pressure (Ppa) > 20 mmHg. Proof of cor pulmonale was found in 40% of patients with COPD in one autopsy study. The prevalence of Pulmonary Artery Hypertension is higher as COPD worsens, PAH is present in an estimated forty percent of patients whose forced expiratory volume in 1 second (FEV1) is < 1 L, and in up to 70% of patients with FEV1 ≤ 0.6 L.

Cor pulmonale can domain clinically from mild changes in right ventricular function to explicit right heart failure and is suppose to be responsible for an estimated 10 to 30% of all hospitalizations for heart failure in the United States.[6]

Pathogenesis:

[Figure 1]

Hypoxia

Chronic hypoxia plays a role in the pathogenesis of Pulmonary Hypertension in COPD by inducing vascular remodeling. Hypoxic vasoconstriction may become increasingly significant during exercise due to decreased mixed venous partial pressure of oxygen. Hypercarbia and acidosis may also cause elevations in pulmonary artery pressures either by amplification of hypoxic vasoconstriction or by stimulating hyperventilation.

Vascular remodeling

Structural alteration in the small pulmonary arteries in lungs of patients with COPD have been seen . Intimal and medial thickening have seen in the small pulmonary arteries of patients with COPD; nevertheless, intimal thickening with composition of cellular hypertrophy and hyperplasia have been consider the most persistently demonstrated morphologic features . Identical features have been seen in pulmonary arteries in chronic hypoxemia. Nevertheless, hypoxemia alone cannot considered for all of these alterations , because intimal thickening is seen in mild COPD, as well as in smokers without obstruction and with normal arterial oxygenation . Itsalso clear that morphologic alterations in the pulmonary vascular bed are not just accountable for the development of Pulmonary Hypertension , because the link between Ppa at rest and morphometry are weakly .

Pulmonary artery endothelial dysfunction occurs in Pulmonary Hypertension. For example, abnormal vascular ring relaxation in vitro inversely proportional with the level of intimal thickening . Mediators that involves in pulmonary artery vasodilation, including nitric oxide synthase (NO) and prostacyclin synthase (PC) , are lacking in the COPD pulmonary vascular bed. Endothelin-1, a strong pulmonary artery vasoconstrictor, happen in high concentrations in the tissue and serum of patients with COPD compared with normal subjects. Vascular endothelial growth factor is elevated in COPD lung tissue, and its quantity correlates with the level of intimal thickening. Serotonin has also been implicated in the pathogenesis of pulmonary vascular remodeling in COPD because polymorphisms of the serotonin transporter (5-HTT) gene seem to correlate with the severity of PH . Various studies now state that inflammation plays a local role in the COPD pulmonary vascular disease. Increases in vascular wall inflammatory cells are correlated with pulmonary arterial wall thickness as well as with abnormal vascular relaxation .

Elastic recoil

It has been proposed that, in emphysema, loss of tethering effect from reduced lung elastic recoil is partly responsible for the development of Pulmonary Hypertension and subsequent Right Ventricular dysfunction.

Dynamic hyperinflation

Dynamic hyperinflation is a consequence of severe emphysema. Gas trapping during exercise may cause dynamic compression of the pulmonary arteries. [5]

Figure 1

Pathophysiology of cor pulmonale in COPD.

Clinical Manifestation

Clinical manifestations of Pulmonary Artery Hypertension may include facial plethora due to polycythemia, clubbing, prominence of the jugular veins, and apparent or palpable impulse or rising of the lower left sternal margin due to enlargement of the Right Ventricle . Peripheral pulses might be weak and rapid because of diminished Cardiac Output in persons with severe Pulmonary Artery Hypertension .Pulsus paradoxus may be appreciated. There may be accentuation of the pulmonic component of the 2nd heart sound or a pulmonic ejection click, murmurs of pulmonary insufficiency and tricuspid regurgitation, widening of the splitting of the second heart sound as Pulmonary Artery Hypertension progresses to Right Ventricular failure, and hepatomegaly, ascites, and peripheral and sacral edema in progressive cor pulmonale. Cardiac findings may be disorganized during auscultation by chest hyperinflation and rotation of the heart in patients with COPD.[6]

Diagnosis

Echocardiography

Hyperinflation precludes optimal visualization of the heart. In a cohort of lung transplant nominees appreciation of systolic PAP (sPAP) was possible in only 38% of the 253 patients with COPD. Hyperinflation with a residual volume of more than 150% reduce the likelihood of sPAP estimation. Sensitivity, specificity, negative predictive value and positive predictive value of sPAP estimated by echocardiography for the diagnosis of Pulmonary Hypertension were 76%, 65%, 93%, and 32 %, respectively(Arcasoy et al 2003)[7]. In the absence of sPAP appreciation, figures for right ventricular abnormalities were 84%, 56%, 96%, and 22 % respectively. in spite the negative predictive value is high enough to exclude PH, the presence of a high sPAP or RV abnormalities requires confirmation by right heart catheterization.[Figure 2]

Figure 2.Echocardiogram demonstrating dilatation of the right atrium and ventricles on an apical four-chamber view. The left ventricle chamber dimensions are normal.

Magnetic resonance imaging

In COPD, the echocardiographic window might be obscured by hyperinflation. Contrast MRI provides excellent images of right ventricular structure and function. Right ventricular wall thickness has a high correlation with the mean Pulmonary Artery Pressure (r = 0.9)  (Saito et al 1992) [8].

Right heart catheterization

Right heart catheterization is the gold standard to locate the exact PAPs. It also allows measurement of the transpulmonary gradient, measurement of cardiac output, with calculation of the pulmonary vascular resistance and determination of reversibility with a vasodilator. Exercise induced pulmonary hypertension can also be evaluated.

The degree of Pulmonary Hypertension in stable COPD is usually mild to moderate – mPAP <35 mm Hg. A mPAP more than 40 mm Hg is rare in COPD and should start a search for an further causes of Pulmonary Hypertension eg, left heart disease, sleep apnea syndrome, pulmonary embolism. Rarely a COPD patient may exhibit with severe Pulmonary Hypertension(Chaouat et al 2005;Thabut et al 2005) [9] . They are characterized by mild to moderate airway obstruction, severe hypoxemia, hypocapnia and a very low diffusing capacity . They also complain from more intense exertional dyspnea and have a low survival. These patients may have an overstated response to chronic hypoxemia as may be seen in particular high altitude dwellers.

Brain natriuretic peptide

BNP is now broadly accepted as a diagnostic tool in the management of left ventricular dysfunction[10] . The role of BNP in the assessment of RV dysfunction, especially in the setting of chronic lung disease, is less clear. A recent study of patients with chronic lung disease showed BNP to be high in patients with significant Pulmonary Hypertension and was a predictor of death . This study was underrepresented in patients with both significant Pulmonary Hypertension and COPD, nevertheless, the use of BNP as a biomarker of Right Ventricular dysfunction in patients with chronic lung disease appears promising.

Chest Radiography

A change in the diameter of the right descending pulmonary artery to >16 mm on the postero-anterior projection combined with a diameter of the left descending pulmonary artery of >18 mm on the left lateral projection can distinguish Pulmonary Hypertension with 98% sensitivity.

ECG

The sensitivity for right ventricular hypertrophy is only 25%–40%. Presence of S1S2S3 or right atrial overload pattern ie, P wave axis of +90° or more, presuppose a poor prognosis.[5]

Therapy of cor pulmonale

The goals of therapy include reduction of Pulmonary Artery Hypertension , augmentation of Right Ventricular performance, alleviation of clinical symptoms, and improvement of survival. Oxygen, vasodilators, theophylline, and inotropic medications have been assessed for these purposes.

in spite pulmonary hypertension in COPD is usually mild – mPAP 20–35 mm Hg, it may increase markedly during exercise, sleep , and exacerbations. Frequent exacerbations can promote the development of right heart failure and this should be preventable by general management measures recommended for COPD.

Oxygen is the best pulmonary vasodilator in COPD patients with cor pulmonale but not all patients benefit from it. Calcium channel blockers, β2-agonists, nitrates, angiotensin converting enzyme inhibitors, theophylline, and α1-antagonists have also been used. Most of these cause a modest decrease in PH accompanied by an increase in cardiac output and a decreased pulmonary vascular resistance. Most of them are also related to systemic hypotension and with worsening of ventilation-perfusion mismatch that may or may not be offset by the improvement in cardiac output. None has been studied long enough to determine any survival benefit.[6]

Oxygen

Several major trials have been applied on the use of long-term oxygen therapy in patients with COPD.

In the Medical Research Council Working Party trial, 87 patients in the United Kingdom were randomly chosen to take or oxygen for 15 hours daily or placebo. Mortality within 5 years was 45% in the oxygen-treated group and 67% in the group that did not take oxygen. Mean Ppa and PVR, determined at the time of entry and again after 1 year, remained unchanged in patients receiving long-term oxygen therapy but increased in control subjects.

In the Nocturnal Oxygen Therapy Trial study in North America, more than two hundred patients with COPD were randomly divided into receiving nocturnal oxygen therapy (averaging 12 hours/d) or continuous oxygen therapy (averaging 17 hours/d). The mortality rate after a year was 20.6% and 11.9% in the nocturnal oxygen group and the continuous oxygen group, respectively. After 6 months of therapy, mean Ppa decreased slightly in patients taking continuous oxygen therapy but increased slightly in the nocturnal oxygen therapy group. Pulmonary Vascular Resistance increased by 6.5% in the group taking nocturnal oxygen therapy but decreased by 11.1% in the continuous oxygen therapy group.

Weitzenblum et al also showed a retraction in the progression of Pulmonary Artery Hypertension in COPD patients with severe hypoxemia which took continuous oxygen therapy for fifteen to eighteen hours a day for one to six years. Whereas Ppa had been increasing at an average annual rate of 1.47 mmHg before starting with long-term oxygen therapy, it reduced significantly by 2.5 mmHg yearly with oxygen therapy.

The acute oxygen induced reversibility of PAH may predict the outcome from long-term oxygen therapy. Ashutosh et al classified forty three patients with COPD and cor pulmonale as "oxygen-responders" if their Ppa reduced by at least 5 mmHg during a 24-hour administration of 28% oxygen, and as "oxygen nonresponders" if the fall in Ppa was less. All patients were then given continuous long-term oxygen therapy. In contrast with non – responders, the oxygen-responders had a markedly higher survival at 1- 3 years.

Nonetheless, not all studies detect a positive hemodynamic reaction following oxygen administration . MacNee et al failed to document any short-term improvement in ventricular contractility on oxygen administration in fourteen patients with cor pulmonale due to COPD.

Possible mechanisms responsible for this beneficial effect on survival and pulmonary hemodynamics include relief of pulmonary vasoconstriction with reduction of Ppa and PVR secondary to enhanced sympatholytic effect or decreased cytoplasmic calcium ion entry, and/or increase of oxygen delivery to the brain, heart, and other vital organs.

It remains uncertain whether the salutary hemodynamic effects contribute to the improved survival related to oxygen therapy. in spite continuous oxygen therapy reduced both mortality and Pulmonary Vascular Resistance , itspossible that results may be unrelated. In the Nocturnal Oxygen Therapy Trial study, continuous oxygen therapy resulted in improved survival only in patients whose baseline Pulmonary Vascular Resistance was low, there was no change in survival in patients with a high resistance.[6]

Medications

Almitrine: Almitrine, a respiratory stimulant, has a salutary effect on gas exchange -increase in pO2 and decrease in pCO2, cardiac index (CI), and systolic ejection work. Not all studies, demonstrate this beneficial action on arterial blood gas tension. The mechanism of almitrine's advantageous effects on arterial blood gases still undefined, in spite it has been suggested that it may be due to alterations in breathing pattern, better peripheral chemoreceptor responsiveness to hypoxia, and a decreasing in ventilation-perfusion mismatching secondary to enhanced hypoxic pulmonary vasoconstriction. The last action may cause detrimental long-term consequence, including the development and progression of Pulmonary Artery Hypertension .

Alpha-Adrenergic Blockers: Alpha-adrenergic blocking agents (e.g., phentolamine, prazosin, urapidil) cause pulmonary vasodilatation, which reduce Ppa and Pulmonary Vascular Resistance and increases Cardiac Output . Nevertheless, side effects, including exacerbate dyspnea and arterial oxygen desaturation, limit their clinical use.

Amrinone: Van Mieghem et al reported that amrinone, an inotropic agent, significantly decreased mean Ppa and Ppcw (pulmonary capillary wedge pressure) without a accompanying change in Cardiac Output , systemic blood pressure, or arterial blood gas values in 10 patients with COPD and cor pulmonale when given at an intravenous bolus dose of 1.0 mg/kg body weight.

Beta-Adrenergic Agonists: Beta-agonists generally cause trivial changes in Ppa, but may reduce Pulmonary Vascular Resistance , and augment Cardiac Output and Right Ventricular Ejection Fraction. Terbutaline administered to persons with COPD increased Right Ventricular Ejection Fraction, left ventricular ejection fraction (LVEF), and CI, and decreased Pulmonary Vascular Resistance. Salbutamol has a positive chronotropic effect and vasodilator action on both the pulmonary and the systemic circuits when given to persons with COPD.

Digitalis : Recent evidence does not support the use of cardiac glycosides in patients with cor pulmonale except if left ventricular failure is present as well. In a double blind, crossover trial done by Mathur et al, 15 subjects with COPD were randomized to digoxin (0.25 mg/day) or placebo for 8 weeks. Digoxin therapy ameliorate Right Ventricular function only in those with a reduced initial left ventricular ejection fraction and failed to alter pulmonary function, cardiopulmonary performance during exercise, or subjective feeling of well-being.

Diuretics: Ppa and Right Ventricular workload in patients with cor pulmonale may be improved by reducing pulmonary blood volume using diuretics. Nevertheless, overzealous diuresis can cause metabolic alkalosis and hypercapnia, which can, in turn, spoil Left Ventricular function. Intravascular volume depletion can, likewise, reduce Right Ventricular preload and Cardiac Output .

Methyldopa: Methyldopa is an aromatic amino acid decarboxylase inhibitor used as an antihypertensive agent. A slight reduction in Pulmonary Vascular Resistance, both at rest and with exercise, was noted in 25 patients with cor pulmonale secondary to COPD who were given methyldopa (750 mg/d). Nevertheless, the use of methyldopa was complicated by postural hypotension that limited the dose that could be administered.

Nitric Oxide :Oxygenation and hemodynamic indices were measured in eighteen patients with COPD taking long-term oxygen therapy following consecutive additions of 5-, 10-, and 20-ppm NO to the inspired oxygen mixture. Maximal improvement in oxygenation was attaining at 5-ppm nitric oxide concentration. Hemodynamic parameters get better (decrease in mean Ppa and Pulmonary Vascular Resistance and increase in Right Ventricular Ejection Fraction) in a dose-dependent fashion, reaching a maximal change with 20-ppm NO.

Prostaglandins: The prostaglandins PGE1 and PGI2 have pronounced vasodilator effects on the pulmonary circulation, and their perturbation may be responsible for the deregulation of the pulmonary vascular tone. Prostaglandins reduce Ppa and Pulmonary Vascular Resistance, and increased Cardiac Output and oxygen delivery when administered to persons with COPD. Studies of the long-term efficacy of prostaglandins are needed to determine their role in the therapy of cor pulmonale secondary to COPD.

Theophylline: Theophylline modestly decrease both Ppa and Pulmonary Vascular Resistance and ameliorate right and left cardiac systolic pump function. These beneficial effects are postulated to be secondary to a reduction in ventricular afterload and a positive ventricular inotropic effect. Matthay et al noted that oral theophylline ameliorate Right Ventricular Ejection Fraction significantly after 72 hours of therapy in fifteen persons with COPD. Right Ventricular Ejection Fraction normalized in seven of ten patients with depressed baseline Right Ventricular function, including two patients with cor pulmonale. The improvement in Right Ventricular Ejection Fraction was prolonged after an average of 4 months of therapy in 11 patients treated with oral theophylline.

Vasodilators: In patients with Pulmonary Artery Hypertension, vasodilator agents generally cause modest reductions in both Ppa and Pulmonary Vascular Resistance, and an improvement in Cardiac Output. Vasodilators, such as calcium channel blockers, nitrates, hydralazine, and angiotensin-converting enzyme inhibitors, produce modest, short-term hemodynamic benefits in cor pulmonale secondary to COPD; these effects are generally not sustained with long-term therapy.[6]

Reduction in hematocrit

Polycythemia increases the viscosity of blood, the resistance to blood flow through the pulmonary circulation and augments hypoxic pulmonary vasoconstriction by causing a local deficiency of nitric oxide (NO). Phlebotomy is indicated in patients with a severe increase in hematocrit not responding to Long Term Oxygen Therapy , so far its effects may be short lived. After repeated phlebotomy followed by volume replacement over 3 months  (Borst et al (1999)[11],  showed improvement in exercise tolerance with a decrease in mean PAP. The mean Hct in this group of 7 was 53, lower than is commonly related to the requirement for phlebotomy.

Activation of the renin-angiotensin system may contribute to polycythemia in COPD. Plasma renin and aldosterone levels are increased in such patients when matched with controls for hypoxemia. The mechanism of action is serum erythropoietin independent. In a small study, losartan was used in weekly escalating doses to a maximum of 100 mg daily for four weeks in 9 stable severe COPD patients with polycythemia (hematocrit >52%). The regimen lead to significant reduction in the hematocrit of all patients from 56 ± 0.9% to 46 ± 0.7% (p < 0.001). The higher the baseline value, the greater the reduction in hematocrit (r = 0.7085; p < 0.05) (Vlahakos et al 2001) [12]. At three months after discontinuation of losartan the hematocrit increased to 50 ± 0.7%. This ‘bloodless phlebotomy’ appears to be a favorable therapy. In a randomized controlled study in 60 COPD patients irbesartan induced a significant decrease in hematocrit “Andreas et al 2006”[13].

Lung volume reduction surgery (LVRS)

LVRS provides a model to study the effects of reduction in hyperinflation and amilorate gas exchange on pulmonary hypertension. In a small study of in 9 patients who underwent LVRS resting mPAP remained unchanged whereas exercising mPAP decreased slightly but not significantly. Nevertheless, the improvement in arterial oxygenation during exercise was closely correspond with the improvement in exercise mPAP, whereas it was unrelated to changes in FEV1 (Oswald-Mammoser et al 1998) [14]. Itspossible that LVRS results in better distribution of pulmonary blood flow and ventilation perfusion matching. In another small study (Weg et al 1999) [15] nevertheless mean PAP in 9 subjects rose from 26.5 to 31.8 mm Hg without change in pulmonary artery occlusion pressure 3 months after surgery. In 3 patients pulmonary artery systolic pressure raise to 60 mm Hg or greater. In retrospect of these subjects may have been unsuited candidates for LVRS by current selection criteria.[5]

Prognosis

In the era before the widespread availability of long term oxygen therpay the presence of PH doubled the mortality in COPD (Oswald-Mammosser et al 1995) [16]. Studies showed an increase in PAP between 1.5–2.8 mm Hg/year (MRC trial 1981; Weitzenblum et al 1985)[17] [18]. Nevertheless, even on Long Term Oxygen Therapy the 5-year survival rate is only 36% in those whose initial mPAP is >25 mm Hg compared to 66% in those whose initial mPAP is <25 mm Hg (Oswald-Mammosser et al 1995)[19]. Long Term Oxygen Therapy appears to stabilize but not reduce Pulmonary Artery Pressure indicating that other factors responsible for prognosis in these patients Those who develop severe PH (mPAP >40 mm Hg) suffer an extremely poor prognosis (5-year survival ~15% vs~55% in those with less severe PH (mPAP 20–40).

In those with mild or moderate hypoxemia (>65 mm Hg), Pulmonary Hypertension develops in 25% over a 6-year follow up but is usually mild(Kessler et al 2001) [20]. These patients are characterized by worsening hypoxemia and hypercapnia Those with Pulmonary Hypertension during exercise at initial catheterization have a greater risk of progression. It may be necessary to follow such patients with periodic arterial blood gases and BNP.

Only continuous Long Term Oxygen Therapy has been shown to amelioratesurvival in cor pulmonale. Itsunclear if this is the result of improved oxygen delivery to vital organs, reduction of systemic inflammation related to COPD or of the reversal or stabilization of Pulmonary Hypertension.[5]

*Coronary Artery Disease:

Prevalence

Patients with COPD are also at increased risk for Coronary artery disease and other smoking related illnesses. In a recent large cohort of nearly 400,000 veterans with COPD admitted to a Veterans Administration (VA) hospital or VA clinic, the prevalence of Coronary Artery Disease was 33.6%, significantly higher than the 27.1% prevalence seen in a matched cohort without COPD[21] . Others have also confirmed a high prevalence of Coronary Artery Disease in COPD.

Pathogenesis

Diffrent studies have reported a strong relation between the occurrence of COPD and the presence of Coronary Artery Disease. The causal link between these diseases has historically been -cigarette smoking-, but the exact mechanisms have only recently been studied. Epidemiologic proof supports the role of systemic inflammation in the pathogenesis of atheroma formation and ischemic heart disease, and recent studies have indicated that patients with COPD have a prominent systemic inflammatory response . C-reactive protein (CRP), a known marker of systemic inflammation, for example, has been shown to be elevated in patients with both stable COPD and during exacerbation. Because elevations in CRP have been linked to Coronary Artery Disease, it appears as though the pathogenesis of both COPD and Coronary Artery Disease may stem from enhanced systemic inflammation. in spite data supporting the use of statin therapy for primary prevention of Coronary Artery Disease are currently lacking, there are data showing that the use of statins decrease systemic inflammation as evidenced by decreasing CRP. In addition, the observation that the use of statin therapy is related to a significant reduction in respiratory-related mortality after a COPD exacerbation further underscores the likely importance of inflammation in this disease.

Diagnosis

Noninvasive assessment of coronary disease in COPD is problematic because patients with COPD are often ventilatory limited in exercise, and pharmacologic stress testing -including adenosine and dipyrimadole may be related to bronchospasm . in spite a rigorous nurse-directed protocol may permit dipyrimadole testing to be done safely in some patients with COPD, itsnot recommended in severe disease .

in spite recent data highlight the safety of dobutamine echocardiography in the general patient population, its safety and efficacy in COPD is not known . Hyperinflation accompanying COPD may limit the diagnostic accuracy of transthoracic echocardiography for detecting wall motion abnormalities with stress.

Recent data indicate that noninvasive 64-slice multidetector computed tomography (64-MDCT) coronary angiography has comparable diagnostic accuracy to traditional invasive quantitative coronary angiography . Nevertheless, its usefulness for evaluating Coronary Artery Disease in COPD has not been determined. Given the increasing recognition of the potential importance of Coronary Artery Disease to the natural history of COPD, evolution of noninvasive techniques to evaluate coronary disease in this population is required.

Treatment

in spite β-blockade plays a central role in the management of Coronary Artery Disease , there has been longstanding concern that it may precipitate bronchospasm in COPD. Nevertheless, the use of cardioselective β-blockers such as atenolol and metoprolol, appears to be safe. Camsari and colleagues assessed the use of metoprolol in 50 patients with COPD mean FEV1, 50% of predicted and found no side effects [22]. 2 recent meta-analyses evaluate single-dose as well as possible chronic β-blocker treatment in patients with reactive airway disease and COPD reveal no evidence of adverse respiratory effects. In addition to their role in Coronary Artery Disease , the use of β-blockers has become standard of care for most patients with left ventricular dysfunction. in spite most studies examining the use of β-blockers in heart failure have excluded patients with COPD, available proofs has shown that the use of nonselective α- and β-blockers such as carvedilol is safe in these patients, despite the fact that caution should be used in patients with reversible airflow obstruction as in asthma. Given the demonstrated efficacy of these agents in Coronary Artery Disease and heart failure, existing data propose that these agents should not be routinely retain in patients with concomitant COPD.

Bounded data exist concerning the safety and efficacy of coronary revascularization in COPD. Prospectively collected data on 183 patients with COPD under going percutaneous coronary intervention find out no increase in in-hospital adverse cardiac outcomes; patients with COPD had increased long-term mortality when compared with those without COPD[23]. Likewise, surgical revascularization can be performed safely in patients with CAD and concomitant COPD, in spite long-term survival in patients with COPD is significantly reduced[24]. Zhu and colleagues performed a backdated analysis comparing conventional coronary artery bypass grafting (CABG) with off-pump CABG in COPD, and found less postoperative respiratory complications and a increased PaO2/FiO2 ratio with off-pump CABG.

*Cardiac Arrhythmias :

prevalence

The prevalence of cardiac arrhythmia in COPD is estimated at around 12–14%. The majority of these are atrial fibrillation and incident cases are more common with increasing disease severity and are likely to be related to underlying Ischemic Heart Disease and potentially a higher frequency of exacerbations.

Pathogenesis

The cardiac arrhythmias commonly related to chronic obstructive pulmonary disease (COPD) are varied. They may be associated primarily to COPD or its treatment, or to concomitant cardiac disease. Exacerbation of pulmonary disease may affect cardiac function, and cardiac dysfunction may complicate the management of COPD .

COPD is related to increased airway resistance, alveolar and pulmonary capillary destruction, air trapping, chronic hypoxemia and increased work of breathing. In an attempt to ameliorate oxygenation of the blood, pulmonary vessels adjacent to underventilated alveoli tend to constrict -hypoxic reflex pulmonary vasoconstriction, increasing both pulmonary vascular resistance and the work of right heart i.e. COPD imposes chronic strain on the right side of heart resulting in cor pulmonale.

Common Cardiac arrhythmias in COPD

Many patients with COPD have an abnormal resting ECG even when they are in normal sinus rhythm. The most common findings are right axis deviation; T wave inversions in leads [V.sub.1]-[V.sub.3]; inferior ST depressions; right bundle branch block; and low voltage [Figure 3,4 ] which may be caused by the volume of the hyperinflated lungs between the recording electrodes and the heart .

In the later stages of COPD, cor pulmonale, or secondary right heart dilatation and hypertrophy may develop as a result of pulmonary hypertension. At this point, the patient's ECG typically demonstrates evidence of right ventricular hypertrophy and right atrial enlargement with tall, peaked P waves in lead II; right axis deviation; right bundle branch block; an R:S ratio greater than 1 in [V.sub.1]; ST-T wave changes in leads [V.sub.1]-[V.sub.3]; and S waves in the lateral leads.[25]

Atrial arrhythmias

Supraventricular rhythm abnormalities are common in patients with COPD . in spite serious atrial arrhythmias are more likely to occur in acutely ill patients, premature atrial contractions have been reported, using ambulatory ECG monitoring, in 64% to 86% of patients who have stable COPD.

Sinus tachycardia is the most common arrhythmia seen during an acute exacerbation of COPD. It occurs in up to 61% of patients. Nevertheless, other atrial arrhythmias often complicate the management of decompensated respiratory disease. These include multifocal atrial tachycardia (MAT), which occurs in 6% to 17% of patients; atrial fibrillation or flutter, in 2.5% to 18% of patients; and atrial tachycardia, in as many as 16% of patients.

Multifocal atrial tachycardia is defined electrocardio-graphically as an atrial tachycardia with an overall rate greater than 100 beats per minute and distinct P waves of at least three different morphologies. Both PR and R-R intervals are variable. Multifocal atrial tachycardia has been related to exacerbations of pulmonary disease and with the use of methylxanthines. Conversely, pulmonary disease is present in 39% to 92% of patients who have Multifocal atrial tachycardia.

[Figure 3]

[Figure 4]

Ventricular arrhythmias

Also common in patients with COPD are ventricular arrhythmias, but they are often asymptomatic. Many patients who have COPD are of an age when primary cardiac disease-specifically, coronary artery disease, hypertensive heart disease, and cardiomyopathy is common. The significance of any ventricular arrhythmia must be viewed in the context of both the primary cardiac disease and the pulmonary disease.[25]

Treatment

The general program to treat dysrhythmias in COPD is same to that used in the general population. there are a number of special discretion in COPD. Supraventricular tachyarrhythmias (SVTs) are common after CABG in COPD. in spite these rhythms are often benign in the non-COPD patient, in COPD, these SVTs ,commonly atrial fibrillation and Multifocal atrial tachycardia may last for a longer period of time and cause hypotension, systemic embolization, congestive heart failure, and anxiety and may prolonged the postoperative hospitalization period. A recent randomized controlled trial has shown that post-CABG amiodarone prophylaxis in patients with COPD significantly decrease the incidence of SVT, MAT, as well as hospital and ICU-related length of stay[26].

The treatment of Multifocal atrial tachycardia directed primarily on managing the trigger cause of rhythm disturbance. Multifocal atrial tachycardia is not obliging to cardioversion and can be successfully rate controlled with β-blockers or diltiazem. Other options include amiodarone and high-dose magnesium[27] . Medically refractory Multifocal atrial tachycardia has been successfully treated with catheter-directed radiofrequency ablation, which may ameliorate quality of life and left ventricular function in selected patients. Furthermore, this approach appears to be cost-effective and consumes fewer health care resources [28].

Other COPD Complications

Acute Exacerbations

Acute exacerbations of COPD are characterized by a sudden increase of symptoms. Cough and sputum production increases. Wheezing is often increased or noted for the first time. Dyspnea -shortness of breath is increased or apparent for the first time. Exacerbations are caused by bronchial infections in most cases. Fever is uncommon. A person with COPD may initially have 1 or 2 acute exacerbations per year, which resolve readily with therapy. The number of exacerbations per year raisee as the diseases proceed.

During an acute exacerbation, there is increased airway narrowing due to bronchospasm -contraction of the bronchi and bronchioles, edema, and excessive mucus production. If narrowed airways cause a maximum increase in the work of breathing that cannot be maintained, the patient will die, unless there is intervention. Often the patient needs mechanical support till the acute decline has solved. Regrettably, some patients don't recover enough from the acute episode to allow them to breathe on their own. There is no way of knowing who will ameliorate and who will not after such an episode. Generally, those who have worse lung function and functional status are less likely to regain independent breathing.[29]

End-stage Lung Disease

When respiratory failure occurs in a patient who has end-stage lung disease, there is a slow decline in lung function and rising levels of carbon dioxide in the blood. The increasing carbon dioxide generate a narcotic effect in the patient, who slowly loses consciousness and stops breathing.

Respiratory failure can occur during an acute exacerbation of COPD or in a patient who has end-stage lung disease.

Pneumonia caused by bacterial infection can lead to respiratory failure in these patients. Streptococcus pneumoniae is the most common cause of bacterial pneumonia in patients with COPD.

Pneumothorax occurs when a hole develops in the lung, allowing air to escape into the space between the lung and the chest wall and collapsing the lung. Patients with COPD are at increased risk for spontaneously developing these holes because of weakened lung structure. A pneumothorax can lead to severe respiratory distress and is treated by inserting a tube into the space between the lung and the chest wall (pleural space) to allow the air to escape out of the space and re-expanding the lung. The tube must remain in the space until the hole is repaired.

Polycythemia in COPD is the body's attempt to adjust to decreased amounts of blood oxygen by increasing the production of oxygen-carrying red blood cells. While this may be helpful in the short term, overproduction eventually clogs small blood vessels.[29]

Obstructive sleep apnea syndrome)OSAS(, COPD, and cardiovascular risk

Systemic inflammation is being considered as a risk factor for a number of different complications including atherosclerosis and is play a role in the pathogenesis of cardiovascular disease (CVD). There is increasing consideration that COPD is a systemic disease with various effects on end organs including organs in the cardiovascular system.

The pathophysiology of how COPD increases cardiovascular risk is largely unknown. Several studies have detect that reduced lung function is related to an elevation in a variety of systemic inflammatory markers.  conducted a systematic review of studies involving the connection between COPD, forced expiratory volume in one second (FEV1), and levels of various systemic inflammatory markers.

Compared to healthy controls, COPD patients were found to have significantly elevated levels of C-reactive protein (CRP), fibrinogen, leucocytes, and tumor necrosis factor-alpha -TNF-α. All of which indicate persistent systemic inflammation. This finding may explain, at least in part, the high prevalence of systemic complications (including cardiovascular diseases) among patients with COPD.C-reactive protein is an important serum marker of inflammation and an independent predictor of cardiovascular disease. CRP is increased in COPD patients and may be a systemic marker of the inflammatory process.

A number of epidemiological studies have shown that Obstructive sleep apnea syndrome is associated to cardiovascular morbidity. In this disease, intense local and systemic inflammation occurs. These patients present elevated inflammatory mediators such as TNF-α and interleukin 6 , leptin, and adhesion molecules. The levels of these mediators amelioratewith CPAP treatment.

As in COPD, patients with Obstructive sleep apnea syndrome present elevated levels of CRP, which are related to disease severity .

Endothelial dysfunction is an indicator of myocardial or vascular dysfunction before the appearance of clinical signs of overt cardiovascular disease. A various of studies involving OSAS patients indicate related endothelial dysfunction which improved after CPAP treatment. Few studied, nevertheless, have focused on the relation between endothelial dysfunction and COPD.  evaluated a variety of plasma markers of endothelial dysfunction in 14 COPD patients, finding changed level of tissue factor pathway inhibitor and selectins.

Furthermore, there is evidence of a concerned neurohumoral regulatory system in COPD patients and Obstructive sleep apnea syndrome patients.[30]

Clinical characteristics

The most common symptoms of Obstructive sleep apnea syndrome patients include chronic loud snoring, excessive daytime sleepiness, personality changes, and deterioration of quality of life. COPD patients, on the other hand, may present cough, sputum production, and/or dyspnea.

Special attention should be taken of suggestion that in Obstructive sleep apnea syndrome patients appears with permanent pulmonary hypertension, bronchial obstruction is generally not severe and the level of hypoxemia and hypercapnia is unpretentious. Hence, chronic airway obstruction in these patients may be asymptomatic, making it requisite to systematically implement pulmonary function tests in all patients diagnosed with Obstructive sleep apnea syndrome by polysomnography.[31]

Quality of sleep

There is evidence that insomnia and other sleep problems are increased in patients with COPD. Especially in elderly COPD patients, sleep quality is reduced in the form of morning tiredness and early awakenings. In addition, data from sleep studies has shown remarkable elevation in stage alteration, repeated arousals and awakenings, long sleep latency, and reduced sleep efficiency .

All these sleep disturbance are likely to have multifactorial origins. Symptoms or comorbid conditions such as nocturnal cough, wheezing, depression, drugs, sedentary lifestyle, and shortness of breath may also contribute .[32]

In Obstructive sleep apnea syndrome patients, one of the most incapacitating symptoms is excessive daytime somnolence, which results from disrupted sleep or nighttime oxygen desaturation . Nevertheless, COPD patients did not have any notable daytime sleepiness, despite feeling somewhat tired .

No remarkable differences were found in sleep structure with respect to FEV1. , in a community-based study, showed that sleep structure changes did not change in subjects with a history of lung disease. In addition, they found that sleep stage allocation varied in accordance with Apnea Hypopnea Index level.

Poor-quality sleep may also be related to hypoxemia and increased superficial sleep .

Diagnostic procedures

The diagnosis of Obstructive sleep apnea syndrome should be based on clinical findings and confirmed by a full-night polysomnography, which has traditionally been regarded as the gold standard for diagnosis. Nevertheless, alternatives that are less expensive and time consuming are increasingly becoming popular .[Figure 5]

[Figure 5] Simultaneous recording of nocturnal oximetry and heart rate in a patient with COPD.

With respect to COPD, clinical evaluation should include questions about sleep quality and possible co-existing Obstructive sleep apnea syndrome. Polysomnography investigation are not indicated in COPD except in special circumstances which include a clinical suspicion of OSAS -hypersomnolence, nocturnal hypoxemia complications not explained by waking arterial oxygen levels, and pulmonary hypertension that is not related to the severity of pulmonary function derangement.[33]

Treatment

All patients with Obstructive sleep apnea syndrome should be counseled about the potential advantages of therapy and the risks of not taking therapy. Furthermore, they should be advised of the significance of obviate factors that increase the severity of upper-airway obstruction such as sleep deprivation, the use of alcohol, hypnotic agents, and increased weight . in spite CPAP therapy is a well-based, Broadly used treatment, itsnot suitable for all patients . [34]

Conventional O2 therapy is prescribed to stable COPD patients who appears with marked and persistent hypoxemia. This therapy is sufficient for correcting even severe nocturnal desaturation and has convenient effects on the observed hypoxemia related peaks of pulmonary hypertension . Some authors report that oxygen therapy improves the quality of sleep by shortening latency to sleep, increasing REM sleep as well as stages 3 and 4, and by decreasing number of arousals. Nevertheless, discrepant results exists, which may be due to differences in the severities of daytime and nighttime hypoxemia, as well as study design.

In some patients, especially those with hypercapnia, higher oxygen flows may lead to further carbon dioxide retention which will lead to morning headache and confusion. Nevertheless, if there is a pronounced worsening in hypercapnia with oxygen therapy, noninvasive nocturnal ventilation (NIPPV) may be added. in spite the exact mechanisms are not yet clear, NIPPV could ameliorate gas exchange in COPD patients by resting the respiratory muscles, resetting the respiratory centers and improving respiratory mechanics. Nevertheless, there are inconsistent results about the use of this treatment in long-term COPD, especially during sleep.[35]

Additional treatment options include theophylline, ipratropium bromide tiotropium .

Certain drugs should be administered with caution. Hypnotics, for example, can adversely affect respiration and gas exchange in patients with COPD by decreasing upper airway muscle tone and blunting the respiratory drive. Itsalso advisable for COPD patients to avoid alcohol ingestion before sleep because it appears to worsen hypoxemia or lead to hypercapnic respiratory failure . [36]

CPAP treatment may have other potentially benefits. As COPD is an inflammatory airways disorder, it may be that Obstructive sleep apnea syndrome acts as an inflammatory stimulus. Thus, the improvement in Obstructive sleep apnea syndrome resulting from the use of CPAP may, in turn, lead to an improvement in the coexistent COPD. Nevertheless, further study is still needed.

Clinical cases

Patient Nr.1:

Age – 64 years old

Cause of hospitalization- Exacerbation of COPD

Main complains: dyspnea , productive cough , chest pain

History of the disease: patient was diagnosed with COPD on 2009

Co-morbidities :

1.hypertension – 2000

2. diabetes mellitus – 2009

Patient smokes since 1973 till 2000 , he smokes 1 pocket of cigarete per day.

Paraclincal investigations:

1.Pulmonary Function Test

2.ECG

3.CAT

4.CT

*Pulmonary Function Test:

Conclusion- severe obstruction- FEV1/FVC%- 57%

*ECG:

Conclusion:

Sinus tachycardia

Frequency 105 b/m

Middle axis

Signs of right ventricle hypertrophy

*CAT test:

Patient score 36

A score between 31 and 40 suggests a very high impact. This score should only be interpreted and acted on in partnership with your healthcare professional.