Drugs and Toxins Induced Cardiomyopathies 

Effects of Alcohol on the Heart

• 2 forms of cardiotoxicity associated with alcohol: Development of dilated cardiomyopathy. Most common toxin is alcohol. Development of atrial fibrillation. Excessive consumption of alcohol contributes to 10% cases of heart failure, secondary to dilated cardiomyopathy. Excessive consumption of alcohol also causes exacerbation of heart failure. Structural changes are in the form of dilatations. More common in men.
• Development of atrial fibrillation: Holiday heart syndrome: Name given by western community. Binge consumption of alcohol during weekends or holidays. Atrial fibrillation can occur in early and advanced stages of alcoholic cardiomyopathies. 
• Dilated cardiomyopathy and atrial fibrillation both occur with excessive consumption of alcohol.

Primary metabolite that attribute to the toxicity of alcohol is acetaldehyde. Alcohol in the presence of alcohol dehydrogenase is metabolised to acetaldehyde. Acetaldehyde is responsible for alcoholic cardiomyopathy. In oxidative pathway - Acetate is excreted out by liver. Alcohol oxidised by non-oxidative pathway is also responsible for liver injury.

Effects of Chronic Heavy Exposure of Alcohol 

Alter metabolism, protein synthesis, substrate utilisation and Induce oxidative stress.

How Does Alcoholic Cardiomyopathy Occurs?

It occurs due to gene alteration required for the synthesis of alcohol dehydrogenase. Polymorphism of genes encoding alcohol dehydrogenase and ACE will influence development of alcoholic cardiomyopathy in individual with superimposed vitamins deficiency and poor nutrition. Gene mutations are also responsible for formation of cardiac muscle structure.

Gene Responsible for Alcoholic Dilated Cardiomyopathy

Gene responsible for alcoholic dilated cardiac is TTN gene. TTN gene provides instructions for making large proteins called Titin. Titin is present in skeletal muscle and cardiac muscle. Titin protein in skeletal muscle is required for movement. Titin Protein in cardiac muscle provides spring like action in the heart muscle. Limit the excessively stretched movement.

Due to alcohol consumption, TTN gene is mutated. Titin protein is not formed. Spring action is lost which results is dilated cardiomyopathy. 

Other gene responsible for dilated cardiomyopathy

LAMIN A/C gene - It undergoes missense mutation upon excessive alcohol consumption. Responsible for dilated cardiomyopathy and conduction system disease.

Is alcoholic cardiomyopathy reversible?

Due to alcoholic cardiomyopathy, cardiac impairment develops, a part of which can be permanent. A substantial component can be reversible after cessation of alcohol. 

Treatment of Alcoholic Cardiomyopathy 

Alcohol cardiomyopathy leads to the development of HFrRF with pulmonary edema. Diuretics are given. Neurohormonal antagonists- Once the cardiac output is reduced, the BP also reduces. Excessive activation of sympathetic outflow and RAAS causes cardiac remodelling. Cardio selective Beta blockers are given- Metoprolol, Bisoprolol, Carvedilol. Start with low dose and then step up based on tolerability. 

In case of acute heart failure or acute left ventricular failure with pulmonary edema. Beta blockers are avoided. ACE inhibitors/ARBs should be given- Aldosterone antagonists: Spironolactone and Eplerinone. If there is no withdrawal, patient may develop exacerbations. Arrhythmia and sudden cardiac death.

• Lifestyle modifications- Consumption of healthy diet, fibre rich and low fat and carbohydrate diet. Regular exercise. Once the alcohol is withdrawn for 3-6 months, then even severe form of disease can be reversed. If the individual continues the alcohol consumption, prognosis worsens.
• Cardiac rehabilitation- It a program that helps heart disease patients to improve heart health through exercise, education and counselling. Individuals with increased risk of sudden cardiac death and arrhythmias. ICD must be placed (implantable cardioverter defibrillator), prevents sudden cardiac death from arrhythmias
• Other devices- Cardiac resynchronisation therapy Helps in dilated cardiomyopathy with wide QRS complex (>120 msec). Medical management is done. If individual is refractory to medical management for nearly around 3-6 months with wide QRS complex - Ideal for cardiac resynchronisation therapy. It improves ejection fraction and reduces hospitalisation and exacerbation, improves lifestyle.

Cocaine, amphetamines and related catecholaminergic stimulants 

• Cardiac pathology secondary to these drugs- reveals microinfarcts. These drugs cause small vessel ischemia. Microinfarcts – Also seen in Pheochromocytoma. Thrombosis secondary to cocaine administration.
• Cardiac effects- development of dilated cardiomyopathy. Dilated cardiomyopathy occurs secondary to ischemia caused by microinfarcts. Tachyarrhythmias can be the form of ventricular tachycardia and fibrillation. Malignant hypertension (BP>180mmHg). Development of aortic dissection and haemorrhagic stroke. 

Chemotherapy agents

• One of the most common drugs in toxic cardiomyopathy. Patients on chemotherapy agents can develop heart failure (stage B).

• Once the clinical features appears, prognosis worsens. Risk factors- excessive alcohol consumption, chemotherapy drugs, DM and hypertension.

Anthracyclines

• Ex: Doxorubicin. Histological changes within cardiac muscle with vacuolar degeneration and myofibrillar loss. Risk factors old age, past history of cardiac disease, high dose of doxorubicin, left side chest irradiation. 
• Multiple mechanisms by which Doxorubicin will induce toxicity. Reactive oxygen species, accumulation of Iron compounds, mitochondrial damage, hypoxia induced factor. Inhibition of topoisomerase 2
• Clinical features- Systolic dysfunction, dyspnea due to pulmonary edema, fatigue due to reduced cardiac output, hypotension, palpitations secondary to arrhythmias 
• Management- Diuretics – For fluid overload, beta blockers – Prevent cardiac remodelling and reduce mortality. ACE inhibitors/ARBs, aldosterone antagonists. In HFrEF, if there is no improvement with ACE inhibitors/ARBs, ARNI (Angiotensin receptor blocker neprilysin inhibitor) is given- Valsartan + Sacubitril 
• These drugs also prevent complication secondary to cardiac toxicity like atrial fibrillation, hypertension.

Trastuzumab (Herceptin)

• It is a humanised monoclonal antibody. It interferes with human epidermal growth factor 2. Given in treatment of HER II receptor positive tumor like breast cancer, cardiac adaptation.  Clinical features – Similar to HFrEF. Combination of Trastuzumab with paclitaxel or doxorubicin, causes high intensity cardiotoxicity.  It is reversible when supplementation is stopped. In 1/3rd of patient, it progresses to significant heart failure (Stage III) and death. 
• Treatment- Diuretics – For fluid overload, Beta blockers – prevent cardiac remodelling and reduce mortality. ACE inhibitors/ARBs, aldosterone antagonists. In HFrEF, if there is no improvement with ACE inhibitors/ARBs, ARNI (Angiotensin receptor blocker neprilysin inhibitor) is given- Valsartan + Sacubitril 
• Other drugs: Cyclophosphamide and Ifosfamide. Used in patients with nephrotic syndrome. High doses can cause cardiac toxicity. 5- fluorouracil and cisplatin- cause recurrent coronary spasm with depressed ejection fraction. 
• Interferon alpha and interleukin 2- causes hypotension and arrhythmias.

Tyrosine kinase inhibitors 

• Therapeutic use- Malignancies related to breast cancer, lung and Urinary bladder. Endogenously, there can be production of vascular endothelial growth factor. It induces angiogenesis by activating VEGF signalling pathways. VEGF should not be released in excessive quantities. Tyrosine kinase inhibitors is required for inhibition of VEGF signalling pathways. 
• Cardiotoxicity induced by tyrosine kinase inhibitors- Hypertension, Proteinuria, HFrEF and peripheral fluid accumulation. Treatment- stop supplementation of tyrosine kinase inhibitors which will prevent the progression of heart failure 
• Examples of TKIS include: Axitinib, Dasatinib, Erlotinib, Imatinib, Nilotinib, Pazopanib and Sunitinib 
• Newer TKIS: Alectinib, Brigatinib, Dabrafenib and Trametinib 

Immune Checkpoint Inhibitors

• They block natural counter regulatory T cells causing T cell suppression.  They can induce inflammation in multiple organs. In heart it can induce myocarditis and vasculitis. Examples include:
  • Pembrolizumab: Treat cancers including melanoma, non small cell lung cancer and head, neck cancer. Nivolumab: Treat cancers including melanoma, non small cell lung cancer and kidney cancer. Ipilimumab: Treats advanced melanoma. Atezolizumab: Treats lung and bladder cancer. Durvalumab: Treats lung cancer.

Proteasome Inhibitors    

Ex: Carfilzomib, Bortezomib. Carfilzomib is more cardiotoxic than Bortezomib. They are used in treatment of multiple myeloma. They are at increased risk of development of hypertension and ischemic events. They can induce heart failure and thromboembolic events. 

Also Read: Super Speciality in Medicine : Merits, Demerits, Scope, Career Outside India

Antiretroviral Therapies

NRTIs (Nucleotide reverse transcriptase inhibitors)

• Zidovudine- First antiretroviral drug used in HIV.
• Didanosine- In high doses can cause cardiomyopathy. 
• Stavudine - Can cause peripheral neuropathy and cardiomyopathy. 
• Abacavir (NRTA) -In high doses for longer durations, can cause development of coronary artery disease and MI.

Chloroquine and Hydroxychloroquine

• They are used in the treatment of SLE and RA. These can induce dilated cardiomyopathy & restrictive cardiomyopathy. These can also induce conduction block. 
• Biological DMARTs used in RA. TNF alpha antagonists, Adalimumab: S/C, Etanercept: S/C, Infliximab: IV, Certolizumab: S/C and Golimumab: S/C (Used in RA, Psoriatic Arthritis, Crohn's disease). Adalimumab, Etanercept, Infliximab, Certolizumab are used in the treatment of RA, Psoriatic Arthritis and Ankylosing spondylitis. 

Other therapeutic drugs causing cardiotoxicity:

• Carbamazepine: DOC in Focal epilepsy. Clozapine: Used in Schizophrenia. Lithium: Used in Bipolar disorders. Carbamazepine, Clozapine, Lithium can also cause dilated cardiomyopathy. 

Toxic Exposures     

• Hydrocarbons- Fluorocarbons, Arsenic, Lead, Mercury. All these can cause dilated cardiomyopathy. Secondary to dilated cardiomyopathy there can be development of arrhythmia and respiratory failure.

Hemochromatosis

• It is metabolic or storage disease: There is excessive accumulation of iron within cardiomyocytes.  RCMP< DCMP. It has an autosomal recessive inheritance.  HFE gene is mutated. Responsible for excessive accumulation of iron. In alcoholic individuals, chances of cardiotoxicity are high.
• Cardiac Siderosis is not due to hemochromatosis: It is a form of iron overload. Iron overload is due to hemoglobinopathies in which there is requirement of recurrent blood transfusion. Excess iron gets deposited in the peri nuclear compartment causing cardiomyopathy and damage to intracellular architecture and mitochondrial function.

Diagnosis

• Elevated serum iron levels. Elevated transferrin saturation, In men> 60% and in females > 45-50%. MRI: quantitates iron stores in liver and heart.  In liver it can cause micronodular cirrhosis
• Endo myocardial biopsy- Staining of iron is done. Early treatment: phlebotomy. Phlebotomy is avoided in anaemia. In severe iron overload, iron chelating agents are given Deferoxamine and Deferasirox.

Endomyocardial biopsy 

• Hemochromatosis: Microscopic image of an endomyocardial biopsy showing extensive iron deposition within the cardiac myocytes with the Prussian blue stain.

Hope you found this blog helpful for your NEET SS Cardiovascular preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.