Disease burden: (Yes, a huge burden of morbidity and mortality)
Globally, about 17 million people die from cardiovascular disease every year, accounting for 31% of all deaths worldwide. India has one of the highest burdens of cardiovascular disease worldwide. Cardiovascular disease represents 27% of all deaths in India of which more than half the deaths are due to coronary artery disease. The mean age for the first presentation of acute myocardial infarction (popularly known as heart attack) in Indians is 53 years, which is around 5 years earlier than other Asian countries and 10 years earlier than European countries. Similarly, deaths due to AMI in South Asians occur 5-10 years earlier than the western population. Coronary artery disease prevalence rates in India ranged from 2% to 7% in rural populations and from 7% to 13% in urban populations. There has been a 4-fold rise in this prevalence in India during the past 40 years. Asians in general and Indians in particular are at increased risk of myocardial infarction (MI) at an even younger age; the first AMI occurs in 4.4% of Asian women and 9.7% of men at age less than 40 years, which is 2- to 3.5-fold higher than in the West European population. South Asian men encountering AMI were 5.6 years younger than women. It has been reported that more than 50% of coronary artery disease associated deaths in India occur before the age of 50 years and 25% of myocardial infarctions occur before the age of 40 years.
Risk factors: (Yes, most of them are modifiable)
A large multinational INTERHEART study showed higher risk for MI in South Asians in their younger age is largely determined by nine risk factors (abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial stress, lack of fruits & vegetables in diet, high alcohol consumption and lack of regular physical activity), which accounted around 90 percent of the MI risk in south Asians. Among patients who get MI below the age of 40 years, smoking is the most important risk factor. South Asians have significantly higher population-attributable risk associated with high waist-hip ratio.
Pathogenesis: (Yes, it can regress)
Acute MI happens when the oxygen supply through the circulating blood in the coronary arteries is obstructed abruptly, leading to the death of myocardial muscle cell fibers. The majority of these patients have an underlying atherosclerotic plaque, which predisposes arterial endothelium to thrombus formation if it ruptures or erodes. The primary event that triggers atherosclerotic plaque formation is an accumulation of plasma-derived abnormal lipid accumulation (oxidized LDL) in coronary intima. Atherosclerotic plaque formation is a chronic immuno-inflammatory process in which oxidative stress and endothelial dysfunction also take place in pathogenesis. In a minority of patients, especially younger victims (and more so after the COVID era), a clot may form without underlying atherosclerosis.
Bad or good lipids: (Cholesterol, a word of phobia)
A worldwide study demonstrated that among all modifiable risk factors of cardiovascular disease, abnormal serum levels of cholesterol were associated with the highest attributable risk for the occurrence of coronary artery. However, heart attacks can occur with normal lipid levels too, when the other major risk factors are present. A lipoprotein is a biochemical assembly whose primary function is to transport fat molecules in our body. There is a significant association of coronary events with raised apolipoprotein B, total cholesterol, LDL cholesterol, non-HDL cholesterol and an inverse association with high apolipoprotein A and HDL cholesterol. LDL cholesterol has been identified as the main risk factor for CVD by many epidemiological and interventional studies because LDL-C plays a major role in the pathogenesis of atherosclerosis.
It is well recognized that Indians develop coronary artery disease about a decade earlier than the Western populations, despite having lower levels of low-density lipoprotein cholesterol (LDL-C). Studies have reported that high cholesterol is present in 25–30% of urban and 15–20% of rural Indian populations, which has been a rising trend for 20 years, particularly total cholesterol, LDL cholesterol and triglyceride levels. This prevalence is lower than in high-income countries. The most common dyslipidemia in India is a triad of borderline high LDL cholesterol, low HDL cholesterol and high triglycerides.
A prospective multicenter study in India on acute coronary syndrome patients showed that 33.4% were younger than 50 years. The young age of onset renders conventional Western clinical risk assessment tools less relevant because, in all of them, age has an overriding influence on the estimated risk. Secondly, the high incidence of early onset coronary artery disease necessitates the early institution of aggressive preventive measures to protect the young population before the development of acute events. Early treatment yields both short-term and long-term benefits. Results from Mendelian studies have clearly shown that, in people with high LDL cholesterol, even a small reduction in LDL cholesterol achieved at an early age and maintained over decades leads to several-fold greater reductions in MI risk compared to more aggressive LDL cholesterol lowering initiated later in life.
Statin: (Yes, a major game changer)
In patients with high LDL cholesterol levels, its reduction has been repeatedly proven to be beneficial. In patients with normal or mildly raised LDL cholesterol levels, further lowering has much lesser benefit. A reduction of LDL cholesterol by 50% is necessary to halt the progression of atherosclerotic plaque. Statins and non-statin are widely available, enabling the majority of patients to achieve recommended LDL cholesterol lowering goals. These recommended goals have been steadily lowered over the last three decades, the current recommendations being debatable and having several counter opinions by experts. Statins are the primary and initial agent for achieving LDL cholesterol lowering. Recent dyslipidemia guidelines suggest that ezetimibe, bempedoic acid, PCSK9 inhibitors and inclisiran may be considered for additional LDL-C reduction if target is not achieved by maximum tolerated attain therapy. PCSK9 inhibitors and inclisiran are injectable and more potent; however, they are quite expensive.
Pharmacodynamics & kinetics: Statins are a selective, competitive inhibitor of HMG-CoA reductase, the enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol synthesis pathway. By reducing hepatic cholesterol synthesis, an upregulation of LDL receptors and increased hepatic uptake of LDL cholesterol from the circulation occurs. It also reduces the hepatic production rate of apo B100 containing lipoproteins, leading to a decrease in both cholesterol and triglyceride concentrations. HMG CoA reductase inhibitors have pleiotropic effects and inhibit the synthesis of isoprenoid intermediates required for activating intracellular or signaling proteins. Consequently, statins have anti-inflammatory, antioxidant, antiproliferative, and immunomodulatory effects. In addition, statin promote plaque stability and prevent platelet aggregation.
Statin & Liver disease: All statins are contraindicated in active liver disease. Statins are associated with mild-to-moderate liver enzyme elevations during therapy that are temporary, asymptomatic and usually resolve without dose adjustment. Statins with minimal hepatic metabolism, such as rosuvastatin and pravastatin, are preferred in chronic liver disease.
Statin & Renal disease: Atorvastatin appears to be the statin of choice in chronic kidney disease. A network meta-analysis demonstrated that high doses of atorvastatin and fluvastatin 20 mg/ezetimibe 10 mg significantly prevented eGFR decline and proteinuria. Dose adjustment is required with other statins in patients with advanced chronic kidney disease (creatinine clearance < 30 mL/min).
Special considerations: Statins are typically contraindicated in pregnancy and should not be used during breastfeeding due to disruption in the infant’s lipid metabolism. They can, however, be safely use in pediatric and older patients. Statin medications can be ingested with or without food. Grapefruit juice should be avoided with some statins to minimize CYP3A4 interactions that could increase serum concentrations. Due to the diurnal variation in hepatic cholesterol synthesis, synthesis is highest in the early morning. An evening administration is the recommended dosing approach for fluvastatin, lovastatin, pravastatin, and simvastatin. Atorvastatin, pitavastatin and rosuvastatin dosing do not require morning or evening administration, but their administration should be at the same time of day.
Adverse Effects: Statins are usually well-tolerated, with myopathy, hepatotoxicity, and diabetes mellitus being the most common adverse reactions. The incidence of myopathy is dose-dependent and generally self-resolving after stopping the statin. Rhabdomyolysis is the most serious complication of statin use, but the occurrence is rare. Statin-associated immune-mediated necrotizing myopathy is due to the development of antibodies against the HMG-CoA reductase enzyme. Symmetrical, proximal muscle weakness with significantly increased CPK persists for months after discontinuation of statins, which is common in statin-associated immune-mediated necrotizing myopathy. Elevated hepatic transaminases can occur, which is usually transient and resolves with continued therapy or after a brief therapy interruption. Patients with statin-induced hepatotoxicity have hepatocellular but cholestatic or mixed hepatic injury can occur with atorvastatin. Statin-associated cognitive dysfunction is a rare adverse drug reaction; changing lipophilic to hydrophilic statins may resolve cognitive impairment.
Bardolia, Chandni & Amin, Nishita & Turgeon, Jacques. (2021). Emerging Treatment Options for Lowering Low-Density Lipoprotein Cholesterol. Frontiers in Cardiovascular Medicine. 8. 789931. 10.3389/fcvm.2021.789931.
Salient features in Indians:
In India, the prevalence of various dyslipidemias has increased over the past 30 years. This is in contrast to developed countries where it is declining.
The propensity for dyslipidemia is noted at a younger age among Indians. Prone to develop CAD before 40 years of age.
Five-fold more prone to myocardial infarction and cardiovascular death compared to Caucasians.
High prevalence of atherogenic dyslipidemia: high LDL, high triglycerides, low HDL and high levels of lipoprotein(a).
Indians achieve higher levels of circulating statins compared to the Caucasian population when administered equivalent doses.
Life’s Simple 7 rules to reduce heart disease (American Heart Association):
- Get active Aim for at least 150 minutes of moderate-intensity physical activity per week
- Manage blood pressure: Aim for a blood pressure of less than 130/80 mmHg
- Eat better add fruits, vegetables, whole grains, limiting saturated and trans fats
- Healthy weight (BMI<25)
- Manage blood sugar: Aim for a fasting blood glucose level of less than 100 mg/dL
- Quit smoking
- Control cholesterol: Aim for a total cholesterol level of less than 200 mg/dL, LDL <100mg/dl
Targets and management:
High-intensity statin (LDL-C lowering > 50%): rosuvastatin 20-40 mg, atorvastatin 40-80 mg
Moderate-intensity statin (LDL-C lowering 30% to 49%): atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, lovastatin 40-80 mg, fluvastatin 80 mg
Low-intensity statin (LDL-C lowering < 30%): simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg
Target to reduce LDL<100 mg/dl, non-HDL<130 mg/dl, ApoB<90 mg/dl
In case of high-risk subjects: target to reduce LDL<70 mg/dl, non-HDL<100 mg/dl, ApoB<80 mg/dl
Next-line management: Ezetimibe, Bempedoic acid and or PCSK9 Inhibitor
Further management: PCSK9 inhibitor, Inclisiran
Written By:
Dr Yash Lokhandwala
Dr. Yash Lokhandwala (Age 63) is a Partner at Arrhythmia Associates and a renowned Electrophysiologist with over 21,000 RF ablation procedures to his credit. He serves as visiting faculty at LTMG Hospital and Asvini Naval Hospital, Mumbai, and has previously held academic roles at premier institutions including KEM Hospital, IIT Bombay, CMC Vellore, and SGPGI Lucknow. A former President of both the Indian Heart Rhythm Society and the Indian Society of Electrocardiology, Dr. Lokhandwala has 246 PubMed-indexed publications and regularly trains EP fellows across the country.
&
Dr Gaurav Kumar Mittal
Dr. Gaurav Kumar Mittal is an Assistant Professor of Cardiology at Geetanjali Medical College & Hospital, Udaipur, with over 7 years of experience in interventional cardiology. He completed his MBBS from JLNMC, Ajmer (RUHS), MD in Internal Medicine from VIMSAR, Odisha (Sambalpur University), and DM in Cardiology from JIPMER, Pondicherry. His clinical expertise includes complex percutaneous coronary interventions (PCIs), pacemaker implantations, structural heart interventions, and pediatric cardiac procedures. Dr. Mittal has contributed to research in electrophysiology, including a case report titled “Coumel’s sign reversed: What is the mechanism?” published in the Indian Pacing and Electrophysiology Journal. He is a permanent member of the ACC, ESC, and CSI cardiology societies and has a keen interest in advancing his skills in electrophysiology and radiofrequency ablation.
