“CAROL DAVILA” UNIVERSITY OF MEDICINE AND PHARMACY. FACULTY OF MEDICINE. DIPLOMA THESIS Title of the thesis SCIENTIFIC COORDINATOR: TUTOR: GRADUATE:… [301818]
“CAROL DAVILA” UNIVERSITY OF MEDICINE AND PHARMACY. FACULTY OF MEDICINE.
DIPLOMA THESIS
Title of the thesis
SCIENTIFIC COORDINATOR:
TUTOR:
GRADUATE:
BUCHAREST 2019
Table of contents
Page
Introduction 1
General Part
Heart failure
1.1 Introduction 2
1.2 Classification 2
1.3 Etiology 4
1.4 Evaluation 5
II.Pathophysiology of the Left Heart Failure (Congestive Heart Failure).
2.1 Ventricular remodeling 14
2.2 Inflammatory, neurohumoral, and metabolic processes 18
III. Treatment for the heart failure
3.1 Treatment targets 22
3.2 Non-pharmacological treatment 23
3.3 Treatment for the heart failure with reduced ejection fraction 23
IV. Comorbidities for heart failure
4.1 The chronic heart failure syndrome – a systemic disorder 26
4.2 [anonimizat], and‘reverse epidemiology’ 27
4.3 [anonimizat] 29
4.4 The anemia of chronic heart failure 30
4.5 Chronic obstructive pulmonary disease and chronic heart failure 31
4.6 Depression in chronic heart failure 32
Special Part
5.1 Aim of study 35
5.2 Material and methods 36
Inclusion Criteria of the Study 36
Exclusion Criteria of the Study 37
5.3 Clinical data 37
5.4 Observational results 39
Conclusions 65
Bibliography 67
Abbreviations 77
Annex 79
Introduction
Heart failure (HF), also known as chronic heart failure (CHF), is when the heart is unable to pump sufficiently to maintain blood flow to meet the body's needs. [anonimizat], and leg swelling. [anonimizat], and may wake the person at night. A limited ability to exercise is also a common feature. [anonimizat], does not typically occur due to heart failure.
Common causes of heart failure include coronary artery disease including a previous myocardial infarction (heart attack), high blood pressure, atrial fibrillation, valvular heart disease, excess alcohol use, infection, and cardiomyopathy of an unknown cause.These cause heart failure by changing either the structure or the functioning of the heart. The two types of heart failure – heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved ejection fraction (HFpEF) – are based on whether the ability of the left ventricle to contract is affected, or the heart's ability to relax.
Heart failure also brings the disadvantage of empowering other comorbidities. Some of them appear before the heart failure and bring a higher risk for getting heart failure and some of them are a consequence of the heart failure itself. The most important aspect is that everytime patients are affected because of the disease and their quality of life is decreasing.
The reason why I chose this subject is that I think is very important to know which are the most found comorbidities for the heart failure with the reduce ejection fraction, taking into account also the mid-range ejection fraction in order to prevent and also to treat the status of the patient, to eliminate the possible risks of getting other comorbidities and also the risk of having a much decreased ejection fraction with its consequences.
I. Heart Failure
1.1 Introduction
Heart failure is defined as a pathophysiologic condition in which the heart is unable to generate an optimal cardiac output such that there is increased diastolic filling pressure of the left ventricle or inadequate perfusion of tissues, or both, so that pulmonary capillary pressures are increased.
Ischemic heart disease and hypertension are the most important risk factors. Other risk factors include:
obesity,
age,
renal failure,
diabetes,
valvular heart disease,
myocarditis,
cardiomyopathies,
congenital heart disease
excessive alcohol use.
An increased risk for heart failure has been linked to genetic polymorphisms , including genes for cardiomyopathies, myocyte contractility and neurohumoral receptors.
The dysfunction of the left ventricle (systolic and diastolic heart failure) is the dysfunction that led to many causes of HF. In pulmonary disease(right ventricular failure) the right ventricle also may be dysfunctional.Normal or elevated cardiac output(high-output failure) can lead to inadequate perfusion.
1.2.Classification
The New York Heart Association (NYHA) functional classification defines four functional classes as:
Class I: HF does not cause limitations to physical activity; ordinary physical activity does not cause symptoms.
Class II: HF causes slight limitations to physical activity; the patients are comfortable at rest, but ordinary physical activity results in HF symptoms.
Class III: HF causes marked limitations of physical activity; the patients are comfortable at rest, but less than ordinary activity causes symptoms of HF.
Class IV: HF patients are unable to carry on any physical activity without HF symptoms or have symptoms when at rest.
The American College of Cardiology/American Heart Association (ACC/AHA) staging system is defined by the following four stages:
Stage A: High risk of heart failure, but no structural heart disease or symptoms of heart failure;
Stage B: Structural heart disease, but no symptoms of heart failure;
Stage C: Structural heart disease and symptoms of heart failure;
Stage D: Refractory heart failure requiring specialized interventions.
Other possibilities for the classification of heart failure are:
Depending on the clinical manifestations: left (pulmonary congestion and symptoms of low cardiac output), right (systemic congestion) or global
Depending on the mode of onset and the duration: acute or chronic,
Depending on the ejection fraction: systolic or diastolic(Figure 1 )
1.3. Etiology
There are many conditions that can develop into chronic heart failure. The etiology varies depending on several parameters (age, gender, geographic region comorbidities, etc.) and is often complex because a patient can have many other pathologies 2, 3.
There are four factors involved in the etiology of chronic heart failure:
Overload pressure:
– valve stenosis
– hypertension
Volume Overload:
– valvular regurgitation
– arteriovenous fistula
– intracardiac shunts
Decreased myocardial contractile efficiency:
There are many diseases which can cause physiological damage to the myocardium and the most frequent etiology according to studies conducted in the Western European countries is the ischemic heart disease (a consequence of atherosclerotic coronary artery disease). In developing countries, however, the most common cause is the nutritional deficits. 4
Decrease cardiac filling with :
shortening of diastole
pericardial diseases
infiltrative diseases
intracardiac obstruction
The most common cause, is the noncompliant non-pharmacological treatment (high consumption of salt / fluid, excessive exercise) and / or pharmacological. To this can be added the use of other drugs with negative inotropic effect.
Other factors that are commonly found beside the etiological factors explained above:
myocardial ischemia,
cardiac or systemic infection,
arrhythmias,
hypertensive crisis,
aggravated kidney failure,
endocrine disease (hyperthyroidism) 5 , 6 , 7 , 8
1.4. Evaluation
The clinical manifestations of HFrEF are the result of pulmonary vascular congestion and inadequate perfusion of the systemic circulation. Individuals experience :
dyspnea,
orthopnea,
cough of frothy sputum,
fatigue,
decreased urine output,
edema.
Physical examination often reveals
pulmonary edema (cyanosis, inspiratory crackles, pleural effusions),
hypotension or hypertension,
an S3 gallop,
and evidence of underlying CAD
hypertension. 9
History and Physical Examination in HF
HISTORY
Potential clues suggesting etiology of HF –A careful family history may identify an underlying familial cardiomyopathy in patients with idiopathic DCM.10
Duration of illness- A patient with recent-onset systolic HF may recover over time.11
Severity and triggers of dyspnea and fatigue, presence of chest pain,exercise capacity, physical activity, sexual activity–To determine NYHA class; identify potential symptoms of coronary ischemia.
Anorexia and early satiety, weight loss -Gastrointestinal symptoms are common in patients with HF. Cardiac cachexia is associated with adverse prognosis.12
Weight gain- Rapid weight gain suggests volume overload.
Palpitations, (pre)syncope, ICD shocks- Palpitations may be indications of paroxysmal AF or ventricular tachycardia. ICD shocks are associated with adverse prognosis.13
Symptoms suggesting transient ischemic attack or thromboembolism- Affects consideration of the need for anticoagulation.
Development of peripheral edema or ascites- Suggests volume overload.
Disordered breathing at night, sleep problems -Treatment for sleep apnea may improve cardiac function and decrease pulmonary hypertension.14
Recent or frequent prior hospitalizations for HF -Associated with adverse prognosis.15
History of discontinuation of medications for HF -Determine whether lack of GDMT (Guidline directed medical therapy) in patients with HFrEF reflects intolerance, an adverse event, or perceived contraindication to use. Withdrawal of these medications has been associated with adverse prognosis.16,17
Medications that may exacerbate HF- Removal of such medications may represent a therapeutic opportunity.
Diet -Awareness and restriction of sodium and fluid intake should be assessed
Adherence to medical regimen- Access to medications; family support; access to follow-up; cultural sensitivity
Physical Examination
BMI and evidence of weight loss -Obesity may be a contributing cause of HF; cachexia may correspond with poor prognosis.
Blood pressure (supine and upright)- Assess for hypertension or hypotension. Width of pulse pressure may reflect adequacy of cardiac output. Response of blood pressure to Valsalva maneuver may reflect LV filling pressures.18
Pulse- Manual palpation will reveal strength and regularity of pulse rate.
Examination for orthostatic changes in blood pressure and heart rate -Consistent with volume depletion or excess vasodilation from medications.
Jugular venous pressure at rest and following abdominal compression -Most useful finding on physical examination to identify congestion.19;20-23
Presence of extra heart sounds and murmurs- S3 is associated with adverse prognosis in HFrEF.20 Murmurs may be suggestive of valvular heart disease.
Size and location of point of maximal impulse- Enlarged and displaced point of maximal impulse suggests ventricular enlargement.
Presence of right ventricular heave -Suggests significant right ventricular dysfunction and/or pulmonary hypertension.
Pulmonary status: respiratory rate, rales, pleural effusion- In advanced chronic HF, rales are often absent despite major pulmonary congestion.
Hepatomegaly and/or ascites- Usually markers of volume overload.
Peripheral edema -Many patients, particularly those who are young, may be not edematous despite intravascular volume overload. In obese patients and elderly patients, edema may reflect peripheral rather than cardiac causes.
Temperature of lower extremities Cool lower extremities may reflect inadequate cardiac output.
A thorough history and physical examination should be obtained/performed in patients presenting with HF to identify cardiac and non-cardiac disorders or behaviors that might cause or accelerate the development or progression of HF.
2. In patients with idiopathic DCM, a 3-generational family history should be obtained to aid in establishing the diagnosis of familial DCM.
3. Volume status and vital signs should be assessed at each patient encounter. This includes serial assessment of weight, as well as estimates of jugular venous pressure and the presence of peripheral edema or orthopnea.20-23
Initial laboratory evaluation of patients presenting with HF should include:
1. Complete blood count, urinalysis, serum electrolytes (including calcium and magnesium), blood urea nitrogen, serum creatinine, glucose, fasting lipid profile, liver function tests, and thyroid-stimulating hormone.
2. Serial monitoring, when indicated, should include serum electrolytes and renal function.)
3. A 12-lead ECG should be performed initially on all patients presenting with HF.
In addition to routine clinical laboratory tests, other biomarkers are gaining greater attention for their utility in HF management. These biomarkers may reflect various pathophysiological aspects of HF, including myocardial wall stress, hemodynamic abnormalities, inflammation, myocyte injury, neurohormonal upregulation, and myocardial remodeling, as well as extracellular matrix turnover. Thus, these biomarkers are potentially powerful adjuncts to current standards for the diagnosis, prognosis, and treatment of acute and chronic HF
BNP
BNP or its amino-terminal cleavage equivalent (NT-proBNP) is derived from a common 108-amino acid precursor peptide (proBNP 108) that is generated by cardiomyocytes in the context of numerous triggers, most notably myocardial stretch. Following several steps of processing, BNP and NT-proBNP are released from the cardiomyocyte, along with variable amounts of proBNP 108 , the latter of which is detected by all assays that measure either “BNP” or “NT-proBNP.”
Assays for BNP and NT proBNP have been increasingly used to establish the presence and severity of HF. In general, BNP and NT-proBNP values are reasonably correlated, and either can be used in patient care settings as long as their respective absolute values and cut points are not used interchangeably.
BNP and NT-proBNP are useful to support clinical judgment for the diagnosis or exclusion of HF, in the setting of chronic ambulatory HF 24-30 or acute decompensated HF 31-36 ; the value of natriuretic peptide testing is particularly significant when the etiology of dyspnea is unclear.
Although lower values of BNP or NT-proBNP exclude the presence of HF and higher values have reasonably high positive predictive value to diagnose HF, clinicians should be aware that elevated plasma levels for both natriuretic peptides have been associated with a wide variety of cardiac and noncardiac causes 37-40
BNP and NT-proBNP levels improve with treatment of chronic HF,41,42-44 with lowering of levels over time in general, correlating with improved clinical outcomes.34,45,46,47
Thus, BNP or NT-proBNP “guided” therapy has been studied against standard care without natriuretic peptide measurement to determine whether guided therapy renders superior achievement of GDMT in patients with HF. However, RCTs have yielded inconsistent results.
The positive and negative natriuretic peptide–guided therapy trials differ primarily in their study populations, with successful trials enrolling younger patients and only those with HFrEF. In addition, a lower natriuretic peptide goal and/or a substantial reduction in natriuretic peptides during treatment are consistently present in the positive “guided” therapy trials.275 Although most trials examining the strategy of biomarker “guided” HF management were small and underpowered, 2 comprehensive meta-analyses concluded that BNP-guided therapy reduces all-cause mortality in patients with chronic HF compared with usual clinical care,48,49 especially in patients <75 years of age.
This survival benefit may be attributed to increased achievement of GDMT. In some cases, BNP or NT-proBNP levels may not be easily modifiable. If the BNP or NT-proBNP value does not fall after aggressive HF care, risk for death or hospitalization for HF is significant. On the other hand, some patients with advanced HF have normal BNP or NT-proBNP levels or have falsely low BNP levels because of obesity and HFpEF. All of these patients should still receive appropriate GDMT
Biomarkers of Myocardial Injury: Cardiac Troponin T or I
Abnormal concentrations of circulating cardiac troponin are found in patients with HF, often without obvious myocardial ischemia and frequently in those without underlying CAD. This suggests ongoing myocyte injury or necrosis in these patients.50-53,54
In chronic HF, elaboration of cardiac troponins is associated with impaired hemodynamics,50 progressive LV dysfunction,51 and increased mortality rates.50-53,54 Similarly, in patients with acute decompensated HF, elevated cardiac troponin levels are associated with worse clinical outcomes and mortality 55 ,56,57; decrease in troponin levels over time with treatment is associated with a better prognosis than persistent elevation in patients with chronic or acute HF.
Given the tight association with ACS and troponin elevation as well as the link between MI and the development of acute HF, 58 the measurement of troponin I or T should be routine in patients presenting with acutely decompensated HF syndromes.
Other investigations:
The chest x-ray is important for the evaluation of patients presenting with signs and symptoms of HF because it assesses cardiomegaly and pulmonary congestion and may reveal alternative causes, cardiopulmonary or otherwise, of the patient’s symptoms. Apart from congestion, however, other findings on chest x-ray are associated with HF only in the context of clinical presentation. Cardiomegaly may be absent in HF. A chest x-ray may also show other cardiac chamber enlargement, increased pulmonary venous pressure, interstitial or alveolar edema, valvular or pericardial calcification, or coexisting thoracic diseases. Considering its low sensitivity and specificity, the chest x-ray should not be the sole determinant of the specific cause of HF. Moreover, a supine chest x-ray has limited value in acute decompensated HF.
Although a complete history and physical examination are important first steps, the most useful diagnostic test in the evaluation of patients with or at risk for HF (eg, postacute MI) is a comprehensive 2-dimensional echocardiogram; coupled with Doppler flow studies, the transthoracic echocardiogram can identify abnormalities of myocardium, heart valves, and pericardium.
Echocardiography can reveal subclinical HF and predict risk of subsequent events. 59-63 Use of echocardiograms in patients with suspected HF improves disease identification and provision of appropriate medical care. 64 Echocardiography evaluation should address whether LVEF is reduced, LV structure is abnormal, and other structural abnormalities are present that could account for the clinical presentation.
This information should be quantified, including numerical estimates of EF measurement, ventricular dimensions, wall thickness, calculations of ventricular volumes, and evaluation of chamber geometry and regional wall motion. Documentation of LVEF is an HF quality-of-care performance measure.65 Right ventricular size and function as well as atrial size and dimensions should also be measured. All valves should be evaluated for anatomic and flow abnormalities. Secondary changes, particularly the severity of mitral and tricuspid valve insufficiency, should be determined.
Noninvasive hemodynamic data constitute important additional information. Mitral valve inflow pattern, pulmonary venous inflow pattern, and mitral annular velocity provide data about LV filling and left atrial pressure. The tricuspid valve regurgitant gradient, coupled with measurement of inferior vena cava diameter and its response during respiration, provides estimates of systolic pulmonary artery pressure and central venous pressure. Many of these abnormalities are prognostically important and can be present without manifest HF.
Serial echocardiographic evaluations are useful because evidence of cardiac reverse remodeling can provide important information in patients who have had a change in clinical status or have experienced or recovered from an event or treatment that affects cardiac function. However, the routine repeat assessment of ventricular function in the absence of changing clinical status or a change in treatment intervention is not indicated.
The preference for echocardiography as an imaging modality is due to its widespread availability and lack of ionizing radiation; however, other imaging modalities may be of use.
Magnetic resonance imaging assesses LV volume and EF measurements at least as accurately as echocardiography. However, additional information about myocardial perfusion, viability, and fibrosis from magnetic resonance imaging can help identify HF etiology and assess prognosis.66 Magnetic resonance imaging provides high anatomical resolution of all aspects of the heart and surrounding structure, leading to its recommended use in known or suspected congenital heart diseases.
Cardiac computed tomography can also provide accurate assessment of cardiac structure and function, including the coronary arteries.67 An advantage of cardiac computed tomography over echocardiography may be its ability to characterize the myocardium, but studies have yet to demonstrate the importance of this factor. Reports of cardiac computed tomography in patients with suspected HF are limited.
Furthermore, both cardiac computed tomography and magnetic resonance imaging lose accuracy with high heart rates. Radionuclide ventriculography may also be used for evaluation of cardiac function when other tests are unavailable or inadequate. However, as a planar technique, radionuclide ventriculography cannot directly assess valvular structure, function, or ventricular wall thickness; it may be more useful for assessing LV volumes in patients with significant baseline wall motion abnormalities or distorted geometry. Ventriculography is highly reproducible.68 Single photon emission computed tomography or positron emission tomography scans are not primarily used to determine LV systolic global and regional function unless these parameters are quantified from the resultant images during myocardial perfusion and/or viability assessment.69,70
Candidates for coronary revascularization who present with a high suspicion for obstructive CAD should undergo coronary angiography. Stress nuclear imaging or echocardiography may be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina unless they are ineligible for revascularization.71 Although the results of the STICH (Surgical Treatment for Ischemic Heart Failure) trial have cast doubt on the role of myocardial viability assessment to determine the mode of therapy,72 the data are nevertheless predictive of a positive outcome. When these data are taken into consideration with multiple previous studies demonstrating the usefulness of this approach, it becomes reasonable to recommend viability assessment when treating patients with HfrEF who have known CAD.
II .Pathophysiology of the Left Heart Failure (Congestive Heart Failure)
Left heart failure, also known as congestive heart failure, can be heart failure with reduced ejection fraction (systolic heart failure) or heart failure with preserved ejection fraction (diastolic heart failure). These two types of heart failure can occur together in one individual or singly.
Heart failure with reduced ejection fraction (systolic heart failure) is described as an inability of the heart to generate an adequate cardiac output to keep perfusing the vital tissues and it has an ejection fraction of <40% . Cardiac output depends on the heart rate and stroke volume. Stroke volume is influenced by three major factors: preload, afterload and contractility. Contractility is reduced by diseases that is damaging the myocyte activity. Myocardial infarction is the most common cause of decreased contractility. Other causes include myocarditis and cardiomyopathies. Secondary causes of decreased contractility, such as myocardial ischemia and increased myocardial workload, contribute to inflammatory, immune and neurohumoral changes (activation of the SNS and RAAS) that mediate a process called ventricular remodeling.
SNS-Sympathetic nervous system
RAAS-renin-angiotensin-aldosterone-system
2.1 Ventricular remodeling
Results in damage of the normal myocardial extracellular structure with the result of progressive myocyte contractile dysfunction and dilation of the myocardium over time (Figure 2).
When contractility is decreased, left ventricular end-diastolic volume (LVEDV) increases and stroke volume falls, this causes an increase in preload and dilation of the heart.
Preload, or LVEDV, increases with an excess of plasma volume (intravenous fluid administration, renal failure, mitral valvular disease) or when there is decreased contractility.
Increases in LVEDV can actually improve cardiac output, but as preload continues to rise, it causes a stretching of the myocardium that can lead to decreased contractility and to a dysfunction of the sarcomeres (Figure3).
Increased afterload is usually a result of increased peripheral vascular resistance (PVR), such as that seen with hypertension (Figure 4).
Most of the cases of heart failure have antecedent hypertension.73 There are also times when the heart failure is the result of aortic valvular disease. With an increased PVR, there will be resistance to ventricular emptying and usually more workload for the left ventricle, that will respond with hypertrophy of the myocardium. This process differs from the usual physiologic myocyte response to increased workload ,case in which the workload is intermittent rather than sustained, resulting in an increased muscle mass but with no distortion of the cardiac architecture.74
Sustained afterload leads to pathologic hypertrophy mediated by catecholamines and angiotensin II.
This pathologic increase in muscle mass brings an increase in energy and oxygen demand. The myocardium consumes an immense amount of metabolic energy and relies on the production of ATP. This production of ATP depends on the normal myocytes getting enough fuel , using an effective creatine kinase system and having an adequate mitochondrial function. When demand for energy is much more than the ability to supply the necessary ATP, contractility of the myocardium is damaged.
An energy-starved state develops mechanisms of change in the myocytes themselves and ventricular remodeling that significantly impairs contractility and therefore ventricular function.75
Remodeling results in the deposition of collagen between the myocytes, which can bring a disruption in the integrity of the muscle, make the ventricle more likely to dilate, decrease contractility and fail.76 Weakness of the cardiac muscle due to hypertension-induced hypertrophy is defined as hypertensive hypertrophic cardiomyopathy.
When cardiac output falls, renal perfusion diminishes with activation of the RAAS, which will act to increase plasma volume and PVR,thus increasing afterload and preload . Baroreceptors in the central circulation detect the decrease in perfusion and then stimulate the SNS to cause more vasoconstriction and to cause the hypothalamus to produce antidiuretic hormone. This cycle of increasing preload, decreasing contractility, and increasing afterload causes progressive worsening of left heart failure (Figure 5).
In addition to these hemodynamic interactions, systolic congestive heart failure is characterized by inflammatory,neurohumoral, and metabolic processes
2.2 Inflammatory,neurohumoral, and metabolic processes
1. Catecholamines For a decrease in cardiac output sympathetic nervous system activation initially compensates by increasing peripheral vascular resistance and heart rate.Also, catecholamines cause numerous nocive effects on the myocardium, including induction of myocyte apoptosis, direct toxicity to myocytes, down-regulation of adrenergic receptors, myocardial remodeling, potentiation of autoimmune effects on the heart muscle and facilitation of dysrhythmias.
2. RAAS
a. Angiotensin II (Ang II).
The activation of the RAAS can cause an increases in preload and afterload and also direct toxicity to the myocardium (see Figure 2).Ang II mediates remodeling of the ventricular wall,contributing to loss of the normal collagen matrix, interstitial fibrosis and sarcomere death,. This leads to changes in myocardial compliance, ventricular dilation and decreased contractility.
b. Aldosterone.
Except the salt and water retention by the kidney, aldosterone also contributes to myocardial fibrosis, autonomic dysfunction, and dysrhythmias. It also has been implicated in prothrombotic effects and endothelial dysfunction.77
3. Arginine vasopressin.
Arginine vasopressin is also known as antidiuretic hormone and causes both renal fluid retention and peripheral vasoconstriction. These actions exacerbate edema and hyponatremia in heart failure.
4. Natriuretic peptides.
Atrial and BNPs are increased and may have some protective effect by decreasing preload; Even so, their compensatory mechanisms are inadequate in heart failure.78
5. Inflammatory cytokines
a. Endothelial hormones. Endothelin is associated with a poor prognosis in individuals with heart failure and is also a potent vasoconstrictor.
b. TNF-α and IL-6. TNF-α is found elevated in heart failure and contributes to remodeling and myocardial hypertrophy.79,80 It induces myocyte apoptosis, down-regulates the synthesis of the vasodilator nitric oxide (NO), and may contribute to weakness and weight loss in individuals with heart failure (cardiac cachexia). IL-6 also is elevated and can contribute to further deleterious immune activation.
6. Myocyte calcium transport.
Calcium transport into, within and out of myocytes is very important to normal contractile function. Changes in calcium ion channels, intracellular transport mechanisms and calcium cycling have been implicated in decreased myocardial contractility and heart failure.81
7. Insulin resistance and diabetes.
Insulin resistance is a contributor and also a complication of heart failure. Insulin resistance can cause abnormal myocyte fatty acid metabolism, which can contribute to remodeling and decreased myocardial contractility 82. Heart failure activates the SNS and RAAS, which can both contribute to insulin resistance.
Diabetes contributes to heart failure because of the changes in fatty acid and glucose metabolism, disturbed calcium metabolism, oxidative stress, and mitochondrial dysfunction. Many of the new medications used to treat diabetes and insulin resistance have deleterious side effects on cardiac functioning;
The interaction of these metabolic, inflammatory and neurohumoral processes, results in a decline in myocardial function. Then the heart muscle exhibits decreased contractility, abnormal fibrin deposition in the ventricle wall, myocyte apoptosis and necrosis, myocardial hypertrophy, and changes in the ventricular chamber geometry. These changes reduce cardiac output, myocardial function and lead to increased morbidity and mortality. These findings have led to the ordinary use of ACE inhibitors, aldosterone blockers, and beta-blockers in the management of heart failure, which has resulted in significant decreases in morbidity and mortality.83
All the aspects presented above, can be concluded in one schematic diagram. (Fig 6)
III Treatment of heart failure
3.1 Treatment targets
Are reducing mortality, relieve symptoms, increase exercise capacity, quality of life, reduce hospitalizations and preventing worsening of the structural functions.(Figure 7.)
3.2 Non-pharmacological treatment
Consists in adopting a certain lifestyle and a certain diet. It indicates a low sodium diet (reduction of salt to 3-4.5 g / day) and severe forms of heart failure with hyponatremia, refractory to therapy is indicated restriction 1-1.5 l of water intake. Smoking is contraindicated, low alcohol: 10 to 20 g / day (1-2 glasses of wine / day) may be accepted, provided depressive effect on myocardial contractility. Alcohol consumption is prohibited in ethanol cardiomyopathy. It indicated weight loss in obese patients in mild forms of HF to improve symptoms and quality of life. In advanced forms of HF appears in significant weight loss – malnutrition – due to changes in metabolism, loss of appetite, edema and inflammation affecting the gastrointestinal tract, this decrease in weight having a negative prognostic. Vaccination (anti-pneumococcal and antiinfluenza) has a beneficial effect. Physical training is beneficial and is recommended for all stable patients, increases skeletal muscle strength, muscle mass, normalize muscle metabolism, improve endothelial function and better adaptation of the autonomic nervous system to effort. Beneficial effect translates into increased capacity exercise, reduce mortality and hospitalizations. Adherence to lifestyle and treatment is essential, stopping their being frequently a cause of worsening. The patient is encouraged to monitor disease manifestations (body weight, presence of edema, etc.).
3.3 Treatment of the heart failure with reduced ejection fraction
There are five main goals of therapy in patients with chronic heart failure and a reduced EF:
1. Identification and correction of the underlying condition causing heart failure. In some patients, this may require surgical repair or replacement of dysfunctional cardiac valves, coronary artery revascularization, aggressive treatment of hypertension, or cessation of alcohol consumption.
2. Elimination of the acute precipitating cause of symptoms in a patient with heart failure who was previously in a compensated state. This may include, for example, treating acute infections or arrhythmias, removing sources of excessive salt intake, or eliminating drugs that can aggravate symptomatology (e.g., certain calcium channel blockers, which have a negative inotropic effect, or nonsteroidal anti-inflammatory drugs, which can contribute to volume retention).
3. Management of heart failure symptoms:
a. Treatment of pulmonary and systemic vascular congestion. This is most readily accomplished by dietary sodium restriction and diuretic medications.
b. Measures to increase forward cardiac output and perfusion of vital organs through the use of vasodilators and positive inotropic drugs.
4. Modulation of the neurohormonal response to prevent adverse ventricular remodeling in order to slow the progression of LV dysfunction.
5. Prolongation of long-term survival. There is strong evidence from clinical trials that longevity is enhanced by specific therapies, as described below.
The last 50 years have witnessed great strides in the management of HFrEF. The treatment of symptomatic heart failure that evolved from diuretics and hemodynamic therapy model (digoxin, inotropic therapy) ushered in the era of disease-modifying therapy with neurohormonal antagonism. In this regard, RAAS blockers and beta blockers form the cornerstone of pharmacotherapy lead to attenuation of decline and improvement in cardiac structure and function with consequent reduction in symptoms, improvement in QOL (quality of life), decreased burden of hospitalizations, and a decline in mortality from both pump failure and arrhythmic deaths.
Management of HFrEF is aimed at interrupting the worsening cycle of decreasing contractility, increasing preload, and increasing afterload, as well as blocking the neurohormonal mediators of myocardial toxicity.84 The acute onset of left heart failure is most often the result of acute myocardial ischemia and must be managed in conjunction with the underlying coronary disease. Oxygen, nitrates, and morphine administration improve myocardial oxygenation and help relieve coronary spasm while lowering preload through systemic venodilation. Diuretics reduce preload and are the mainstay of therapy. Intravenous inotropic drugs, such as dobutamine and milrinone, increase contractility and can help raise the blood pressure in hypotensive individuals; however, long-term use is associated with a high mortality.85
Calcium-sensitizing inotropic drugs (e.g., levosimendan) have shown promise for acute heart failure in selected individuals.85 ACE inhibitors (which reduce preload and afterload) and intravenous beta-blockers (which reduce myocardial demand) have been found to reduce mortality but must be used with caution in hypotensive individuals. Intravenous administration of nesiritide (recombinant BNP) also improves preload and contractility; however, results of this therapy have been mixed and new natriuretic peptides (human recombinant ANP and ularitide) are being evaluated.87,88 Individuals with severe systolic failure because of myocardial ischemia may benefit from acute coronary bypass or PCI. Those with refractory hypotension may be supported with the intra-aortic balloon pump (IABP) until they can be taken safely to the operating room; the IABP is positioned in the aorta just distal to the aortic valve and is inflated during diastole to improve coronary perfusion and deflated during systole to reduce afterload.
Management of chronic left heart failure also relies on increasing contractility and reducing preload and afterload.
In all patients with reduced ejection fraction, ACE inhibitors and beta blockers are indicated to reduce mortality. Salt restriction, loop diuretics, and aldosterone-blockers such as spironolactone and eplerenone are effective in reducing preload and improving outcomes.89,90 ACE inhibitors reduce preload and afterload and have been shown to significantly reduce mortality in chronic left heart failure. ARBs do not improve morbidity or mortality in individuals with heart failure and should be used only in those who do not tolerate ACE inhibitors.91 Beta-blockers, especially some of the newer drugs, such as bisoprolol, improve symptoms and increase survival.92 Catheter-based renal sympathetic denervation is being explored for heart failure.93 The inotropic drug digoxin may be considered in some individuals, especially those with atrial fibrillation. Statins are not indicated for the treatment of heart failure unless other comorbid conditions (e.g., CAD) are present. Anticoagulants and antithrombotics may be indicated in selected individuals, particularly those with intracardiac thrombi or atrial fibrillation. Although many individuals with left heart failure die suddenly from dysrhythmias, prophylactic administration of antidysrhythmics has not been shown to improve survival. In individuals with sustained ventricular tachycardia, amiodarone or ICDs are indicated. Cardiac resynchronization therapy is proving to be an important modality in selected individuals.94 Coronary bypass surgery or PCI may improve perfusion to ischemic myocardium (hibernating myocardium) and improve cardiac output. Other types of surgical intervention that improve ventricular geometry may be considered. Heart transplant may be the only remaining option.
Experimental therapies, including gene and stem cell therapies, are being explored 95,96
IV Comorbidities for heart failure
Even though there were improvements in pharmacotherapy, the morbidity and mortality rates in the populations with chronic heart failure (CHF) have remained high,97 exceeding by far those reported in the treatment guidelines for CHF . This divergence between clinical study participants and the ‘real world’ CHF population is explained by restrictive study enrolment criteria, and only the ones that are elderly, fit the profile of typical clinical trial populations. The most important differences are that these patients often have preserved left ventricular systolic function and most of the times suffer from multiple comorbidities.98
4.1 The chronic heart failure syndrome – a systemic disorder
Figure 8 depicts the pathophysiological cascade of the CHF syndrome. Various conditions predispose to its development. The occurrence of CHF transforms the clinical manifestations and the prognosis of the underlying diseases profoundly. For example, inpatients after a myocardial infarction, mortality rates increase by a factor of four with the onset of CHF. CHF is fairly uniformly characterized by a specific set of symptoms in the medical history (dyspnea, fatigue, and cerebral dysfunction) and physical signs (edema, ales, and muscle wasting) in the physical examination.99
Although CHF symptoms tend to progress, their severity may fluctuate. With appropriate medication and lifestyle modifications, some patients may experience remarkable clinical recovery, which may also be associated with improvements in cardiac structural and functional abnormalities. Although the CHF syndrome has traditionally been looked upon as a hemodynamic disorder, the correlation between measures of cardiac performance and CHF symptoms may be poor in the individual patient. The mechanisms responsible for the exercise intolerance of patients with CHF have not been clearly defined. Thus, severely impaired left ventricular pump function is sometimes present in clinically asymptomatic patients, whereas individuals with preserved systolic function may experience severely disabling CHF symptoms. This apparent discordance between left ventricular ejection fraction and the degree of individual functional impairment is not well understood and may only partially be explained by factors such as cardiac rhythm, left ventricular asynchrony, secondary valvular incompetence, or the degree of right ventricular impairment.
Instead, there is growing evidence that various disease conditions affecting other organs than the heart are patho-physiologically closely interrelated with the occurrence of CHF, and impact on both disease progression and the prognosis of the patient, rendering it a complex systemic syndrome. There is a likely possibility of preexisting organ damage (e.g. renal impairment in patients with hypertension), most comorbidities and functional abnormalities are diagnosed at the time of the first clinical manifestation of CHF. These conditions comprise renal dysfunction with abnormal sodium handling, anemia, and hemodilution; respiratory disorders including sleep-disordered breathing; depression and cognitive dysfunction; changes in peripheral muscular and vascular function; wasting and cachexia; neurohormonal and reflex autonomic activation; and coagulation abnormalities increasing the risk of thromboembolism and stroke. Although for the most part considered complications following the presence of CHF, most of these disorders appear to be interrelated with the CHF syndrome by adversely influencing cardiac remodeling, maintaining and enhancing disease progression, aggravating symptoms, and worsening prognosis. This may explain why hemodynamic improvement, e.g. as a result of resynchronization therapy and/or pharmacological treatment, will not necessarily translate into immediate clinical improvement and in some cases altogether fail to ameliorate the patient’s condition.
4.2 Risk factors, risk modifiers, and‘reverse epidemiology’
The increasing incidence and consistently high morbidity and mortality rates in CHF suggest that risk factors and risk modifiers of pathogenetic relevance have – by and large – remained unaltered by the presently available CHF treatment options. Immune activation and systemic inflammation, which frequently have been associated with adverse outcomes in the past, may represent such unmodified mechanisms. However, considering that studies which investigated the effects of anticytokine therapy on outcome in CHF showed no or even adverse effects, it appears that the role of inflammation in CHF is probably more complex and may also involve adaptive and even cardioprotectiveeffects.100 More recently, hyperuricemia has been highlighted as
feature of metabolic imbalance and was identified as an independent marker of adverse prognosis in CHF patients.101 Hyperglycemia and insulin resistance in diabetic patients can induce myocardial contractile systolic and diastolic abnormalities at the cellular level. Although multiple mechanisms are responsible for the development of CHF in diabetes, atherosclerosis leading to ischemic heart disease probably plays the most important role.102 Further, mortality rates are again significantly higher for patients with CHF and concomitant diabetes mellitus than for non-diabetics. Left ventricular hypertrophy is a potent, independent predictor of cardiac events, which besides increasing the risk of CHF also augments the risk of coronary and cerebrovascular diseases; more-over, it may contribute directly to CHF development and progression through pathological changes in cardiac structure.99 The term ‘reverse epidemiology’ refers to paradoxical and counterintuitive epidemiological associations between classical cardio-vascular risk factors such as obesity, high blood pressure, and hypercholesterolemia and prognosis.8 In distinct populations suffering from chronic progressive diseases such as CHF, advanced renal failure, or chronic obstructive lung disease (COPD), these risk factors were repeatedly shown to correlate with better survival. As a common characteristic, these diseases share a progressive catabolic state associated with anorexia, decreasing muscle and fat mass leading to weight loss, and abnormalities of hepatic, glucose, and lipid metabolism. In this context, ‘wasting’ may be described as the end stage of an inappropriate interplay between multiple cytokines, neuropeptides, stress hormones, and intermediate substratemetabolism.103 The survival paradox observed in such populations may be related to multiple factors such as better hemodynamic stability in hypertension and obesity, protective adipokine profiles, endotoxin – lipoprotein interaction, toxin sequestration of fat, a antioxidation of muscle. It becomes clear from these considerations that risk factors and comorbid conditions acting as risk mediators in cardiovascular disorders apparently change their role as the disease progresses. It is presently unclear at which stage of the disease continuum the risks associated with the chronic progressive ‘wasting’ process supersede those originally mediated by the classical risk factors.
4.3 The cardio-renal syndrome
The term ‘cardio-renal syndrome’ refers to the complex inter-relation between heart and kidneys, and denotes the decline of renal function in the setting of CHF. It originates from the observation that even minor alterations in renal function, as evidenced by reduced glomerular filtration rate and microalbuminuria, represent potent cardiovascular risk factors. The excess cardiovascular risk related to renal damage is partly related to a higher prevalence of traditional atherosclerotic risk factors, but also to specific features of chronic kidney disease itself. Renal damage promotes hypertension and dyslipidemia, which in turn enhance the progression of chronic renal dysfunction, and – at the same time – are associated with increased sympathetic nervous system activity, systemic inflammation, and activation of the rein-angiotensin system. In industrialized countries, diabetic nephropathy is the leading cause of renal damage. Thus the triad of hypertension, dyslipidemia, and diabetes represents an important part of the overall cardiovascular risk burden, which appears to be related to enhanced production of reactive oxygen species, endothelial dysfunction, and subsequent atherosclerosis, leading to a higher incidence of coronary and peripheral arterial disease, as well as CHF.104 Specific risk factors related to kidney disease include hyperphosphoremia and elevated calcium – phosphorous product, predisposing to the formation of cardiovascular calcifications. Further, renal disease is a major contributing factor to anemia in CHF, which among other negative effects enhances left ventricular hypertrophy.
Figure 9 shows a simplified representation of this complex vicious circle which inevitably promotes progression of all three conditions – renal dysfunction, anemia, and CHF – and is there-fore sometimes also termed the ‘cardio-renal anemia syndrome’. Therapeutic strategies in the cardio-renal syndrome need to aim at both cardiovascular and renal protection. Adequate blood pressure control is mandatory in order to slow down worsening of renal damage and to prevent cardiovascular events. Better out-comes of renal function but also improved morbidity and mortality rates from CHF are achieved by inhibition of the renin-angiotensin system in both diabetic and non-diabetic patients. Thus, angiotensin- converting enzyme (ACE) inhibitors and/or angiotensin 2 type 1receptor blockers (ARBs) are considered an integral part of current antihypertensive organ-protective pharmacotherapy.
4.4 The anemia of chronic heart failure
Anemia is also common in CHF, with prevalence rates between 20% and 50%. The incidence increases with New York Heart Association (NYHA) functional class. Anemia has consistently emerged as a strong independent predictor of impaired survival and is associated with increased morbidity and hospitalization rates.105,106 Bone marrow depression, reduced intestinal iron uptake, sodium and water retention, hemodilution, and systemic inflammation leading to erythropoietin resistance have been recognized as important mediators, and the use of ACE inhibitors and ARBs may additionally inhibit the bone marrow response to
erythropoietin. Old age, female sex, renal insufficiency, decreased body mass index, peripheral edema, neurohormonal activation, and plasma levels of pro-inflammatory cytokines and other markers of inflammation such as C-reactive protein were found to be inversely related to hemoglobin levels.106 In this context, we must be aware, however, that hemodilution caused by CHF may also mimic anemia. Compared with non-anemic patients, the presence of anemia is associated with clinically worse cardiac status, left ventricular hypertrophy, more severe systolic or diastolic dysfunction, higher plasma levels of natriuretic peptides, increased extracellular and plasma volume, a more rapid deterioration of renal function, a lower quality of life, and increased health care expenditure.105 The only way to determine whether anemia is merely an indicator of more severe CHF or actually contributes to CHF progression is to investigate if the treatment of anemia favorably influences CHF. In several reports of both controlled and uncontrolled studies, correction of anemia with various erythropoiesis-stimulating agents in conjunction with oral and intravenous iron has been associated with an improvement in clinical status, decreased hospitalizations, improved cardiac and renal function, and improved quality of life.
4.5 Chronic obstructive pulmonary disease and chronic heart failure
COPD is frequent in patients with CHF, with a prevalence ranging from 20% to 30%. Since the coexistence of both conditions has important therapeutic implications, early recognition is critical. However, COPD may be missed in patients with CHF, because dyspnea is by mistake attributed to CHF, and vice versa. Measurement of plasma natriuretic peptide levels may be useful to uncover unsuspected CHF in COPD patients. Non-invasive cardiac imaging, preferably using echocardiography, is superior to biomarkers for the detection of left ventricular functional abnormalities in patients with stable COPD.107 Tobacco constitutes a well-known risk factor for both COPD and cardiovascular disease. Cigarette smoke causes inflammation in the airways, leading to airway obstruction, and in the lung tissues, leading to emphysema. Further, it induces systemic inflammation, vasomotor and endothelial dysfunction, and augmented serum concentrations of pro-coagulant and inflammatory factors.
Although the interrelations are incompletely understood, this may help to explain the dramatic increase in cardiovascular risk in patients with COPD. Having symptoms of chronic bronchitis alone increases the risk of a cardiovascular death by 50%.108 CHF and COPD share adverse health effects including weight loss, nutritional abnormalities, skeletal muscle dysfunction, and low grade inflammation, the latter being present even in non-smokers with COPD. As outlined above, COPD is also associated with ‘reverse epidemiology’ regarding traditional cardiovascular risk factors. Correspondingly, improvement of pulmonary or cardiac function cannot be expected to translate into improved functional state in patients with COPD or CHF unless the systemic alterations regress concomitantly. The presence of COPD may impact on the treatment of CHF, as COPD is still often viewed as a contraindication to beta-blockade. However, a large body of data indicates that patients with COPD tolerate well selective beta-blockade, which should not be with-held from CHF patients with concomitant COPD. Treatment of CHF according to guidelines may have additional beneficial effects, as ACE inhibitors and ARBs may reduce pulmonary obstruction by decreasing angiotensin II levels, decrease pulmonary inflammation and pulmonary vascular constriction, and ameliorate alveolar – membrane gas exchange.109 Statins may, due to their anti-inflammatory potential and possibly other pleiotropic effects, also be beneficial.107 Aldosterone antagonists may have positive effects on gas diffusion, as aldosterone harms the alveolar –capillary membrane.109
4.6 Depression in chronic heart failure
Compared with the general population, depression is four to five times more common in CHF. There has been demonstrated a significantly higher short- and long-term morbidity and mortality risks in patients with CHF suffering from major (but not minor) depression as a comorbidity.110,111 Worse outcome in terms of health-related quality of life and higher medical costs has also been reported. Possible mechanisms mediating these effects include biological, behavioral, genetic, and psychosocial factors. Figure 10 depicts hypotheses regarding the interrelationship between CHF and depression. Besides the possibility of independent coincidence, shared pathogenetic pathways have been postulated. On the one hand, there is evidence to suggest that CHF causes and aggravates depression; it has been hypothesized that elevated plasma levels of pro-inflammatory cytokines, as frequently observed in CHF, may induce cytokine production in the brain, which then activates the hypothalamus-pituitary-adrenal axis, elicits a stress response, and inhibits serotonin activity, thus inducing the increased prevalence of depressive symptoms in CHF.
On the other hand, depression has been shown to increase the risk for cardiac events even among initially healthy individuals. People with clinically significant depression have, compared with the general population, a high risk of myocardial infarction or cardiac death.112 Dysregulation of autonomic nervous control represents one plausible mediator of the adverse effects of depression in CHF. Reduce parasympathetic and increased sympathetic tone lowers the threshold for myocardial ischemia and cardiac events. High levels of circulating catecholamines may contribute to recurrent endothelial injury. Most studies investigating the role of the sympathetic nervous system in depression found a higher resting heart rate, decreased heart rate variability, and increased norepinephrine excretion – all serious risk factors, even in the general population. Last but not least, depression may also adversely impact on behavioral factors such as smoking, diet, physical activity, and compliance with treatment recommendations. Beyond the desirable goal of improvement of depression and quality of life in individual patients, there are presently no evidence-based treatment recommendations for depressed subjects with cardiovascular diseases in general and CHF in particular. If physicians wish to prescribe an antidepressant, SSRIs (Selective serotonin reuptake inhibitors) are a reasonable option in view of their lack of significant cardiovascular side effects and relative lack of toxicity at overdose. The low potential for drug – drug interactions is also attractive in CHF patients, who usually suffer from numerous other comorbidities and take a variety of concomitant medications. Other antidepressant drugs, in particular tricyclic antidepressants, should not be used in CHF because of their recognized cardiovascular side effects. Economy and management of heart failure – an issue of comorbidities . Another problem related to multiple comorbidities is polypharmacy, as the risk of drug – drug interactions rises exponentially in users of more than five different drugs.113 Conversely, the presence of several concurrent diseases may also lead to underutilization of evidence-based CHF pharmacotherapy because of safety concerns(e.g. diminished utilization of aldosterone antagonists in patients with renal dysfunction or of beta-blockers in patients with asthma). If discharge management is inadequate, patients may, in addition, be unable or lack insight into the necessity to comply with complex treatment regimens frequently introduced during hospitalization. Thus, comorbidities appear as a critical, yet frequently neglected determinant of both clinical management requirements and outcome of CHF patients, as well as costs.
Personal research
OBJECTIVES OF THE STUDY
this study purpose is to identify which were the most frequently comorbidities in a group of patients diagnosed with heart failure with reduced ejection fraction of the left ventricle.
The secondary objectives were:
1. Identification of the patients with reduced ejection fraction,
2. Clinical and paraclinic parameters representative of chronic heart failure:
NYHA class,
Etiology of the heart failure,
Cardiovascular risks:
Sex (M/F)
Age
Dyslipidemia
Diabetes mellitus
Abdominal obesity
Visceral obesity
Increased blood pressure
Smoking
Standard echocardiography parameters,
Atrial and ventricular arrhythmias
Multiple comorbidities found in patients
Treatment of the heart failure with reduced ejection fraction
M=male
F=Female
5.2 MATERIALS AND METHODS
this research can be included is in the category of descriptive studies.
Material
The inclusion criteria:
1. The diagnosis of chronic heart failure was established in accordance with the criteria of the current European Cardiology Society guidelines issued in 2016, which are presented in Table I.
2. Age over 18 years,
3. Signature of the informed consent at the admission (a model is attached in the Annex).
4. Ejection fraction <40%
Table I. Classification of chronic heart failure based on LVEF34
a.The signs may be absent in the initial stages of HF (especially in the form of HF with preserved EF) and in patients receiving diuretics.
Considering the aforementioned criteria, the patients from where the information was taken were admitted to the Department of Cardiology and Internal Medicine of "Prof. Dr. Theodor Burghele ", Bucharest from this period :January 1st 2017 to November 1st 2018 .
The exclusion criteria from the study were as follows:
1. Age<18
2. Ejection fraction >40%
3. Active or previous neoplasms with radiotherapy or chemotherapy treatment in the last 6 months – 1 year,
4. Severe infections in the last month
5. Decompensated heart failure
Method
Clinical data was obtained through anamnesis and examination of the patients made by the doctors.Paraclinical examination of the patients from the sheets was taken from the computer database of the hospital. (Hipocrate).
Only patient status data at the time of this hospitalization, which occurred between January 1st 2017 to November 1st 2018 , were used, without taking into account previous biological constants and without following the patient after discharge.
5.3 Clinical data
Using the data from the other admissions of the patients, information about the history of interest-heart failure (diagnosis, disease progress, symptoms for NYHA ) and about the comorbidities that the patients presented were obtained in order to have a better look about the actual and possible risk factors for the evolution of heart failure.
The inclusion and exclusion criteria were done using the anamnesis or also consulting the sheets from other medical consultations. A particular importance was given to the presence of risks, the cardiovascular risks.:smoking,obesity,dyslipidemia,hypertension,diabetes mellitus, increased values of the glucose levels and also to the significant family history of other cardiovascular pathologies.
Also, using the anamnesis, the doctors obtained information about the patient’s comorbidities-when they were presented for the first time at the hospital for comorbidities, what kind of comorbidities do they have, which was the evolution of each comorbidity. In this thesis there will be presented the kind of comorbidities met in the group of patients and also the distribution of the gender for each comorbidity. Patients were also asked about the treatment that was being given to them (in particular to the doses, the schedule they are taking them and for the possible adverse reactions).
For each patient it was conducted full physical examination with systolic and diastolic TA, BMI and heart rate at the time of inclusion.
The Body Mass Index (BMI) was calculated at the time of inclusion and it is presented as the ratio between the actual weight of the patient measured in kilograms and the square height (kg / m2). According to the recommendations of the guides ,the categories of the BMI were:
a) BMI between 18.5-24.9 → normal weight
b) BMI between 25-29.9 → overweight,
c) BMI between 30-34,9 → grade I obesity,
d) BMI between 35-39.9 → second degree obesity,
e) BMI over 40 → Grade III obesity.
Measurement of systolic and diastolic blood pressure was performed to each patient and according to the recommendations issued by the European Society of Cardiology through the guide for the management of hypertension delivered in 2013.
The measurement was done for both arms, each with two examinations at 1-2 minutes. Also the measurement was done in clinostatism and standing A third measurement was made only if there was a significant difference between the two examinations.
Paraclinic Investigations
Willing to see the pathological changes that are usually found in association with heart failure (left ventricular hypertrophy, ischemic changes, and rhythm or conduction disorders), an electrocardiogram in 12 standard derivates was performed for each patient.
Another paraclinical investigation was the transthoracic echocardiography examination, using 2D, Doppler pulse, Continuous Doppler, Tissue Doppler and Doppler ultrasound.
The following were evaluated:
1. Valve morphology and their competence,
2. Wall thickness (interventricular septum, posterior wall), relative parietal thickness (GRP), index VS mass and atrial / ventricular volumes,
3. The left ventricular ejection fraction to accommodate patients in a category (preserved, intermediate, low) according to the ESC
Biochemical analysis
Patients also had a biochemical analysis at the presentation to the hospital. Most of them had a basic metabolic panel that measures sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), magnesium, creatinine, glucose, +/- calcium. Tests that focused on cholesterol levels determined LDL and HDL cholesterol levels, as well as triglyceride levels.
Some tests, such as those that measure glucose or a lipid profile, required fasting (or no food consumption) eight to twelve hours prior to the drawing of the blood sample.
The results of the investigations for the blood tests will not be presented as there were patients that were already having such results even before presenting for the heart failure. The results just helped the doctors to make the diagnostic easier.
Statistical analysis
A database was created using the Microsoft Excel 2013 database. Information about each patient was obtained and filled in the database. The statistical assays used were mean, median and standard deviation.
RESULTS OF THE STUDY
Demographic aspects
Age
In this study, there were taken into account 250 patients, but only 119 (Table II) met the inclusion criteria with having the ejection fraction <40 %( reduced ejection fraction).
The age of patients with chronic heart failure with reduced ejection fraction included in the study group ranged from 30-100 years old. The mean age of these patients was 69.65 years and with a median of 70.
The highest number of patients were from the category 61-70 years old (27.27%). (Figure 11)
From 30 to 40 there was only one case (0.84%). (Figure 12)
Figure 11 Distribution by age -using intervals
Figure 12 Distribution by age-using percentage
Gender
Dividing the population of study using the gender criteria, it was observed that between the patients with chronic heart failure with reduced ejection fraction ,most of them were females, with a predominance of 67 patients (56.3%) ,unlike the male population with 52 patients (43.7%) Comparing the percentages, there is not a big difference between the divisions based on gender (56% over 44%). (Figure 13)
Figure13-Gender distribution
Clinical data
Body mass index
Considering the body mass index from the study group, the mean was 27.62 ± 6.45 kg / m2.
Normal weight was reported for most of the patients- 68 patients (57.14%) . (Figure 14)
On the second place was grade 1 obesity [IMC (30-34,9) kg/m2] that was found in 20 patients (16.80%) and on the third place extremely obese grade 2 [ IMC (35-39,9 kg / m2) ] that was reported in 12 patients (10.08% ). (Table III) No patient was underweight.
Figure. 14 Distribution of the BMI using intervals
Cardiovascular risk factors
Smoking
In the study group, the patients with heart failure with reduced ejection fraction had a lot of cardiovascular risks. One of them was smoking. But only 17 patients were smokers (14.28%).
(Figure 15) In terms of gender distribution of smokers in this batch, 12 were men (70.58% from the total of smokers and 10.08% of the total of patients with reduced ejection fraction), while women were in a few number 5 patients (29.41% of the number of smokers and 5.55% of the total of 119 patients).
For information about how many pack/year did they smoke, some of the patients did not know to estimate the numbers, so this information was not taken into account.
The highest percent was the one of non-smokers-85.71% (Figure 16)
Figure 15 -Smoking habits
Figure 16 Percentage of smokers and non-smokers
Dyslipidemia
Another risk factor was dyslipidemia. Most of the patients were already diagnosed based on the paraclinic investigations and some of them found out about this problem when they were admitted to the hospital.
In the study group, most of the patients- 72 patients (60.50%) had dyslipidemia, unlike 47 patients (39.49%) that were proven not to have dyslipidemia and also had no modification at the blood tests that could have demonstrated such pathology. (Figure 17)
Figure-17 Dyslipidemia Distribution
Hypertension
All the patients had their blood pressure measured. Most of the them -109 patients (91.59%) were found with high blood pressure. Some of the patients discovered for the first time the increased value of the arterial systolic and dyastolic pressure, while some of the patients were already on medication for the disease.
The other 10 patients had no modification at the systolic arterial blood pressure (8.41%)
The majority of patients that had increased values of the arterial blood pressure were females 65 patients (59.63% from the total of the patients with hypertension and 54.62% from the entire study group) ,while 44 were males (40.36% from the total of patients with hypertension and 36.97% from the total of the entire study group) (Figure 18)
Figure 18 Distribution by gender for the patients with high blood pressure
Diabetes mellitus
As diabetes mellitus is also a cardiovascular risk factor, the blood glucose levels were also obtained from the patients with heart failure with reduced ejection fraction. A minority of patients from the study group, 45 patients (37.41%) were known to have or discovered diabetes and were on treatment , while the majority of the patients: 74 (62.59%) ,were not known to have diabetes mellitus and also had no modifications in the blood tests.(Figure 19)
Some of the patients had also in the past history increased levels of glucose that were managed and now they were having normal levels of glucose. As a treatment, patients were taking insulin, oral antidiabetic medications or they were controlling their glucose levels through diet.
Figure 19 Diabetes Mellitus prevalence
Visceral and abdominal obesity
In the study group, almost half of the patients were presenting abdominal or visceral obesity, a risk factor for the heart failure.
Having abdominal obesity were 50 patients (42.01% from the total of 119 patients), and 48 patients were identified with visceral obesity (40.33% from the total of 119 patients). (Figure 20)
In the study group there were patients that had both abdominal and visceral obesity, and also patients that had neither abdominal, nor visceral obesity.
Figure. 20 Number of patients with visceral or abdominal obesity
Family history
Considering the family history, only 37 patients from the group of study were known to have important family history. Patients were asked about: age, obesity, diabetes, hypertension, diet, smoke, lifestyle, stroke met in their families
The majority of patients -82 patients (68.90%) were not having family history that proved important to be taken into account, a family history that could have led to heart failure. (Figure 21)
Figure 21 Family history
Etiology of chronic heart failure
Heart failure has a lot of etiologies. (Figure-22)
Some of them that were presented in the study group were: cardiomyopathy, coronary ischemic disease, significant hemodynamic valvular disease.
Most patients were presenting multiple etiologies. (Figure 23)
The most frequent etiology in the study group was the hemodynamic valvular disease discovered at 82 patients (68.90%) (Figure 24)
The second most frequent etiology was the ischemic disease, with 45 patients (37.81)
About the dilatative cardiomyopathy, there were one patient with toxic etiology and also one with an idiopathic etiology. (Figure 25)
Figure.22 Distribution of the etiology of CHF
Figure-23 Multiple etiologies
Figure 24 Valvular Etiology
Figure.25 Cardiomyopathy
NYHA class
Dividing the patients based on the NYHA class, the highest number of them was in NYHA class I (31 patients representing 26.05%) (Table IV), followed closely by NYHA class III -28 patients (23.52%) (Figure 26)
Only 8 patients (6.72%) were in NYHA Class III-IV. (Figure 27)
Table IV. Distribution by NYHA classes in the study group
Figure.26 Distribution by NYHA classes using percentage
Figure 27 Distribution by NYHA classes using the number of patients
EKG
On the EKG findings, most of the patients were presenting no arrhythmia. The patients from the study group that were having modifications on their ECG, were presenting atrial or ventricular arrhythmias. Atrial fibrillation was the one that was found in most of the patients 46 (38.65%). (Figure 28) Only 3 patients were presenting ventricular arrhythmias. (2.52%). (Figure 29)
Some of the patients already knew they were having arrhythmias diagnosed.
Figure.28 Arrhythmias-using percentage
Figure. 29 Arrhythmias –Based on the number of patients
Comorbidities
The patients in the study group were all presenting comorbidities at the admission to the hospital. The majority of patients were presenting renal problems – 67 patients (56.30%).
On the second place, were the pulmonary problems 48.73% and on the third place the hepatic problems met in 15.96% of the patients. (Figure 30)
The least problem that was found in the study group was equally the psychiatric disorder and the endocrine disorder (hypo- or hyper-thyroid), both with 4 cases each. (Figure 30)
Other comorbidities that were presented in the study group were: urologic problems and tumoral comorbidities.
Figure 30 Comorbidities of the study group – using numbers
Based on gender, the comorbidities were different. (Figure 31)The only comorbidity with almost the same amount of patients was the renal one with a number of 33 male (47.76&) over 35 female (52.22%). (Figure 32)
The pulmonary, hepatic (most of them because of the alcohol use), urologic (because of prostate conditions) and psychiatric disorders had a predominance of males over females. The only comorbidities where the females were in majority were: endocrine (75% were females) (Figure 33). And tumoral disease (57.14% were females).
The highest percentage of males was found for the urologic condition (83.33%), followed by the hepatic condition. Most of the patients had prostate problems and also some of them had urethritis and bladder stones (Figure 34)
Figure 31 Distribution of the comorbidities based on gender
Figure 32 Distribution of the renal comorbidity
Figure 33 Endocrine distribution
Figure 34 Distribution of the urologic condition
Treatment for heart failure with reduced ejection fraction
Diuretics
Discussing about medication, some of the most usual drugs given to the patients with heart failure are diuretics.
Diuretics have therapeutic effects: can ameliorate dyspnea and edema. (Reduce preload)
Most of the patients with chronic heart failure with reduced ejection fraction from the study, received aldosterone antagonist(spironolactone) 63 patients (52.94%) ,while 56 patients received loop diuretics (47.05%).(Table V) (Figure 35)
Table V – Diuretics for the study group
Figure.35 Number of patients receiving diuretics
ACE inhibitor
Another medication that was used for the study group was the ACE Inhibitor (angiotensin-converting-enzyme inhibitor). Most of the patients received the drug for their condition – 80 patients (67.22%), while 39 patients were not prescribed this medication (32.77%). (Figure 36)
Figure 36 ACE Inhibitor
Beta blockers
Beta blockers can be used with other drugs concomitantly.
Most of the patients from the study- 95 patients took beta blockers (80.67%). (Figure 37)
That was one of the medication that was mostly found in the study group.
Figure.37 Beta blockers
Calcium channel blockers.
In the study group ,only 2 patients(1.68%) had DHP calcium channel blocker and there was no patient receiving Non-DHP.(Figure38 )
DHP= dihydropyridine
Non-DHP = non-dihydropyridine
Figure 38 –Calcium channel blockers
Antiplatelet and anticoagulant drugs
Comparing the antiplatelet and the anticoagulant drug used for treating patients presenting heart failure with reduced ejection fractions, the most preferred therapy was the one with anticoagulants 82 patients(68.90%).(Figure39 )(Figure 40)
The antiplatelet drug was chosen only for 37 patients (31.09%). (Figure 41)
Figure 39 Anticoagulant Drugs
Figure 40 Percentage of anticoagulant drugs
Figure. 41 Antiplatelet drug
Statins
Based on the blood tests, there were also indications for the patients to start taking statins. Because some of the patients knew already about their condition, there were taking statins before the admission to the hospital.
In the study group, the majority of patients (more than half of the patients) had statins as a treatment – 65 patients (54.62%). (Figure 42)
Figure 42 Statins
Insulin and oral antihyperglycemic drugs
Because there were some patients that were having problems with their glucose level, a treatment based on insulin or oral antihyperglycemic drug was intended.
Most of the patients were chosen to have an oral antihyperglycemic drug- 13 patients (10.92%), while there were also 9 patients (7.56%) that had treatment with insulin. (Figure 43) (Figure 44)
Other patients were only varying their glucose lever through diet.
Figure 43 Insulin and oral antihyperglycemic drugs
Figure 44 Percentage of the insulin and oral antihyperglycemic drugs
Antihyperuricemic drug
One of the other drugs that were used for treating the patients with heart failure from the study group ,was Allopurinol,an antihyperuricemic drug. Anti-hyperuricemic drugs are used to treat hyperuricemia, the state of having too much uric acid in the blood.
Few of the patients – 29 patients had Allopurinol administered.(24.36%).
Most of the patients did not have an antihyperuricemic drug (75.63%). (Figure 45)
Figure 45 Antihyperuricemic drugs
Conclusions
In the study group, the highest number of patients were the ones from the interval 61-70 years old, and from the interval 30-40 there was only one patient.
There was a female predominance, in comparison to the males. Comparing the percentages, there is not a big difference between the divisions based on gender.
In the study group, most of the patients had normal weight, then on the second place was grade I obesity and on the third place grade II obesity.
Most of the patients that were admitted to the hospital were non-smokers. This aspect can bring a low cardiovascular risk for the progression of the heart failure.
Dyslipidemia and visceral/abdominal obesity were two of the cardiovascular risk factors that could influence the success of the treatment. For the patients with chronic heart failure with reduced ejection fraction. Over half of the patients were presenting dyslipidemia .Abdominal obesity and visceral obesity were also found in the study group, but there were patients that were having both of them and patients that were having only one kind of obesity.
The majority of patients were presenting increased values of the blood pressure, with a predominance of the females.
Family history was not proved to have a big influence for the heart failure met in the study group.
There were not so many patients that were presenting diabetes mellitus, but most of them were already having medication (oral medication), insulin or were controlling the glucose levels through diet.
About the etiology, most of the patients from the study group were presenting valvular etiology, followed by ischemic etiology. There were only two patients that were presenting dillatative etiology: one-toxic and one-idiopathic.
.In the study group, the most found distribution based on NYHA classes was NYHA I, followed by NYHA class III.
Analyzing for arrhythmias, there were few patients presenting atrial fibrillation and also there were few cases with ventricular arrhythmia.
Almost all the patients presented with comorbidities at the admission to the hospital, maybe the age influenced this diversity. The most found comorbidity was the renal disease, on the second place was the pulmonary disease and on the third place the hepatic problems.
The distribution based on gender proved that the renal problem was found in both females and males and the percentage did not differ that much
The hepatic, pulmonary and urologic conditions were found mostly in males, over females
The highest percentage of females was found for the endocrine disease, followed by the tumoral disease.
The highest percentage of males was found for the urologic condition, followed by the hepatic disease.
Diuretics were given to more than half of the patients. Aldosterone antagonists were preferred over loop diuretics. ACE inhibitors were also given to the patients and this therapy was the third most used one for the disease.
Beta-blockers were the most given drug therapy for the patients in the study group.
Calcium channel blockers were not indicated to many patients, still the ones that were prescribed calcium channel blockers had DHP , preferred over Non-DHP.
In the study group, anticoagulant drugs were preferred over antiplatelet drugs. Most of the patients received anticoagulant drugs, this being the second most used type of treatment for the disease.
Statins were also used for more than half of the population from the study, most of the patients were presenting dyslipidemia.
Another drug used for treating the patients with heart failure with reduced ejection fraction was an antihyperuricemic drug- Allopurinol. Few of the patients had this medication as they were not having modifications at the blood tests: increased uric acid.
After beta-blockers, anticoagulant drugs and ACE Inhibitors, spironolactone was on the fourth place of the most used medication for the patients that were having heart failure with reduced ejection fraction.
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114.:Lilly –Pathophysiology of the heart disease.
115 PATHOPHYSIOLOGY: THE BIOLOGIC BASIS FOR DISEASE IN ADULTS
AND CHILDREN, SEVENTH EDITION
116 Journal of clinica medicine -Heart Failure: Diagnosis, Management and Utilization (J. Clin. Med. 2016, 5, 62; doi:10.3390/jcm5070062)
117 : European Journal of Heart Failure Supplements (2009)8, i5 i10doi:10.1093/eurjhf/hfp009
Abbreviations
ACC – American College of Cardiology
ACE-I Inhibitors of angiotensin I converting enzyme
ACS- Acute coronary syndrome
AF-atrial fibrillation
AHA – American Heart Association
ANP – Atrial natriuretic peptide
ARB -Ang II receptor blockers
ATP- Adenosine triphosphate
BMI-body mass index
CAD- Coronary artery disease
CHF-chronic heart failure
CKD – chronic kidney disease
COPD- Chronic obstructive pulmonary disease
CV – cardiovascular
DCM – dilated cardiomyopathy
DM-Diabetes mellitus
ECG-electrocardiogram
EF – ejection fraction
GDMT- Guidline directed medical therapy
HF- heart failure
HFpEF – heart failure with preserved ejection fraction
HFrEF- heart failure with reduced ejection fraction
HTN-hypertension ;
IABP- intra-aortic balloon pump
ICD-implantable cardioverter-defibrilator ;
LV – left ventricular;
LVEDV-left ventricular end-diastolic volume
LVEF – left ventricular ejection fraction
LVH-left ventricular hypertrophy
MCS-mechanical circulatory support ;
MI-myocardial infarction
MRI- Magnetic resonance imaging
NO- vasodilator nitric oxide
NYHA- The New York Heart Association
QOL -quality of life
RAAS – renin-angiotensin-aldosterone system;
RAAS-renin-angiotensin-aldosterone-system
RCT-cardiac resynchronization therapy
RV – right ventricular.
SNS-Sympathetic nervous system
TNF-Tumor necrosis factor
Annex 1
FORMULAR DE CONSIMȚĂMÂNT ÎN VEDEREA CERCETĂRII ȘTIINȚIFICE
Subsemnatul _____________________________________________ domiciliat în__________
______________________legitimat cu B.I/C.I. seria____nr.________în calitate de:
1.pacient internat în secția ________________________________________________________
2.reprezentant legal al copilului _______________________în vârstă de________ani
3.aparținător (soț, soție, frate, soră, fiu – în cazul în care pacientul este în incapacitatea de a decide) al pacientului_______________________internat în secția _________________consimt să fiu înrolat/a în studiul:
“Comorbidities in patients with heart failure with reduced ejection fraction”
______________________________________________________________________________
Natura și scopul, beneficiile și riscurile acestui studiu, mi-au fost explicate pe înțelesul meu de către Dr. ___________________. Mi s-au prezentat riscurile asociate precum și riscurile imprevizibile (inclusiv riscul oricât de mic de deces), consecințele pe care le presupune studiul de față.
Declar că sunt conștient de aceste riscuri și le accept, întrucât scopul acestei cercetari este în folosul progresului medical.
În consecință și în condițiile precizate, îmi dau liber și în cunoștință de cauză, consimțământul de a participa la studiul de cercetare mai sus menționat.
Certific că am citit, am înțeles și accept pe deplin cele de mai sus și ca urmare le semnez.
Semnătura pacientului/reprezentantului legal1 ____________ziua ____luna___anul___________
______________________________________________________________________________
Subsemnatul, în calitate de martor, _________________________confirm că prezentul formular de consimțământ a fost completat în prezența mea și semnat de pacient fără ca asupra lui să se fi exercitat vreo constrângere.
Semnătura martorului _______________________ziua _____luna_______anul______________
______________________________________________________________________________
CONSIMȚĂMÂNT INFORMAT
Am înțeles beneficiile și riscurile investigațiilor non – invazive ce urmează să mi se facă și sunt de acord/nu sunt de acord cu efectuarea acesteia.
Nume……………………………………….. Data ……………………………………
Prenume …………………………………..
1.Se vor nota datele de identitate ale acestuia, gradul de rudenie, precum și datele împuternicirii de reprezentare în cazul tutorilor.
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