Angiotensin Receptor-Neprilysin Inhibitor Therapy and Cardiac Remodeling in Heart Failure: Consensus Statement from India

Adverse cardiac remodeling refers to progressive structural and functional modifications in the heart because of increased wall stress in the myocardium, loss of viable myocardium, and neurohormonal stimulation. The guideline-directed medical therapy for Heart failure (HF) includes Angiotensin receptor-neprilysin inhibitor (ARNI) (sacubitril/valsartan), ?-blockers, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists (MRA). ARNI is under-prescribed in India despite its attractive safety and efficacy profile. Therefore, the consensus discusses objectives and topics related to ARNI in the management of cardiac remodeling, and experts shared their views on the early timely intervention of effective dosage of ARNI to improve the diagnosis and enhance mortality and morbidity benefits in cardiac reverse remodeling (CRR).

Role of Iron Therapy in Heart Failure: A Consensus Statement from India

Iron deficiency (ID) with or without anemia is frequently observed in patients with heart failure (HF). Uncorrected ID is associated with higher hospitalization and mortality in patients with acute HF (AHF) and chronic HF (CHF). Hence, in addition to chronic renal insufficiency, anemia, and diabetes, ID appears as a novel comorbidity and a treatment target of CHF. Intravenous (IV) ferric carboxymaltose (FCM) reduces the hospitalization risk due to HF worsening and improves functional capacity and quality of life (QOL) in HF patients. The current consensus document provides criteria, an expert opinion on the diagnosis of ID in HF, patient profiles for IV FCM, and correct administration and monitoring of such patients.

The Power and Promise of Angiotensin Receptor Neprilysin Inhibitor (ARNI) in Heart Failure Management: National Consensus Statement

Heart failure (HF) is a huge global public health task due to morbidity, mortality, disturbed quality of life, and major economic burden. It is an area of active research and newer treatment strategies are evolving. Recently angiotensin receptor-neprilysin inhibitor (ARNI), a class of drugs (the first agent in this class, Sacubitril–Valsartan), reduces cardiovascular mortality and morbidity in chronic HF patients with reduced left ventricular ejection fraction (LVEF). Positive therapeutic effects have led to a decrease in cardiovascular mortality and HF hospitalizations (HFH), with a favorable safety profile, and have been documented in several clinical studies with an unquestionable survival benefit with ARNI, Sacubitril–Valsartan. This consensus statement of the Indian group of experts in cardiology, nephrology, and diabetes provides a comprehensive review of the power and promise of ARNI in HF management and an evidence-based appraisal of the use of ARNI as an essential treatment strategy for HF patients in clinical practice. Consensus in this review favors an early utility of Sacubitril–Valsartan in patients with HF with reduced EF (HFrEF), regardless of the previous therapy being given. A lower rate of hospitalizations for HF with Sacubitril–Valsartan in HF patients with preserved EF who are phenotypically heterogeneous suggests possible benefits of ARNI in patients having 40–50% of LVEF, frequent subtle systolic dysfunction, and higher hospitalization risk.

Serum Gamma Glutamyltransferase (GGT) in Coronary Artery Disease: Exploring the Asian Indian Connection

Background:There is a need to identify novel markers for CAD, independent of traditional CV risk factors. One of these is gamma?glutamyl transferase (GGT), a marker of increased oxidative stress. Given the high prevalence of CAD in Asian Indians, the link of GGT and CAD in them needs to be studied. Aim: To assess GGT in patients with angiographically documented CAD. Methods and Results: Two hundred patients aged 58.1 ± 9.95 years, 73% males, hypertension 56%, diabetes 40% were included. Mean GGT was 63.6 ± 44.33 (10–269 U/L). The levels of GGT progressively increased in those with single/double or triple?vessel CAD (36.5, 61.5, and 87 U/L, respectively, P < 0.001). Using objective criteria of CAD burden (SYNTAX and Gensini scores), we reaffirmed these findings. GGT in patients with SYNTAX tertiles 0–22, 23–32, and 33 was 33, 62, and 97 U/L, respectively and in Gensini tertiles 0–17.65, 17.66–56.65, ?56.66 was 32, 52, and 88 U/L, respectively, all P < 0.001. SYNTAX score 23 was present in only 23% patients in GGT tertile 1 (<41 U/L), whereas60% and 94% in GGT tertiles 2 and 3 had SYNTAX 23. Significant positive correlation was seen between GGT and SYNTAX (r = 0.634) and Gensini score (r = 0.772). Conclusions: In this study, GGT had an independent correlation with angiographic severity of CAD and SYNTAX and Gensini scores. Although the existing evidence seems biologically plausible, more studies are needed to explore the potential role of this inexpensive marker for predicting disease burden in patients with CAD.

Long?Term Performance of Untreated Fresh Autologous Pericardium as a Valve Substitute in Pulmonary Position

Background:Pulmonary regurgitation is imminent after transannular patch (TAP). We analyze the long?term performance of untreated autologous pericardium (UAP) as valve substitute at pulmonary position in patients requiring TAP. Material and Methods: This cross?sectional study include patients operated between 2007 and 2012 (n = 92). A sample of 19 patients was selected for this study which had a follow?up of more than 3 years. This includes patients with no TAP (n = 4) and with TAP and valve substitute, a monocusp (n = 11) or a tricuspid valve (n = 4) at neopulmonary annulus. Patients underwent echocardiography for assessment of right ventricle function and 18 fluoro?deoxyglucose PET CT scan for measurements of valve substitute at neopulmonary annulus. The target to blood ratio (TBR) of uptake of glucose by monocusp was measured at the cooptation edge of the neopulmonary valve. Results: The median age of the patients is 14 (9 – 37). RV function is preserved (TAPSE 18.9 (10.6 – 22.8)) at a mean follow?up of 4 years (3?9). The measurements of monocusp shows a shrinkage in height of the cusp by 35.5% (70% – 1.0%) and length by 7% (?44% ? +104%). There was less shrinkage observed in patients below 15 years of age. The TBR of monocusp was 0.945 (0.17 – 3.35) with a strong correlation between the TBR values of aortic valve leaflet and monocusp leaflet of same patient. Conclusion: The UAP is functional and successful as a valve substitute at neo pulmonary annulus at long?term follow?up. It has resisted calcification and has shown uptake of glucose in physiological limits.

Exploring the Association of Fibrinogen and CRP with the Clinical Spectrum of CAD and Periprocedural Outcomes in Patients Undergoing Percutaneous Coronary Interventions

Background:The pathophysiology of an atherosclerotic plaque is mediated by the mechanisms involving thrombus formation and systemic inflammation. While C-reactive protein (CRP) levels are useful in predicting a cardiovascular event in intermediate risk population, the usefulness of routinely measuring fibrinogen in patients with acute coronary syndrome (ACS) is debatable. Also, data on the association of these markers with periprocedural outcomes in patients undergoing percutaneous coronary interventions (PCI) is scarce. Aims: The study aimed to determine whether the levels of fibrinogen and CRP vary across the different spectra of CAD and whether they have any correlation with cardiac Troponin I levels. Materials and Methods: A total of 284 patients with coronary artery disease undergoing percutaneous coronary intervention were included in the study. Complete blood count, serum lipid profile, serum CRP, fibrinogen, and troponin I were measured for all patients. Results: Patients with STEMI had significantly higher levels of CRP as compared to those with unstable angina (USA) and chronic stable angina (CSA). Patients presenting with ACS had significantly higher baseline fibrinogen as compared to those with CSA. A significant positive correlation between CRP and admission Troponin I (r = 0.50; P < 0.05) as well as fibrinogen and admission troponin I (r = 0.30; P < 0.05) was observed. The CRP levels were significantly higher in 15 patients with periprocedural MI as compared to those who did not develop periprocedural MI. Conclusions: The levels of the markers of inflammation and atherothrombosis vary with presentation across varied spectra of CAD with generally higher levels in acute presentation and in those who develop periprocedural MI.

Is Indexed Left Atrial Volume (LAVi) in Indian Patients with Acute Coronary Syndrome (ACS) Undergoing Revascularization a Predictor of Cardiovascular Outcomes?

Background: Left atrial volume indexed to body surface area (LAVi) is the recommended method for LA size quantification. Assessing LAVi in Indian patients undergoing coronary interventions for acute coronary syndrome (STEMI, NSTEMI, and UA) is clinically relevant. Methods and Results: Amongst 190 patients (66.4 yrs, 68.4% males), 29.5%, 40.5%, and 30% respectively had STEMI, NSTEMI and UA. Mean LAVi was 32.29 ± 12.06 ml/m2 and 111 (58.4%) had LAVi ?32 while 79 (41.6%) had LAVi <32. Patients were divided into 2 groups (group 1 LAVi >32 and group 2 LAVi <32). Group 1 patients had higher prevalence of TVD [n = 49 vs n = 5, p = <0.001] and higher mean Syntax score (24.47 vs 14.64, p = <0.001). Despite similar LVEF, those with higher LAVi had had higher incidence of mild MR (50.4 vs 27.8, P = 0.0002) and moderate/severe MR was present only in Group 1 patients (27.9% and 5.4%). Grade I, II, and III diastolic dysfunction was present in 71.2, 17.1, and 9.9% patients in Group 1 vs 45.6%, 0%, and 0% in group 2. Diastolic parameters like septal E/e’ and lateral E/e’ratio were also higher in Group 1. Major adverse cardiovascular events? (MACE) at 30 days was significantly higher in group 1 (20.7 vs 6.3%, P = 0.006). On multivariate analysis, triple vessel disease and LAVi were the only predictors of MACE while LVEF was not. ROC curve analysis for LAVi demonstrated that a cut?off 33.35 ml/m2, predicted 30 day MACE with Area under curve (AUC) 0.775 (95% CI 0.700?0.850); sensitivity and specificity of 86.7% and 61.4%. Inter?quartile analysis of LAVi (<26.3, 26.3?33.35, 33.36?36.3, and >36.3 ml/m2) demonstrated that 30 day MACE increased across quartiles (4.16%, 4.25%, 22.44%, and 28.26%, respectively, P < 0.001). Conclusion: Amongst patients with ACS undergoing revascularization, those with higher LAVi had more severe CAD, diastolic dysfunction and higher 30 day MACE. LAVi provides superior prognostic information as compared to conventional LV systolic and diastolic parameters in patients with ACS and should be incorporated in routine echocardiographic analysis. More studies with larger numbers and longer follow up are required to further elucidate on this.

Pseudo inappropriate shock: A technical dilemma

With liberal availability of high end cardiac implantable devices in recent era, we frequently encounter patients who are recipients of implantable cardioverter defibrillators (ICDs) in our routine clinical practice. Despite improvements in shock detecting algorithms by various manufacturers, incidence of inappropriate shock therapy remains high, it is cause of distress to physicians and patients. Here we present an interesting case of inappropriate shock in one of patient.

Assessment of untreated fresh autologous pericardium as material for construction of heart valve: Result at 5 years

Introduction: Tetralogy of Fallot requiring transannular repair of the right ventricular outflow tract (RVOT) are exposed to free pulmonary insufficiency and hence inevitable right ventricular dysfunction. This study analyzes the function and structure of untreated autologous pericardium monocusp used to create a competent pulmonary valve. Materials and Methods: This is a retrospective analysis of 52 cases operated between December 2006 and December 2012. Untreated autologous pericardium was used for creating a competent pulmonary valve following a transannular patch. They are followed for functional and structural assessment of the pulmonary valve by echocardiography. Positron emission tomography (PET) with 18 fluorodeoxyglucose was performed in two cases for profiling the pulmonary valve. Results: Median age was 10.5 years (1–38). The follow-up was complete for 42 (80.76%) patients for 3 years and 25 (48.07%) patients for 5 years. The RVOT gradient was 42 mmHg (16–96) in the year of surgery, which reduced to 26 mmHg (10–58) and pulmonary insufficiency that was present in 8.3% of patients in 1st year was witnessed in 22.7% in the 5th year of follow-up. The monocusp patch was successful in creating a competent valve while maintaining its structure at 3 years; however, it became distorted and retracted at 5 years of follow-up. There was no calcification in any of the patients. PET-computed tomography confirmed the uptake of glucose by monocusp at 1 year of follow-up. Conclusion: The untreated autologous pericardium functioned well when it was used to create a competent pulmonary valve at short term and midterm. Although it changed in its structure; there was no calcification at 5 years of follow-up.

Gerbode defect formation two decades after tetrology of fallot repair

Although most intracardiac defects are congenital, a small fraction may be acquired during life. The Gerbode defect is an abnormal anatomical connection between the left ventricle and the right atrium. We describe herein a patient who initially underwent repair of tetralogy of Fallot (TOF). Years after TOF repair, he developed severe dyspnea. Extensive evaluation revealed that he had developed a Gerbode defect. Very few cases of acquired Gerbode defect have been previously reported. Management options are predominantly surgical interventions

Sternal osteomyelitis by Gordonia Bronchialis in an immunocompetent patient after open heart surgery

Gordonia is a catalase-positive, aerobic, nocardioform, Gram-positive staining actinomycete that also shows weak acid-fast staining. Several Gordonia species are commonly found in the soil. The bacterium has been isolated from the saliva of domesticated/wild dogs as well. In hospitalized patients, most commonly it is found in the setting of intravascular catheter-related infections. However, recent reports show that it is being increasingly isolated from sternal wounds, skin/neoplastic specimens and from pleural effusions. Gordonia shares many common characteristics with Rhodococcus and Nocardia. Ergo, it is commonly misrecognized as Nocardia or Rhodococcus. Since this pathogen requires comprehensive morphological and biochemical testing, it is often difficult and cumbersome to isolate the species. Broad-range Polymerase Chain Reaction (PCR) and sequencing with genes like 16S rRNA or hsp65 are used to correctly identify the species. Identification is essential for choosing and narrowing the right antimicrobial agent. Herein, we report our experience with a patient who presented with sternal osteomyelitis after infection with this elusive bug.

Incidence and predictors of forearm hematoma during the transradial approach for percutaneous coronary interventions

Background The transradial approach for percutaneous coronary intervention (TRA-PCI) reduces vascular complications compared with the transfemoral approach (TFA). Although hematoma formation is less frequent with the TRA than TFA, it is not uncommon, and its presentation ranges from mild hematoma to compartment syndrome. Incidence and predictors of hematoma have not been well studied. Methods and results The present study was conducted to prospectively evaluate the incidence and predictors of forearm hematoma after TRA-PCI. The study population consisted of consecutive patients undergoing TRA-PCI. Baseline and procedural characteristics and clinical outcomes were prospectively collected. All patients were observed for forearm/arm hematoma immediately after procedure, after band removal, before discharge, and whenever the patient complained of pain/swelling in the limb. Logistic regression analysis was performed to determine the predictors for hematoma formation. A total of 520 patients who had successfully completed TRA-PCI were included in the final analysis. The mean age was 55.2 ± 9.5 years, and 24% patients were women. Hematoma occurred in 53 (10.2%) patients. Hematomas were of grade I, II, III, and IV in 22 (4.2%), 9 (1.7%), 18 (3.5%), and 4 (0.8%) patients, respectively. On multivariate logistic regression analysis, age, body mass index, multiple puncture attempt, glycoprotein IIb/IIIa receptor blocker use, nonclopidogrel agent use for dual antiplatelet therapy, and multiple catheter exchanges emerged as independent predictors for hematoma formation. Conclusions Forearm hematoma following TRA-PCI occurs in about 10% patients. Most hematomas occur near the puncture area. The independent predictors for hematoma formation are age, body mass index, multiple puncture attempts, intensive antiplatelet therapy, and multiple catheter exchanges.

The dilemma of the “ischemic-looking” electrocardiogram: Pulmonary embolism or acute coronary syndrome?

Pulmonary embolism (PE) may be potentially fatal if not diagnosed and treated in time. Although specific electrocardiogram (ECG) findings often suggest the diagnosis of PE, occasionally, the ECG may mimic that of an acute coronary syndrome (ACS). We report an interesting case of a 45-year-old female presenting with sudden onset chest pain and shortness of breath with widespread ST depression in anterior precordial leads. Although initially treated and referred as a case of ACS, careful analysis of the ECG and subsequent echocardiography and computed tomography imaging confirmed the diagnosis of PE. Intensivists and cardiologists need to be aware that diagnostic dilemma between PE and ACS is not uncommon due to such “ischemic-looking” ECG as well as elevated troponin levels in both conditions. The use of multimodality imaging techniques is helpful in arriving at the correct diagnosis.

Heart rate manipulation in dilated cardiomyopathy: Assessing the role of Ivabradine

Background Heart rate (HR) reduction is of benefit in chronic heart failure (HF). The effect of heart rate reduction using Ivabradine on various echocardiographic parameters in dilated cardiomyopathy has been less investigated. Methods Of 187 patients with HF (DCM, NYHA II–IV, baseline HR > 70/min), 125 patients were randomized to standard therapy (beta blockers, ACEI, diuretics, n = 62) or add-on Ivabradine (titrated to maximum 7.5 mg BD, n = 63). Beta-blockers were titrated in both the groups. Results At 3 months both groups had improvement in NYHA class, 6 min walk test, Minnesota Living With Heart Failure (MLWHF) scores and fall in BNP, however the magnitude of change was greater in Ivabradine group. Those on Ivabradine also had lower LV volumes, higher LVEF (28.8 ± 3.6 vs 27.2 ± 0.5, p = 0.01) and more favorable LV global strain (11 ± 1.7vs 12.2 ± 1.1, p = <0.001), MPI (0.72 ± 0.1 vs 0.6 ± 0.1, p = <0.001), LV mass (115.2 ± 30 vs 131.4 ± 35, p = 0.007), LV wall stress (219.8 ± 46 vs 238 ± 54) and calculated LV work (366 ± 101 vs 401 ± 102, p = 0.05). The benefit of Ivabradine was sustained at 6 months follow up. The % change in HR was significantly higher in Ivabradine group (−32.2% vs −19.3%, p = 0.001) with no difference in blood pressure. Resting HR < 70/min was achieved in 96.8% vs 27.9%, respectively in the two groups. Conclusion Addition of Ivabradine to standard therapy in patients with DCM and symptomatic HF and targeting a heart rate < 70/min improves symptoms, quality of life and various echocardiographic parameters.

Pharmacological measures to increase HDL-C among high risk isolated low HDL cases: A randomized study amongst north Indians.

Background & objectives: Low serum levels of high density lipoprotein cholesterol (HDL-C) is an established risk factor for coronary heart disease (CHD). Among a variety of lipid modifying drugs, the best single drug therapy to increase HDL-C levels, especially among high risk, isolated low HDL-C (ILHDL-C) cases is yet to be identified. The objectives of the present study were to evaluate the best pharmacological measure among atorvastatin, fenofibrate and niacin aimed to raise HDL-C and its effect in decreasing the estimated Framingham-10-year CHD risk percentage (CHD-RP) among high risk ILHDL-C cases in north India. Methods: Two hundred CHD equivalent (CHD-RP≥20), ILHDL-C cases were randomly assigned for treatment either with atorvastatin 10 mg/day (n=70), micronized fenofibrate 160 mg/day (n=65) or niacin-extended release (ER) 750 mg/day (n=65). After 6 wk of treatment, the dosages of drugs were doubled and the patients were finally assessed after 12 wk for their lipid values. Results: Baseline characteristics were similar in the three groups. Niacin therapy 750 mg and 1.5 g/day resulted in a significant rise in HDL-C by 8.10 ± 3.19 and 12.41 ± 4.39 per cent (P<0.001), respectively. Fenofibrate 160 and 320 mg/day also resulted in a significant rise in HDL-C by 3.85 ± 3.48 and 6.24 ± 4.43 per cent (P<0.001), respectively, while atorvastatin 10 and 20 mg/day resulted in a non-significant increase in HDL-C by 0.13 ± 2.92 per cent and 0.51 ± 2.63 per cent, respectively. By increasing HDL-C values, niacin was found to be most effective in reduction of 10-year CHD-RP (P<0.001), followed by fenofibrate (P=0.010), while atorvastatin had no effect. Interpretation & conclusions: Our findings indicate that niacin rather than fibrates or statins seems to provide a safe and effective therapy for increasing HDL-C, thus reducing the cumulative CHD risk among ILHDL-C cases.

Metabolic syndrome & Framingham Risk Score Observations from a coronary angiographic study in Indian patients.

Background & objectives: Metabolic syndrome (MS) is an important determinant of cardiovascular (CV) risk. Framingham Risk Scores (FRS) often underestimate the CV risk in Asians, younger patients and those with MS. Asians often develop coronary artery disease (CAD) at a younger age and also have a high prevalence of MS. Only limited data are available on the relationship between MS and FRS in such patients and the present study was undertaken to report on this aspect in an Indian patient population with angiographically documented CAD. Methods: Two hundred patients undergoing coronary angiography during a three months study period were included. Diagnosis of MS was based on modified south Asian guidelines. Results: Of the 200 patients (age 56.5 ± 8.6 yr) undergoing coronary angiography, MS was diagnosed in 77 per cent n=154; abdominal obesity, low HDL and hypertension were the commonest of the diagnostic criteria of MS, being present in >70 per cent cases. Patients with MS had significantly higher mean FRS than those without MS (15.1 vs 8.65, P<0.0001). Most patients with MS (74%, n=148) had an intermediate to high 10-year CV risk (>10%) as estimated by FRS. The proportion of patients with MS progressively increased in those with low, intermediate and high FRS (61, 87 and 92%, respectively). Though the prevalence of MS was uniformly similar (74-84%) in all age groups (<45, 45-55, 55-65 and > 65 yr, respectively), amongst those <45 yr, none of the patients could be categorized as having high CV risk as estimated by FRS despite having angiographic CAD, highlighting the limitation of age dependence of FRS. Interpretation & conclusions: MS is common in Indian patients with angiographically documented CAD; most patients with MS have 10-year risk of >10 per cent as estimated by FRS. Though MS is uniformly prevalent across all age groups, using the FRS may underestimate the CV risk in Indian patients despite documented CAD. These findings have significant implications for Asian patients with CAD in whom onset of CAD is often at a younger age than their Western counterparts. There should be continued health care emphasis on detection of MS and intensification of targeted preventive strategies.

Cytochrome P450 (CYP2C9*2,*3) & vitamin-K epoxide reductase complex (VKORC1 -1639G<A) gene polymorphisms & their effect on acenocoumarol dose in patients with mechanical heart valve replacement.

Background & objectives: Studies have demonstrated the effect of CYP2C9 (cytochrome P450) and VKORC1 (vitamin K epoxide reductase complex) gene polymorphisms on the dose of acenocoumarol. The data from India about these gene polymorphisms and their effects on acenocoumarol dose are scarce. The aim of this study was to determine the occurrence of CYP2C9*2,*3 and VKORC 1 -1639G>A gene polymorphisms and to study their effects on the dose of acenocoumarol required to maintain a target International Normalized Ratio (INR) in patients with mechanical heart valve replacement. Methods: Patients from the anticoagulation clinic of a tertiary care hospital in north India were studied. The anticoagulation profile, INR (International Normalized Ratio) values and administered acenocoumarol dose were obtained from the clinical records of patients. Determination of the CYP2C9*2,*3 and VKORC1 -1639G>A genotypes was done by PCR-RFLP (restriction fragment length polymorphism). Results: A total of 111 patients were studied. The genotype frequencies of CYP2C9 *1/*1,*1/*2,*1/*3 were as 0.883, 0.072, 0.036 and that of VKORC1 -1639G>A for GG, AG, and AA genotypes were 0.883, 0.090, and 0.027, respectively. The percentage of patients carrying any of the variant alleles of CYP2C9 and VKORC1 in heterozygous or homozygous form was 34% among those receiving a low dose of ≤20 mg/wk while it was 13.8 per cent in those receiving >20 mg/wk (P=0.014). A tendency of lower dose requirements was seen among carriers of the studied polymorphisms. There was considerable variability in the dose requirements of patients with and without variant alleles. Interpretation & conclusions: The study findings point towards the role of CYP2C9 and VKORC1 gene polymorphisms in determining the inter-individual dose variability of acenocoumarol in the Indian patients with mechanical heart valve replacement.