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Systolic Heart Failure

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Description: Systolic heart failure is a condition where the heart's left ventricle cannot contract effectively, leading to inadequate pumping of blood to the body.
Type: Systolic heart failure is not traditionally classified as a single-gene disorder with a specific type of genetic transmission. It is generally considered a complex condition influenced by a combination of genetic and environmental factors. Variants in multiple genes can contribute to susceptibility, and these are typically inherited in a multifactorial manner rather than through a singular Mendelian pattern such as autosomal dominant or autosomal recessive inheritance.
Signs And Symptoms: Congestive heart failure is a pathophysiological condition in which the heart's output is insufficient to meet the needs of the body and lungs. The term "congestive heart failure" is often used because one of the most common symptoms is congestion or fluid accumulation in the tissues and veins of the lungs or other parts of a person's body. Congestion manifests itself particularly in the form of fluid accumulation and swelling (edema), in the form of peripheral edema (causing swollen limbs and feet) and pulmonary edema (causing difficulty breathing) and ascites (swollen abdomen). Pulse pressure, which is the difference between the systolic ("top number") and diastolic ("bottom number") blood pressures, is often low/narrow (i.e. 25% or less of the level of the systolic) in people with heart failure, and this can be an early warning sign.Symptoms of heart failure are traditionally divided into left-sided and right-sided because the left and right ventricles supply different parts of the circulation. In biventricular heart failure, both sides of the heart are affected. Left-sided heart failure is the more common.
Prognosis: Prognosis in heart failure can be assessed in multiple ways, including clinical prediction rules and cardiopulmonary exercise testing. Clinical prediction rules use a composite of clinical factors such as laboratory tests and blood pressure to estimate prognosis. Among several clinical prediction rules for prognosticating acute heart failure, the 'EFFECT rule' slightly outperformed other rules in stratifying people and identifying those at low risk of death during hospitalization or within 30 days. Easy methods for identifying people that are low-risk are:

ADHERE Tree rule indicates that people with blood urea nitrogen < 43 mg/dL and systolic blood pressure at least 115 mm Hg have less than 10% chance of inpatient death or complications.
BWH rule indicates that people with systolic blood pressure over 90 mm Hg, respiratory rate of 30 or fewer breaths per minute, serum sodium over 135 mmol/L, and no new ST–T wave changes have less than 10% chance of inpatient death or complications.A very important method for assessing prognosis in people with advanced heart failure is cardiopulmonary exercise testing (CPX testing). CPX testing is usually required prior to heart transplantation as an indicator of prognosis. CPX testing involves measurement of exhaled oxygen and carbon dioxide during exercise. The peak oxygen consumption (VO2 max) is used as an indicator of prognosis. As a general rule, a VO2 max less than 12–14 cc/kg/min indicates poor survival and suggests that the person may be a candidate for a heart transplant. People with a VO2 max <10 cc/kg/min have a clearly poorer prognosis. The most recent International Society for Heart and Lung Transplantation guidelines also suggest two other parameters that can be used for evaluation of prognosis in advanced heart failure, the heart failure survival score and the use of a criterion of VE/VCO2 slope > 35 from the CPX test. The heart failure survival score is calculated using a combination of clinical predictors and the VO2 max from the CPX test.
Heart failure is associated with significantly reduced physical and mental health, resulting in a markedly decreased quality of life. With the exception of heart failure caused by reversible conditions, the condition usually worsens with time. Although some people survive many years, progressive disease is associated with an overall annual mortality rate of 10%.Around 18 of every 1000 persons will experience an ischemic stroke during the first year after diagnosis of HF. As the duration of follow-up increases, the stroke rate rises to nearly 50 strokes per 1000 cases of HF by 5 years.
Onset: Systolic heart failure, also known as heart failure with reduced ejection fraction (HFrEF), typically has a gradual onset. Symptoms may develop slowly over time, and early signs can be subtle, often becoming apparent during physical exertion before they become noticeable at rest. Common early symptoms include shortness of breath, fatigue, and reduced exercise tolerance. If you have further specific questions or need detailed information, please let me know.
Prevalence: The prevalence of systolic heart failure varies by population and age group but is generally estimated to affect around 1-2% of the general adult population in developed countries. This prevalence increases significantly with age, affecting approximately 10% of those over the age of 70.
Epidemiology: In 2022, heart failure affected about 64 million people globally. Overall, around 2% of adults have heart failure. In those over the age of 75, rates are greater than 10%.Rates are predicted to increase. Increasing rates are mostly because of increasing lifespan, but also because of increased risk factors (hypertension, diabetes, dyslipidemia, and obesity) and improved survival rates from other types of cardiovascular disease (myocardial infarction, valvular disease, and arrhythmias). Heart failure is the leading cause of hospitalization in people older than 65.
Intractability: Systolic heart failure, also known as heart failure with reduced ejection fraction (HFrEF), is not inherently intractable. It can be managed with a combination of lifestyle changes, medications, and in some cases, surgical interventions. Effective treatment can significantly improve symptoms, quality of life, and outcomes for many patients. However, the response to treatment can vary, and some cases may be more challenging to manage.
Disease Severity: Systolic heart failure, also known as heart failure with reduced ejection fraction (HFrEF), is typically classified by the severity of symptoms and the impact on the patient's daily activities. The severity is often categorized using the New York Heart Association (NYHA) functional classification system, which includes:

- **Class I**: No limitation of physical activity. Ordinary physical activity does not cause symptoms of heart failure.
- **Class II**: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of heart failure.
- **Class III**: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of heart failure.
- **Class IV**: Unable to carry on any physical activity without discomfort. Symptoms of heart failure are present even at rest, and any physical activity increases discomfort.

The progression and severity of systolic heart failure can vary widely among individuals. Early diagnosis, lifestyle changes, and appropriate medical treatment are crucial for managing the severity and improving quality of life.
Healthcare Professionals: Disease Ontology ID - DOID:9651
Pathophysiology: Heart failure is caused by any condition that reduces the efficiency of the heart muscle, through damage or overloading. Over time, these increases in workload, which are mediated by long-term activation of neurohormonal systems such as the renin–angiotensin system and the sympathoadrenal system, lead to fibrosis, dilation, and structural changes in the shape of the left ventricle from elliptical to spherical.The heart of a person with heart failure may have a reduced force of contraction due to overloading of the ventricle. In a normal heart, increased filling of the ventricle results in increased contraction force by the Frank–Starling law of the heart, and thus a rise in cardiac output. In heart failure, this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This is due to reduced ability to cross-link actin and myosin myofilaments in over-stretched heart muscle.
Carrier Status: Systolic heart failure is not typically associated with a carrier status because it is generally not a genetic condition that is passed down in a straightforward manner like some other genetic disorders. It is primarily related to issues such as coronary artery disease, high blood pressure, and other conditions that damage the heart. There are no known "carriers" for systolic heart failure in the same context as genetic diseases like cystic fibrosis or sickle cell anemia.
Mechanism: Systolic heart failure, also known as heart failure with reduced ejection fraction (HFrEF), occurs when the heart muscle is unable to contract effectively, leading to insufficient blood being pumped out to meet the body's needs.

Mechanism:
The primary mechanism involves impaired ventricular contraction. As a result, the heart cannot pump blood efficiently during systole (the phase of the heartbeat when the heart contracts). This reduction in cardiac output triggers compensatory mechanisms such as the activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) to maintain blood pressure and perfusion.

Molecular Mechanisms:
1. **Altered Calcium Handling**: Impaired calcium cycling in cardiomyocytes affects excitation-contraction coupling, reducing the efficiency of muscle contraction. Dysregulation of proteins like SERCA2a (sarcoplasmic reticulum Ca2+-ATPase) and phospholamban can lead to decreased calcium reuptake into the sarcoplasmic reticulum.

2. **Beta-Adrenergic Desensitization**: Chronic stimulation of beta-adrenergic receptors by the sympathetic nervous system leads to receptor desensitization and downregulation. This impairs contractile response to catecholamines.

3. **Myocardial Remodeling**: Chronic hypertension, myocardial infarction, and other conditions cause structural changes in the heart, including hypertrophy and fibrosis. These changes adversely affect contractile function.

4. **Oxidative Stress**: Excessive production of reactive oxygen species (ROS) can damage cardiac cells and contribute to apoptosis and necrosis, exacerbating heart failure.

5. **Neurohormonal Activation**: Prolonged activation of neurohormonal systems such as RAAS leads to harmful effects like vasoconstriction, sodium retention, and further myocardial remodeling.

6. **Genetic Factors**: Mutations in genes encoding sarcomeric proteins can lead to familial forms of dilated cardiomyopathy, predisposing individuals to systolic heart failure.

Understanding these mechanisms helps in the development of targeted therapeutic interventions to improve heart function and manage systolic heart failure.
Treatment: **Systolic Heart Failure Treatment:**

The treatment for systolic heart failure typically includes a combination of lifestyle changes, medications, and sometimes medical procedures. Here are key components:

1. **Lifestyle Changes**:
- **Diet**: Low-sodium and low-fat diets are recommended.
- **Exercise**: Regular physical activity as advised by a healthcare provider.
- **Weight Management**: Maintaining a healthy weight.

2. **Medications**:
- **ACE Inhibitors**: Help relax blood vessels.
- **Beta-Blockers**: Reduce heart rate and blood pressure.
- **Diuretics**: Help eliminate excess fluid from the body.
- **Aldosterone Antagonists**: Reduce water retention.
- **Angiotensin II Receptor Blockers (ARBs)**: Used if patients cannot tolerate ACE inhibitors.
- **Neprilysin Inhibitors**: Combined with ARBs to improve heart function.
- **Digoxin**: Sometimes used to enhance the heart's pumping ability.

3. **Medical Procedures**:
- **Implantable Cardioverter-Defibrillators (ICDs)**: To prevent sudden cardiac death.
- **Cardiac Resynchronization Therapy (CRT)**: Uses a special pacemaker to improve the heart's efficiency.
- **Heart Transplant**: In severe cases, when other treatments have failed.

Nan (Nanometre):
- A nanometre (nm) is a unit of length in the metric system, equal to one billionth of a meter (0.000000001 m). It is commonly used in science and engineering to measure very small distances, such as the size of molecules and nanoscale materials.
Compassionate Use Treatment: Compassionate use treatments and off-label or experimental treatments for systolic heart failure include the following:

1. **Left Ventricular Assist Devices (LVADs)**: Typically used in end-stage heart failure patients either as a bridge to transplantation or as destination therapy.

2. **Stem Cell Therapy**: Experimental treatments using stem cells aim to repair damaged heart tissue. Clinical trials are ongoing to determine effectiveness and safety.

3. **Sacubitril/Valsartan (Entresto)**: Initially approved for heart failure with reduced ejection fraction (HFrEF), it's sometimes used off-label in specific patient subsets under close monitoring.

4. **Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors**: Originally developed for diabetes, certain SGLT2 inhibitors like dapagliflozin have shown benefits in heart failure patients, including those with HFrEF.

5. **Gene Therapy**: Experimental gene therapies are being developed to target specific genetic mutations associated with cardiomyopathies leading to heart failure.

6. **Cardiac Resynchronization Therapy (CRT)**: A specialized pacemaker system, an off-label set-up, might be used in certain heart failure patients to improve the heart's efficiency and coordination.

7. **Ongoing Clinical Trials**: Participation in clinical trials for novel drugs or interventions can provide access to cutting-edge treatments under investigative protocols.

These options are typically considered when conventional treatments have been exhausted or are not feasible.
Lifestyle Recommendations: For systolic heart failure, lifestyle recommendations include:

1. **Diet**: Maintain a low-sodium diet to help reduce fluid retention. Incorporate plenty of fruits, vegetables, whole grains, and lean proteins.

2. **Exercise**: Engage in regular physical activity as advised by a healthcare provider to improve overall cardiovascular fitness. Walking, swimming, and cycling are often recommended.

3. **Weight Management**: Maintain a healthy weight to reduce the strain on the heart.

4. **Alcohol and Smoking**: Avoid smoking and limit alcohol intake, as both can exacerbate heart failure symptoms.

5. **Fluid Management**: Monitor and potentially limit fluid intake to prevent fluid overload, as recommended by your healthcare provider.

6. **Medication Adherence**: Take all prescribed medications regularly and follow the healthcare provider's instructions closely.

7. **Stress Management**: Engage in stress reduction activities like meditation, yoga, or deep-breathing exercises.

8. **Regular Check-ups**: Schedule and attend routine appointments with your healthcare provider to monitor the condition and make necessary adjustments to the treatment plan.
Medication: A number of medications may cause or worsen the disease. This includes NSAIDs, COX-2 inhibitors, a number of anesthetic agents such as ketamine, thiazolidinediones, some cancer medications, several antiarrhythmic medications, pregabalin, alpha-2 adrenergic receptor agonists, minoxidil, itraconazole, cilostazol, anagrelide, stimulants (e.g., methylphenidate), tricyclic antidepressants, lithium, antipsychotics, dopamine agonists, TNF inhibitors, calcium channel blockers (especially verapamil and diltiazem), salbutamol, and tamsulosin.By inhibiting the formation of prostaglandins, NSAIDs may exacerbate heart failure through several mechanisms, including promotion of fluid retention, increasing blood pressure, and decreasing a person's response to diuretic medications. Similarly, the ACC/AHA recommends against the use of COX-2 inhibitor medications in people with heart failure. Thiazolidinediones have been strongly linked to new cases of heart failure and worsening of pre-existing congestive heart failure due to their association with weight gain and fluid retention. Certain calcium channel blockers, such as diltiazem and verapamil, are known to decrease the force with which the heart ejects blood, thus are not recommended in people with heart failure with a reduced ejection fraction.Breast cancer patients are at high risk of heart failure due to several factors. After analysing data from 26 studies (836,301 patients), the recent meta-analysis found that breast cancer survivors demonstrated a higher risk heart failure within first ten years after diagnosis (hazard ratio = 1.21; 95% CI: 1.1, 1.33). The pooled incidence of heart failure in breast cancer survivors was 4.44 (95% CI 3.33-5.92) per 1000 person-years of follow-up.Quadruple medical therapy using a combination of angiotensin receptor-neprilysin inhibitors (ARNI), beta blockers, mineralocorticoid receptor antagonists (MRA), and sodium/glucose cotransporter 2 inhibitors (SGLT2 inhibitors) is the standard of care as of 2021 for heart failure with reduced ejection fraction (HFrEF).There is no convincing evidence for pharmacological treatment of heart failure with preserved ejection fraction (HFpEF). Medication for HFpEF is symptomatic treatment with diuretics to treat congestion. Managing risk factors and comorbidities such as hypertension is recommended in HFpEF.Inhibitors of the renin–angiotensin system (RAS) are recommended in heart failure. The angiotensin receptor-neprilysin inhibitors (ARNI) sacubitril/valsartan is recommended as first choice of RAS inhibitors in American guidelines published by AHA/ACC in 2022. Use of angiotensin-converting enzyme (ACE) inhibitors (ACE-I), or angiotensin receptor blockers (ARB) if the person develops a long-term cough as a side effect of the ACE-I, is associated with improved survival, fewer hospitalizations for heart failure exacerbations, and improved quality of life in people with heart failure. European guidelines published by ESC in 2021 recommends that ARNI should be used in those who still have symptoms while on an ACE-I or ARB, beta blocker, and a mineralocorticoid receptor antagonist. Use of the combination agent ARNI requires the cessation of ACE-I or ARB therapy at least 36 hours before its initiation.Beta-adrenergic blocking agents (beta blockers) add to the improvement in symptoms and mortality provided by ACE-I/ARB. The mortality benefits of beta blockers in people with systolic dysfunction who also have atrial fibrillation is more limited than in those who do not have it. If the ejection fraction is not diminished (HFpEF), the benefits of beta blockers are more modest; a decrease in mortality has been observed, but reduction in hospital admission for uncontrolled symptoms has not been observed.In people who are intolerant of ACE-I and ARB or who have significant kidney dysfunction, the use of combined hydralazine and a long-acting nitrate, such as isosorbide dinitrate, is an effective alternate strategy. This regimen has been shown to reduce mortality in people with moderate heart failure. It is especially beneficial in the black population.Use of a mineralocorticoid antagonist, such as spironolactone or eplerenone, in addition to beta blockers and ACE-I, can improve symptoms and reduce mortality in people with symptomatic heart failure with reduced ejection fraction (HFrEF).SGLT2 inhibitors are used for heart failure.
Repurposable Drugs: For systolic heart failure, several repurposable drugs have shown promise. These include:

1. **Metformin** - Typically used for diabetes, it has been investigated for its cardioprotective effects.
2. **SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin)** - Originally for diabetes, have shown benefits in heart failure.
3. **Ivabradine** - Initially for angina, has been found to improve outcomes in certain heart failure patients.
4. **Spironolactone** - A diuretic used for hypertension and heart failure, particularly beneficial in reducing morbidity and mortality.

Always consult a healthcare professional before starting any new treatment.
Metabolites: In the context of systolic heart failure, notable metabolites include:

1. **Lactate**: Elevated levels can indicate anaerobic metabolism due to poor oxygen delivery.
2. **Natriuretic Peptides (BNP and NT-proBNP)**: These biomarkers are elevated in heart failure and are used for diagnosis and monitoring.
3. **Troponin**: While primarily used to diagnose myocardial infarction, elevated levels can also be seen in heart failure.
4. **Amino Acids**: Altered levels, such as increased arginine, can reflect metabolic disturbances.
5. **Fatty Acids**: Dysregulation is common due to changes in energy metabolism in the failing heart.

Overall metabolic profiling can offer insights into disease severity and progression.
Nutraceuticals: Nutraceuticals for systolic heart failure include supplements and dietary components that might support heart health. These can involve omega-3 fatty acids, coenzyme Q10 (CoQ10), L-carnitine, and vitamin D. Each can contribute to heart function and reduce inflammation and oxidative stress. It is essential to consult with a healthcare provider before starting any nutraceutical regimen to ensure safety and appropriateness for individual health needs.
Peptides: In the context of systolic heart failure, natriuretic peptides are significant biomarkers used in diagnosis and management. B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are commonly measured. They are released from the heart ventricles in response to increased wall tension due to volume expansion and pressure overload and are elevated in heart failure patients. Elevated levels of these peptides correlate with the severity of heart failure and can guide treatment decisions.