Utility and pitfalls of the electrocardiogram in the evaluation of cardiac amyloidosis.

BACKGROUND: Cardiac amyloidosis is a protein misfolding disorder involving deposition of amyloid fibril proteins in the heart. The associated fibrosis of the conduction tissue results in conduction abnormalities and arrhythmias. "Classical" electrocardiogram (ECG) findings in cardiac amyloidosis include that of low voltage complexes with increased left ventricular wall thickness on echocardiography. However, this "classical" finding is neither sensitive nor specific. As cardiac amyloidosis is associated with a generally poor prognosis, the need for early recognition of this disease is important given the availability of new treatment options. In this review, we highlight 3 cases of patients with cardiac amyloidosis. Although presenting with typical clinical signs and symptoms, ECG for all 3 patients was not consistent with the classical findings described. They underwent further diagnostic tests which clinched the diagnosis of cardiac amyloidosis, allowing patients to receive targeted treatment. Through the review of the literature, we will highlight the different ECG patterns in patients with different types of cardiac amyloidosis and clinical scenarios, as well as the pitfalls of using ECG to identify the condition. Lastly, we also emphasize the current paradigms in diagnosing cardiac amyloidosis through the non-invasive methods of echocardiography, cardiac magnetic resonance imaging, and nuclear technetium-pyrophosphate imaging. CONCLUSIONS: Electrocardiogram is often the first investigation used in evaluating many cardiac disorders, including cardiac amyloidosis. However, classical features of cardiac amyloidosis on ECG are often not present. A keen understanding on the ECG features of cardiac amyloidosis and knowledge of the diagnostic workflow is important to diagnose this condition.

Prevalence and Risk Factors of Cardiac Amyloidosis in Heart Failure: A Systematic Review and Meta-Analysis.

AIMS: Heart failure (HF) is one of the leading causes of mortality worldwide. Heart failure is also one of the most common presentations of cardiac amyloidosis (CA). Contemporary epidemiological data of CA in HF patients is lacking. Hence, this systematic review and meta-analysis was conducted to determine the prevalence of amyloidosis in HF patients, and to clarify the risk factors of concomitant CA and HF. METHODS: A systematic review and meta-analysis was performed. Studies were retrieved from Medline, EMBASE, Scopus and Cochrane library. The search was not restricted in time, type or language of publication. The prevalence of CA in HF grouped according to diagnostic techniques and risk factors of CA with HF was analysed. RESULTS: Eleven (11) studies were included, involving 3,303 patients. The pooled prevalence of CA in HF was 13.7%. The overall prevalence of CA in HF with preserved ejection fraction was 15.1%, and that of HF with reduced ejection fraction was 11.3%. The main factors associated with the diagnosis of CA in HF included older age, males, raised NT pro-BNP, increased interventricular septal thickness in diastole, apical sparing, and reduced left ventricular systolic function. CONCLUSION: A high index of clinical suspicion is required to identify HF patients with CA. Supportive investigations may be helpful when clinically correlated. A considerable proportion of HF patients have CA and certain risk factors may be helpful in increasing suspicion of CA in HF.

Evaluating the Initiation of Sodium/Glucose Cotransporter 2 Inhibitors within 2 Weeks of an Acute Hospital Admission: A Systematic Review and Meta-Analysis of Nine Clinical Trials.

OBJECTIVE: Recent studies have increasingly shown the benefits of using sodium/glucose cotransporter 2 inhibitor (SGLT2i). However, there are concerns regarding the initiation of SGLT2i during acute hospital admissions due to the potential increased risk of complications. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of SGLT2i initiation within 2 weeks of an acute hospital admission. METHODS: Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched for articles published from inception up to 27 March 2021 that evaluated the efficacy and/or safety of SGLT2i initiation within 2 weeks of an acute hospital admission. Random-effects pair-wise meta-analysis models were utilized to summarize the studies. The protocol was registered with PROSPERO (CRD42021245492). RESULTS: Nine clinical trials were included with a combined cohort of 1,758 patients. Patients receiving SGLT2i had a mean increase in 24-h urine volume of +487.55 mL (95% CI 126.86-848.25; p = 0.008) compared to those not started on SGLT2i. Patients with heart failure treated with SGLT2i had a 27% relative risk reduction in rehospitalizations for heart failure, compared to controls (risk ratio 0.73; p = 0.005). There were no differences in other efficacy and safety outcomes examined. CONCLUSION: There was no increased harm with initiation of SGLT2i within 2 weeks of an acute hospital admission, and its use reduced the relative risk of rehospitalizations for heart failure in patients with heart failure. It was also associated with increased urine output. However, current evidence pool is limited, especially in specific population subtypes.

Comparing the clinical outcomes across different sodium/glucose cotransporter 2 (SGLT2) inhibitors in heart failure patients: a systematic review and network meta-analysis of randomized controlled trials.

PURPOSE: Empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin have been shown in randomized controlled trials to improve cardiovascular, metabolic, and renal outcomes in heart failure patients. To date, there has not been any meta-analysis examining the differences in clinical outcomes across different SGLT2 inhibitors in heart failure patients. METHODS: Four electronic databases (PubMed, Embase, Cochrane, SCOPUS) were searched on 13 September 2020 for articles published from 1 January 2000 to 13 September 2020 examining the effect of SGLT2 inhibitors on cardiovascular, renal, and metabolic outcomes in heart failure patients. Frequentist network meta-analysis was performed on extracted data. RESULTS: Ten randomized controlled trials were included with a combined cohort of 15,373 patients. In heart failure patients, frequentist network meta-analysis demonstrated no demonstrable difference in treatment effect across the SGLT2 inhibitors for heart failure hospitalization, cardiovascular deaths, composite of cardiovascular deaths and heart failure hospitalizations, all-cause mortality, and a composite of cardiovascular deaths and non-fatal myocardial infarction and non-fatal stroke. There was no demonstrable difference in treatment effect for worsening renal function or the weighted mean difference for weight, hemoglobin A1c, and systolic blood pressure. CONCLUSIONS: There were no demonstrable treatment differences across SGLT2 inhibitors across cardiovascular, renal, and metabolic outcomes, although this needs to be interpreted considering the wide confidence intervals, limited number of included studies, and heterogeneity present. Future research of different SGLT2 inhibitors in head-to-head studies is warranted to determine if there is a drug class effect.

Predicting first-year mortality in incident dialysis patients with end-stage renal disease - the UREA5 study.

We aimed to develop a risk prediction model for first-year mortality (FYM) in incident dialysis patients with end-stage renal disease. We retrospectively examined patient comorbidities and biochemistry, prior to dialysis initiation, using a single-center, prospectively maintained database from 2005-2010, and analyzed these variables in relation to FYM. A total of 983 patients were studied. 22% had left ventricular ejection fraction (LVEF) <45%. FYM was 17%, and independent predictors included URate <500 or >600 µmol/l, LVEF <45% (higher odds ratio if <30%), Age >70 years, Arteriopathies (cerebrovascular and/or peripheral-vascular diseases), serum Albumin <30 g/l, and Alkaline phosphatase >80 U/l (p < 0.05, C-statistic 0.74), and these constitute the acronym UREA5. Using linear modeling, risk weightage/integer of 3 was assigned to LVEF <30%, 2 to age >70 years, and 1 to each remaining variable. Cumulative UREA5 scores of ≤ 1, 2, 3, 4, and ≥ 5 were associated with FYM of 6, 8, 22, 31, and 46%, respectively (p < 0.0001). Increasing UREA5 scores were strongly associated with stepwise worsening of FYM after dialysis initiation.

Predictors of Mortality in Acute Myocardial Infarction Complicated by Cardiogenic Shock despite Intra-Aortic Balloon Pump: Opportunities for Advanced Mechanical Circulatory Support in Asia.

Introduction: Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) mortality remains high despite revascularization and the use of the intra-aortic balloon pump (IABP). Advanced mechanical circulatory support (MCS) devices, such as catheter-based ventricular assist devices (cVAD), may impact mortality. We aim to identify predictors of mortality in AMI-CS implanted with IABP and the proportion eligible for advanced MCS in an Asian population. Methods: We retrospectively analyzed a cohort of Society for Cardiovascular Angiography and Intervention (SCAI) stage C and above AMI-CS patients with IABP implanted from 2017-2019. We excluded patients who had IABP implanted for indications other than AMI-CS. Primary outcome was 30-day mortality. Binary logistic regression was used to calculate adjusted odds ratios (aOR) for patient characteristics. Results: Over the 3-year period, 242 patients (mean age 64.1 ± 12.4 years, 88% males) with AMI-CS had IABP implanted. 30-day mortality was 55%. On univariate analysis, cardiac arrest (p < 0.001), inotrope/vasopressor use prior to IABP (p = 0.004) was more common in non-survivors. Non-survivors were less likely to be smokers (p = 0.001), had lower ejection fraction, higher creatinine/ lactate and lower pH (all p < 0.001). On multi-variate analysis, predictors of mortality were cardiac arrest prior to IABP (aOR 4.00, CI 2.28-7.03), inotrope/vasopressor prior to IABP (aOR 2.41, CI 1.18-4.96), lower arterial pH (aOR 0.02, CI 0.00-0.31), higher lactate (aOR 2.42, CI 1.00-1.19), and lower hemoglobin (aOR 0.83, CI 0.71-0.98). Using institutional MCS criteria, 106 patients (44%) would have qualified for advanced MCS. Conclusions: Early mortality in AMI-CS remains high despite IABP. Many patients would have qualified for higher degrees of MCS.

Effects of sex on clinical outcomes of hypertrophic cardiomyopathy in Singapore.

Introduction: Despite the growing recognition that sex can affect the presentation and outcomes in hypertrophic cardiomyopathy (HCM), this relationship is understudied in Asians. Therefore, we aimed to explore sex differences in Asian patients with HCM. Method: A total of 295 consecutive patients diagnosed with HCM were recruited from a tertiary cardiology centre from 2010 to 2017 over a mean of 3.9±2.7 years. We evaluated the effects of sex on the outcomes of HCM in Asian patients. Results: HCM patients were more commonly men (72%). Women were older and had more comorbidities, including hypertension and atrial fibrillation. On transthoracic echocardiography, the indexed left ventricular end-systolic and end-diastolic volumes were similar, but more women had more-than-moderate mitral regurgitation and had a smaller left ventricular outflow tract (LVOT). Women more commonly had findings of obstructive physiology with significant LVOT obstruction, defined as >30 mmHg at rest. The use of implantable cardioverter defibrillators was similar across sexes. On multivariable analysis, women were found to be more likely to develop progressive heart failure requiring admission (hazard ratio [HR] 2.10, 95% confidence interval [CI] 1.05-4.71, P=0.021) but had a lower rate of all-cause mortality (HR 0.36, 95% CI 0.19-0.70, P=0.003). Conclusion: Women diagnosed with HCM were older, had more comorbidities and were more likely to develop heart failure while men had a higher risk of all-cause mortality.

Prevalence and outcomes of concomitant cardiac amyloidosis and aortic stenosis: A systematic review and meta-analysis.

OBJECTIVE: Cardiac amyloidosis (CA) is an increasingly recognised condition in patients with aortic stenosis (AS). However, there is a large variation in the reported prevalence figures, due to differences in populations and diagnostic methods. We aimed to investigate the prevalence, risk factors and outcomes of concomitant CA and AS. METHODS: We performed a systematic review and meta-analysis of the literature searched on MEDLINE, Embase, Scopus and CENTRAL. We analysed the prevalence of CA in patients with AS grouped according to the diagnostic techniques, and the risk factors and outcomes of concomitant CA and AS were analysed in AS patients referred for surgical or transcatheter aortic valve replacement (AVR). RESULTS: A total of 21 studies were included, involving 4,243 patients. The pooled prevalence of CA in patients with AS was 14.4%, with substantial heterogeneity. The pooled prevalence of AS in patients CA was 8.7%, with substantial heterogeneity. Patients with both AS and CA had higher all-cause mortality than those with AS or CA alone. In AS patients requiring AVR, CA was associated with increasing age, male sex, higher NT-proBNP levels, increased interventricular septal end diastole (IVSd) thickness and lower left ventricular ejection fraction. Concomitant AS and CA was associated with increased all-cause mortality and pacemaker implantation post-procedure. Study limitations included heterogeneity of the results and the fair to good quality of the studies published. CONCLUSION: Overall, a substantial proportion of patients with AS may have CA, and they have poorer prognosis. A high degree of clinical suspicion is needed to identify the "red flags" and perform appropriate diagnostic imaging.

Comparing Sacubitril/Valsartan Against Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure: A Systematic Review and Network Meta-analysis.

BACKGROUND AND OBJECTIVE: In recent trials, sodium-glucose cotransporter 2 (SGLT2) inhibitors proved effective as treatment for heart failure. However, the relative efficacy of sacubitril/valsartan against SGLT2 inhibitor in patients with heart failure remains unknown. Hence, we performed a network meta-analysis to compare the effects of sacubitril/valsartan against SGLT2 inhibitors on cardiovascular outcomes in patients with heart failure. METHODS: Four electronic databases (PubMed, Embase, Cochrane, SCOPUS) were searched for randomised-controlled trials (RCTs) published from 1st January 2000 to 25th September 2021. Two additional systematic reviews were conducted for RCTs of enalapril and valsartan to establish a common comparator arm. Frequentist network meta-analysis models were utilised to summarise the studies. RESULTS: Twenty-five RCTs were included, comprising a combined cohort of 47,275 patients. Network meta-analysis demonstrated that compared to SGLT2 inhibitors, sacubitril/valsartan achieved a larger hazard rate reduction in the composite of heart failure hospitalisation and cardiovascular death (hazard ratio [HR]: 0.86; 95% CI 0.75-0.98), cardiovascular death (HR: 0.78; 95% CI 0.65-0.94), and a larger mean change in systolic blood pressure at 8 or more months (weighted mean difference [WMD]: - 7.08 mmHg; 95% CI - 8.28 to - 5.89). There were no significant differences in treatment effects across heart failure hospitalisation, all-cause mortality, diastolic blood pressure at 12 weeks, and systolic blood pressure at 2-4 months. In patients with heart failure with reduced ejection fraction, sacubitril/valsartan achieved a 20% hazard rate reduction for cardiovascular death compared to SGLT2 inhibitors. CONCLUSIONS: In patients with heart failure, sacubitril/valsartan was demonstrated to be superior to SGLT2 inhibitors in the treatment effect for the composite of heart failure hospitalisation and cardiovascular death, cardiovascular death, and long-term blood pressure.

Nitrates in combination with hydralazine in cardiorenal syndrome: a randomized controlled proof-of-concept study.

AIMS: Cardiorenal syndrome (CRS) is a common problem of great morbidity and mortality. Hydralazine-isosorbide dinitrate (H-ISDN) may be used in renal failure and may improve exercise capacity in heart failure (HF). Our proof-of-concept study aimed to evaluate early evidence of efficacy, safety, and feasibility of H-ISDN compared with standard of care in CRS. METHODS AND RESULTS: This multi-centre, single-blind, randomized trial in Singapore enrolled CRS patients, defined as chronic HF with concomitant renal failure [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 ]. The primary outcome was 6 min walk test (6MWT) distance measured at 6 months. Secondary outcomes included study feasibility; efficacy outcomes which included renal, cardiac, and endothelial functions, health-related quality of life using Short Form-36, clinical outcomes; and adverse events. Forty-four patients [71 ± 10 years; 75% male; median (inter-quartile range) N-terminal prohormone brain natriuretic peptide 1346 (481-2272) pg/mL] with CRS (left ventricular ejection fraction 42 ± 12% and eGFR 46 ± 15 ml/min/1.73 m2 ) were randomized into two equal groups. Of these, 39 (89%) had hypertension, 27 (61%) had diabetes mellitus, and 17 (39%) had atrial fibrillation. Six (27%) discontinued H-ISDN owing to intolerance and poor compliance. There was a trend towards improved 6MWT distance with H-ISDN compared with standard of care at 6 months (mean difference 27 m; 95% CI, -12 to 66), with little differences in secondary efficacy outcomes. Giddiness and hypotension occurred more frequently with H-ISDN, but HF hospitalizations and mortality were less. CONCLUSIONS: Our pilot study does not support the addition of H-ISDN on top of standard medical therapy to improve exercise capacity in patients with CRS.