Obesity causes increased levels of leptin and c-reactive protein (CRP) which are involved in leptin resistance and cardiovascular events. ^, Cardiovascular events like hypertension, thrombosis, myocardial injury, insulin resistance and diabetes all predispose individuals to developing heart failure. Obesity also leads to increased circulating galectin-3 protein, leading to myocardial inflammation and fibrosis both of which increase the risk of heart failure. In addition, obesity leads to pulmonary hypertension and may subsequently lead to right heart failure due to sleep apnea or obesity hypoventilation syndrome ( Figure 1 ). A study done in Northern China by Wang et al. found that high BMI with proteinuria significantly increases the risk of heart failure. Initially, obese patients have increased metabolic demand of body tissue which leads to increased stroke volume and heart rate (HR) due to increased sympathetic activity, both of which increase cardiac output (CO). The increase in CO and HR also contributes to increased blood pressure. Obesity causes vascular abnormalities such as endothelial dysfunction and vascular stiffening which increases the risk of cardiovascular mortality and morbidity. Obesity-related vascular abnormalities further increase the risk of hypertension which further increases the risk of cardiovascular abnormalities including heart failure. These changes in hemodynamic parameters lead to LV remodeling which predisposes the heart to a decline in cardiac function and other cardiovascular pathologies, including coronary artery disease and arrhythmias. ^,,, Therefore, management and preventive strategies for reducing obesity decrease the risk of heart disease.

Pathogenesis of Obesity and its association with heart failure.

Encouraging lifestyle modifications, such as adopting a nutritious eating regimen and boosting physical activity, can aid in safely achieving weight loss to combat obesity. These changes assist in reducing calorie intake from food and beverages while enhancing calorie expenditure through activity. Achieving a 5% to 10% weight reduction is widely recognized as clinically significant due to the resulting improvements in cardiometabolic risk factors. According to the most recent ACC/AHA guidelines, ≥5% weight loss is associated with a moderate reduction in blood pressure, improvements in LDL levels and improved glucose levels in overweight individuals. Current guidelines recommend this weight loss target for individuals classified as overweight or obese.

Physical activity in heart failure is associated with decreased cardiovascular risk and mortality, rehospitalization, improved functional capacity, and quality of life. Stable heart failure patients on optimal guidelines-directed medical therapy are candidates for exercise rehabilitation programs. Obese elder populations and heart failure patients are prone to physical frailty. Physical therapy helps to decrease adipose tissue and increase the lean body mass in these populations. However, the combination of physical therapy with nutritional therapy has shown more benefits in mitigating the frailty in obese patients or elderly with heart failure and improving their physical functional status.

Individualized interval exercise training at various intensities for example: 50%, 70%, and 80% of maximal capacity show benefits in chronic heart failure patients. For patients with chronic heart failure, physical therapy includes aerobic and resistive exercise which may include inspiratory muscle exercise. ^,, In stable patients with heart failure, aerobic exercise such as running on a treadmill, dancing or using a cycle ergometer should be included for 20 to 60 min/d, for 3 to 5 d/wk for at least 8 to 12 weeks. Resistive exercise in these patients should focus on major muscle groups of the upper and lower body with 2 to 3 sets in each muscle group lasting for 45 to 60 minutes/sessions and for 3 sessions/week for at least 8 to 12 weeks. Clinicians should also focus on inspiratory muscle exercise independent of baseline inspiratory muscle weakness by using nonflow dependent resistive devices for 30 min/d reaching more than 30% of maximum inspiratory pressure for 5 to 7 d/wk for at least 8 to 12 weeks.

For patients after heart transplantation, an alternate day walking program from 4 to 6 weeks up to 6 months can be instituted to increase the functional capacity of the patients.

LVAD patients are ambulated in 7 to 10 days after surgery with treadmill training at day 21 which is followed by 6-8 weeks of 20 to 30 min/day of treadmill training.

A vegetarian-style diet or low-fat diet has benefits for patients with obesity and cardiovascular disease. It enhances weight loss and decreases the risk of cardiometabolic factors. Cardiometabolic factors such as obesity, type 2 diabetes, hypertension, and dyslipidemia increase insulin and leptin sensitivity and reduce calorie intake by delaying gastric emptying along with improving gut microbiota. A plant-based diet has also been shown to reduce the production of trimethylamine-N-oxide, which is responsible for inhibiting cholesterol reuptake in the liver from the blood and increasing the risk for atherosclerosis. The Mediterranean diet has the additional benefit of reducing the environmental impact of obesity.

Pharmacotherapy should be used in nonpregnant patients who are obese or overweight (BMI ≥27) with weight-related complications. If lifestyle modification is ineffective, antiobesity medication should be used in conjunction with a reduced-calorie diet and physical activity to maintain long-term weight loss. ^, While choosing antiobesity medication, the clinician should focus on the additional benefits of the prescribed drug. Below we describe in detail short and long-term FDA-approved antiobesity drugs, mechanism of action, dose, and adverse reactions to help make the clinical application of multiple categories of pharmacotherapy straightforward in these complex patients.

FDA defines short-term antiobesity drug use as less than 12 weeks and more than 12 weeks for long-term antiobesity drugs. FDA-approved antiobesity drugs for long-term use include GLP-1 agonist- Tirzepatide, semaglutide, liraglutide, retatrutide, and other drugs, including, orlistat, orlforglipron, phentermine/topiramate, naltrexone-bupropion and setmelanotide. antiobesity drugs for short-term use (12 weeks) include diethylpropion, phentermine and phendimetrazine. In some instances, even though not FDA-approved for obesity, some drugs are known to have weight loss as a side effect that is well tolerated. These commonly prescribed off-label drugs include semaglutide, liraglutide, dulaglutide, topiramate, bupropion and metformin. ^,,,, Mechanism of action, dosage, adverse reactions and contraindications are described in Table 2 and notable characteristics are described below.

Tirzepatide: It can be used in NYHA-III heart failure with overweight and obesity. Tirzepatide has also been shown to reduce systolic blood pressure significantly but its effect due to medication itself or weight loss is still unknown. It should be noted that patients experience substantial regain of weight after the stoppage of the drug. ^,

Semaglutide: It improves weight and reduces heart failure symptoms in patients with NYHA II-IV heart failure with preserved ejection fraction with obesity. This drug also has better cardiovascular outcomes in NYHA II-III chronic heart failure in patients with type 2 diabetes. ^,

Liraglutide: It decreases cardiometabolic markers like systolic and diastolic blood pressure, fasting lipid levels, plasminogen activator inhibitor, adiponectin and C-reactive protein. ^,

Orlistat: Orlistat inhibits gastrointestinal lipase to hydrolyze triglyceride to monoacylglycerol and free fatty acid and one-third of triacylglycerol remains unexcreted in stool decreasing the amount of cholesterol and fat-soluble vitamin absorption. The most common side effects are GI-like flatulence with discharge, steatorrhea, fecal urgency, fecal incontinence and oily spotting, and fat-soluble vitamin deficiency- primarily vitamin D, so it is advised to administer multivitamins 2 hours before or 2 hours after orlistat dose. ^,

Phentermine/topiramate: The phentermine/topiramate combination has a more favorable outcome than monotherapy in long term management of obesity in both adults and adolescence. ^, Phentermine monotherapy is used for less than 12 weeks for obesity management. Topiramate had additional benefits in obese patients with migraine headaches, antipsychotic drug induced weight again, binge eating disorder and alcohol induced disorder. The most common side effects include paresthesia, dry mouth, constipation, headache, dizziness, insomnia, dysgyeusia. Phentermine/topiramate combination should not be used in patients with cardiovascular disease, uncontrolled hypertension, uncontrolled hyperthyroidism, history of glaucoma due to the noradrenergic properties of phentermine and it is also contraindicated within 14 days of mono-amine oxidase inhibitor and calcium phosphate nephrolithiasis.

Naltrexone/Bupropion: Bupropion stimulates hypothalamic proopiomelanocortin neurons while naltrexone blocks opioid-mediated proopiomelanocortin autoinhibition which causes decreased food intake and increases energy expenditure and weight loss. Naltrexone and bupropion are commonly used for smoking cessation and obesity. ^,

Setmelanotide: The result is a substantial reduction of hyperphagia and obesity in patients with proopiomelanocortin deficiency (POMC) or leptin receptor deficiency. ^,,

Diethylpropion : It is used for less than 12 weeks along with a controlled diet for substantial weight loss. It is a sympathomimetic drug, which increases noradrenaline release in the central nervous system and reduces the food intake. Diethylpropion causes direct cardiomyocyte injury, so it is contraindicated in obese patients with cardiovascular disease.

Phendimetrazine: It has a high potency for abuse. It should be cautiously used in patients with heart failure, hypertension due to its potency to increase in adrenergic activity, like other sympathomimetic drugs.

Metformin: It has been shown to reduce visceral fat by adaptive thermogenesis and weight gain associated with antipsychotic medications. Metformin has been shown to reduce weight in obese women with polycystic ovarian syndrome. Metformin is contraindicated in patients with heart failure with low ejection fraction, chronic kidney disease with glomerular filtration rate less than 30 and patients with advanced cirrhosis due to elevated risk of anionic gap metabolic lactic acidosis. ^,,

Dulaglutide : Dulaglutide is GLP-1 agonist like semaglutide administered once weekly for the treatment of type 2 diabetes in adults and youths. Dulagludie is also commonly used as an off label drug to manage obesity in patients with type 2 diabetes but dulaglutide is found to be inferior compared to semaglutide in terms of lowering BMI in obese patients and found to have higher gastrointestinal adverse effects than semaglutide. Contraindications are that of other GLP-1 analogues.

Orforglipron : It acts on the GLP-1 receptor but leads to low activation of beta-arrestin, which is responsible for receptor internalization. It decreases systolic blood pressure, and fasting lipid profiles with an increase in pulse. No event of pancreatitis was found in the GZGI trial and other side effects are similar to GLP- 1 analogues.

Retatrutide : It acts on glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon (GCG), amylin, oxyntomodulin, and peptide YY- receptors and signals to reduce energy intake, increase energy expenditure and help in weight loss. It decreases cardiometabolic risk factors for patients with obesity and heart failure. The most common side effects are GI- Nausea, vomiting, constipation, diarrhea. GLP-1 receptor agonist increases heart rate by increasing intracellular cyclic adenosine monophosphate which influx cardiomyocytes with calcium and increases the risk of cardiomyocyte death in patients with HFrEF. Furthermore, some patients of HFrEF have cachexia and substantial weight loss in which GLP-1 agonists may not be favorable for them.

Patients with heart failure are often bridged with a durable LVAD or percutaneous mechanical circulatory support devices such as the Impella until they can receive a heart transplant. At most institutions, obese patients with a BMI> 35 are not eligible for heart transplant. Additionally, in patients with heart failure, LVAD often increases body weight and again further interrupts time to bridge in heart transplant.

Metabolic bariatric surgery (MBS)- laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass improved LVEF in patients with obesity and heart failure. NYHA class also improves after surgery and heart transplantation is successful in 33 % of patients who were listed for transplant after metabolic bariatric surgery. MBS acts as a bridge to transplant in patients with advanced heart failure with left ventricular assisted devices. ^,,,, A case of Impella-supported robotic sleeve gastrectomy has also been reported. The patient experienced significant weight loss after the procedure and was later implanted with an LVAD while awaiting a suitable donor match. Four months after the surgery, his BMI remains stable at 34 kg/m². In the patients undergoing MBS in an obese patient with pulmonary hypertension, there is evidence that they have a higher risk of atrial fibrillation and acute pulmonary embolism, but patients should not be excluded from metabolic surgery. ^,,

Careful preoperative assessment should be done before bariatric surgery in obese patients with heart failure due to early risk of 90 days cardiovascular mortality. MBS is also associated with decreased vasodilator, diuretic, and anticoagulant medication requirements in heart failure patients with LVAD. Thus, MBS is a safe and effective approach to bridge patients with obesity and heart failure for definitive cardiac transplantation ( Figure 3 ).

Metabolic Bariatric surgery as a bridge to heart transplant in patients with obesity and advanced heart failure. LVAD = left ventricular assist device.