Clinical characteristics, etiological profile, treatment and long term outcomes in patients with non ischemic systolic heart failure; Himachal Pradesh heart failure registry (HP–HF registry)

Abstract

Background

The data on clinical characteristics, treatment practices and out comes in patients with Non- ischemic Systolic Heart Failure (NISHF) is limited. We report clinical characteristics, treatment and outcomes in patients with NISHF.

Methods

1004 patients with NISHF were prospectively enrolled and their demographics, clinical characteristics, and treatment were recorded systematically. Patients were followed annually for a median of 3 years (1 year to 8 years) for allcause death, major adverse cardiovascular events (MACE); composite of all-cause death, hospitalization of heart failure, and or for stroke.

Results

Patients of NISHF were middle-aged (58.8±16.2 years) population with severely depressed left ventricular ejection fraction (29.3±7.02%) and 31.1% had symptoms of advanced Heart failure. Hypertension (43.6%), obesity and or overweight (28.0%), Diabetes (15.0%), and valvular heart disease (11.8%) were the common risk factors. The guideline directed medical treatment was prescribed in more than 80% of the study cohort. Incidence of all cause death and MACE was 7 (6.8, 8.8) per 100 person years and 11(10, 13) per 100 person years respectively. The cumulative incidence of deaths and MACE was 35% (30%, 40%) and 49% (44%, 53%) at 8 years of follow-up.

Conclusions

Patients of NISHF were middle-aged population with severely depressed LV systolic function with significant incident morbidity and mortality. Early detection of risk factors and their risk management and enhancing the use of guideline directed treatment may improve the outcomes. Keywords: Non-ischemic systolic heart failure, risk factors, outcomes, guideline directed treatment.

1. Introduction

Heart failure (HF) is a major cause of morbidity and mortality globally and has diverse etiologies, with varied outcomes. Ischemic heart disease is the major cause of heart failure with reduced ejection fraction (HFrEF) globally.¹ Non-ischemic systolic heart failure is the result of heart muscle dysfunction secondary to exposures to; abnormal loading conditions, toxins, metabolic insults, inflammatory injury, infiltrative disorder, hereditary and or mixed etiologies.

The number of registry studies has reported variable incidences of mortality^{1, 2, 3, 4.} The variability in the mortality rates is related to differences in the severity of the heart failure population enrolled (hospitalized vs. outpatient population), ischemic vs. non-ischemic HF, use of guideline directed medical therapy, availability, and access to quality health care services.

The data on clinical characteristics, treatment practices, and outcomes in patients with non-ischemic systolic heart failure is sparse.^2,3 The available contemporary data from India are from a select cohort of high-risk inpatients of HFrEF of ischemic and non-ischemic etiology, admitted with acute decompensated heart failure.^1,4 The data on clinical characteristics, treatment, and long-term outcomes in patients with HFrEF of non-ischemic etiology from India and other low-income countries is lacking.

We report the clinical characteristics, etiological profile, treatment practices, and long term outcomes in patients with non-ischemic systolic heart failure both stable compensated heart failure and acute heart failure and or acute decompensated chronic heart failure seen in tertiary care hospitals in the northern state of India enrolled prospectively and followed annually for predefined outcomes.

2. Methods

2.1. Study design, setting, and patient population

This is a single-center, tertiary care, prospective registry, and longitudinal follow-up of patients with non-ischemic systolic heart failure (NISHF) started in Jan 2011. The registry center is the only tertiary care center in the state of Himachal Pradesh, India, catering to about two-thirds of the state population of about 7 million. All patients with symptoms of heart failure seen at primary and secondary care hospitals in the state are referred to this center for evaluation and management. Thus the data captured about the clinical characteristics, treatment, and outcomes have a fair representation of patients with NISHF in general.

All consecutive patients with HFrEF of non-ischemic etiology admitted with the diagnosis of acute heart failure or decompensated chronic heart failure and or patients with compensated heart failure visiting outpatient clinic of the cardiology department of the registry center were enrolled after obtaining informed consent. The study protocol was approved by the institutional ethical committee.

The non-ischemic systolic heart failure (NISHF) was diagnosed based on the presence of signs and symptoms of heart failure associated with LVEF of less than 40% of non-ischemic etiology The ischemic etiology of systolic heart failure was excluded based on; the absence of obstructive coronary artery disease (CAD) on coronary angiography done in all patients age 40 years and above and those with history of angina in the age group of less than 40 years. The obstructive CAD was defined as luminal diameter narrowing of more than 50% in any one of the major epicardial coronary arteries. Patients with a history of documented myocardial infarction, history of coronary bypass graft surgery (CABG), percutaneous coronary intervention (PCI), and or evidence of regional wall motion abnormalities on echocardiography were also excluded.

2.2. Data collection

The data was collected in all eligible patients consenting to participate after informed consent. The socio-demographic, risk factors of heart failure, clinical characteristics, treatment prescribed were recorded systematically as per pre-designed data recording format. The examination included the recording of weight, height, blood pressure (BP), using validated tools and 12 lead surface electrocardiograms (ECG) to record, the presence of atrial fibrillation, atrioventricular, and his bundle conduction block, and QRS complex duration. The detailed 2D and Doppler echocardiograms were done using I 33 echo machine of Phillips private limited with phased array broadband probes. The LV systolic function was estimated by measuring ejection fraction (EF) using Simpson's biplane method in apical four and two-chamber view. LVEF of ≤40% was used as the cutoff level for diagnosing LV systolic dysfunction. The detailed evaluation of valvular function was done using 2 D guided color flow imaging, and Doppler examination to document the presence and severity of valvular incompetence and obstruction. The severity of valvular dysfunction was assessed using the American Association of Echocardiography criteria.⁵ The blood biochemistry estimation included measurement of glucose, serum creatinine, electrolytes, hemoglobin in all consecutive patients after overnight fasting state. The specific tests were conducted as per the clinical profile of the patients.

2.3. Follow up

Patients were followed annually in person in the outpatient clinic and or telephonically to record outcomes. The outcomes recorded were; all-cause death, hospitalization for heart failure, and or stroke/peripheral thromboembolism. ECG and echocardiography were repeated annually in all patients visiting in person to the registry center.

2.4. Outcomes definitions

2.4.1. Hospitalization for heart failure

Patients with worsening symptoms of heart failure with features of pulmonary and or systemic venous hypertension requiring hospitalization for administration of intravenous diuretics and or inotropes.

2.4.2. Stroke and or peripheral embolism

Stroke was diagnosed based on physician documented acute onset focal neurological deficit may or may not be substantiated by neuro-imaging. Peripheral embolism was labeled if patients had a history of sudden onset of ischemic symptoms associated with loss of palpable pulse of affected limb/and or evidence of absent Doppler signals/blood flow in angiography of affected site after reviewing available medical records.

2.4.3. All-cause death

Deaths due to cardiovascular or non-cardiovascular causes.

2.5. Etiological/heart failure risk factors evaluation

Each patient was evaluated clinically for following etiological risk factors systematically at enrollment and specific confirmatory laboratory investigations were carried out if indicated clinically.

• •Hypertension: Patients were labeled hypertensive if they were diagnosed to have hypertension in past and were on antihypertensive drugs. Patients with the systolic blood pressure of more than 140 mmHg systolic and or diastolic blood pressure of more than 90 mmHg at enrollment.
• •Diabetes: Patients were labeled as diabetic if were on oral hypoglycemic drugs or Insulin and or those having fasting glucose of more than 126 mg/dl.
• •Valvular heart disease: Patients with primary valvular heart disease with severe stenotic and or incompetence of aortic valve and incompetence of mitral valve with LVEF of less than 40% were labeled as HFrEF of valvular etiology. The patients with Rheumatic or non Rheumatic valvular etiology were labeled as valvular heart disease.
• •Thyroid disorders: Symptoms of hyper and hypothyroidism were evaluated clinically and thyroid function tests were done if suspected. Patients on thyroid hormone supplementation or anti-thyroid treatment were labeled as hypo or hyperthyroidism respectively.
• •Alcoholic cardiomyopathy: Patients with a self-reported history of consumption of standard alcohol drinks more than two pegs a day and more than 5 days a week for more than 5 years were labeled as harmful consumption of alcohol.
• •Anthracycline-induced cardiomyopathy: Patients with malignancy with a history of receiving an Anthracycline-based chemotherapy regimen with LVEF of less than 40%.
• •Human immunodeficiency virus (HIV) infection: Patients with diagnosed HIV infection with LVEF less than 40% were labeled as HIV induced cardiomyopathy
• •Non compacted LV: Patients with non-compacted LV with the ratio of non-compacted to compacted myocardium of more than 2:1 affecting more than one segment of LV were diagnosed as non-compacted LV.
• •Hereditary cardiomyopathy: patients with first degree relatives with DCM were labeled with hereditary cardiomyopathy
• •Infiltrative cardiomyopathy: Patients with echo evidence of LV hypertrophy were investigated for amyloid heart disease and storage disorders if they had no risk factors for LV pressure overload.
• •Connective tissue disorders (CTD): Patients with clinical manifestation of CTD supported by lab investigations with LVEF of less than 40% were labeled as CTD induced HFrEF.
• •Tachycardia-induced cardiomyopathy: Patients of HFrEF associated with atrial fibrillation fast ventricular rate, frequent VPCs, couplets or triplets, if on treatment LVEF improves with control of HR and decrease of VPCs were labeled as tachycardia-induced cardiomyopathy.
• •Peripartum cardiomyopathy: was diagnosed if LVEF was less than 40% in pregnant women after the 2nd trimester up to 6 months postpartum.

2.6. Data analysis

The data of patients enrolled from Jan. 2011 to Dec. 2018 was analyzed. A total of 1149 patients with heart failure with reduced ejection fraction with suspected NISHF were screened for enrollment. 24 patients were excluded due to obstructive CAD on coronary angiography. Out of the remaining 1125 patients, 121 were excluded due to missing data. Thus finally data of 1004 patients were analyzed for reporting.

The categorical data are reported as counts and percentages, while continuous variables as mean±sd. The incidence of outcomes was estimated by calculating the earliest time to outcome and data was censored after the occurrence of the first outcome and or at the end of follow-up. The incidence of outcomes was reported as the number of events per 100 years persons. The cumulative incidence of all cause death, hospitalization for heart failure, stroke and composite of all cause mortality, HHF and or stroke was estimated and was reported as percentage and 95% C.I. over 8 years of follow up. The clinical characteristics as the risk predictors were estimated by calculating adjusted hazard ratios, using Cox proportional hazard model by entering all the covariates that were found to have an association with outcomes at a significance level of <0.1 in univariate analysis. The two-sided significance of <0.05 was taken as statistically significant. The statistical analysis was done using statistical software STAT version 13.

3. Results

3.1. Socio-demographic, clinical characteristics, and treatments

The details of socio-demographics, risk factor distribution of the study population are reported in Table 1 and the clinical characteristics and treatment prescribed are reported in Table 2. In brief, the non-ischemic systolic heart failure is a middle-aged (58.8 ± 16.2 years) population without significant gender predilection, 549 (55%) were male. The majority had an education level below the primary level. About two-thirds of the study population had associated risk factors. Hypertension, Diabetes, obesity, valvular heart disease, and harmful consumption of alcohol were the more common risk factors. The toxins, infections, hormonal, tachycardia-induced cardiomyopathy, hereditary and congenital causes formed less than 10% of the attributable risk factors. Chronic kidney disease stage III and above and anemia were the commonly associated co-morbidities. About one-third of the cohort had no apparent risk factors having primary dilated cardiomyopathy (DCM).

Table 1.

Baseline distribution of socio-demographic, risk factor profile of study cohort.

Characteristics	Number of participants with missing data	Overall cohort n = 1004 % (95% C.I.)
Demographics
Sex (male)	Nil	54.6% (51.5%, 57.8%)
Age groups	Nil
≤20 years		2.2% (1.4% 3.4%)
21–30 years		3.4% (2.4% 4.8%)
31–40 years		5.8% (4.5% 7.6%)
41–50 years		14.3% (12.3% 16.7%)
51–60 years		25.4% (22.8% 28.2%)
≥61 years		48.8% (45.7% 51.9%)
Age (mean±sd)	Nil	(58.8 ± 16.2)
Education level	Nil
Below primary (≤5 years of schooling)		60% (55.8% 62.0%)
Middle (6–8 years of schooling)		13% (11.1% 15.3%)
High (9th to 12 years of schooling)		15.8% (13.7% 18.3%)
Higher (≥13 years of regular schooling)		12.1% (10.2% 14.4%)
Number of patients enrolled from in hospital admissions	Nil	204 (20.3%)
Urban background	Nil	7.0% (5.5% 8.8%)
Risk factors
Diabetes	Nil	15% (12.8%, 17.3%)
Hypertension	Nil	43.6% (40.5%, 46.8%)
Overweight (BMI of 25–29.9)	137	20.4% (17.3%, 23.3%)
Obesity (BMI≥30)	137	7.6% (6.0%, 9.6%)
Central obesity	543	40% (35.2% 44.3%)
Harmful Alcohol intake	Nil	10.6% (8.8%, 12.7%)
Valvular heart disease	Nil	11.8% (10.2% 14.3%)
Miscellaneous Risk factors	Nil	81 (8.4%)
Hypothyroidisms		5% (3.5% 6.2%)
Hyperthyroidism		0.2% (0.1% 0.3%)
Peripartum Cardiomyopathy	Nil	2.0% (1.0% 3.9%)
Non compacted Left ventricle	Nil	0.9% (0.4% 1.8%)
Anthracycline induced cardiomyopathy	Nil	6 (0.6%)
Family history of Cardiomyopathy	Nil	0.3% (0.1% 0.9%)
History of HIV	Nil	0.2% (0.0% 1.8%)
Tachycardia induced cardiomyopathy	Nil	0.2% (0% 1.8%
Primary dilated cardiomyopathy	Nil	28% (25.2% 30.8%)
Co morbidities
CKD stage (eGFR <60 ml/min/1.73 M2	643	58.7% (53.4% 63.8%)
CKD stage IV and or V		44/361
Anemia	182	48.3% (44.8% 51.8%)

Table 2.

Clinical, electrocardiographic, echocardiographic characteristics and treatment practices of the study cohort.

Characteristics	Number of patients with missing data	Overall study cohort n = 1004 % (95% C.I.)
NYHA functional Class	Nil
Class I		5.3% (4.0% 6.9%)
Class II		63% (59.8% 65.8%)
Class III		21.7% (19.2% 24.4%)
Class IV		10.1%
Angina	10	25.0% (22.4% 27.9%)
History of Syncope	Nil	9.85% (8.1% 11.9%)
Past CVA/peripheral embolism	Nil	2.3% (1.5% 3.5%)
Electrocardiogram	174
Atrial Fibrillation		13.6% (11.4% 16.2%)
Complete heart block		0.9% (0.4% 2.0%)
Left bundle branch block (LBBB)		33.1% (29.9% 36.5%)
Right Bundle branch block (RBBB)		4.0% (2.8% 5.7%)
QRS duration (mean±sd) milliseconds	245	107.1 ± 33.9
QRS duration (≥150 ms)		17.6% (15.0% 20.5%)
Echocardiography	Nil
LVEF (mean±sd)	Nil	29.3% ± 7.02%
LVEF ≤20%	Nil	13.6% (11.6% 16.0%)
LVEF (21%–30%)	Nil	40.08% (37.1% 43.3%)
LVEF ≥31%–40%)	Nil	46.2% (43.1% 49.4%)
TAPSE	389	17.6 ± 6.88
Right ventricular dysfunction	389	36.9% (33.1% 40.9%)
Right Heart Failure	204	25.5% (22.6% 28.8%)
Tricuspid regurgitation)	6	58.7% (55.5% 61.8%)
PAH (TR velocity≥3.0 m/s)	6	44.7% (40.5% 49.0%)
Severe Mitral Regurgitation	Nil	11.5% (9.7% 13.8%)
Moderate AR	Nil	6 (0.6% (0.2% 1.4%)
Severe Aortic stenosis	Nil	3 (0.3% (0.1% 1.0%)
E/e’ (≥15) yes	507	59% (54.5% 63.3%)
Blood biochemistry
Hyponatremia (≤134 meq/L)	194	11.6% (9.5% 14.1%)
Hyperkalemia (≥5.5 meq/L)	195	11.5% (9.5% 14.0%)
Hypokalemia (≤3.4 meq/L)	195	6.33% (4.8% 8.3%)
Hyperuricemia (≥7.0 mg/dl)	419	48.7% (44.6% 52.8%)
Hypocalcaemia (≤8.0 mg/dl)	430	17.4% (14.5% 20.8%)
Treatment
Beta-Blockers	187	81.3% (78.8% 83.7%)
Rennin angiotensin Aldosterone system	201	80% (73.3% 82.4%)
Mineralocorticoid receptor antagonist	239	76.2% (73.5% 78.8%)
Automatic intracardiac defibrillator	2	0.3% (0.1, 1.0%)
Cardiac resynchronization therapy	2	0.2% (0.0% 1.8%)

Abbreviations: LVEF; left ventricular ejection fraction, TAPSE; tricuspid annular peak systolic excursion, PAH; pulmonary artery hypertension.

About one-third of the cohort was severely symptomatic (New York Heart Association class (NYHA) III/IV). The left ventricular ejection (LVEF) was severely depressed in more than 50% of the cohort. The diastolic dysfunction with an elevated ratio of E/e' was recorded in about two-thirds of the study cohort. The patients of NISHF were complicated with atrial fibrillation in 13.6% and 2.3% had a history of stroke/systemic thromboembolism. About two-thirds had evidence of tricuspid regurgitation (TR) out of which 44.7% had evidence of pulmonary artery hypertension (PAH). Right ventricular (RV) systolic dysfunction and features of Right heart failure were observed in more than one-third and about one-fourth of the study cohort respectively.

Left bundle branch block (LBBB) was the most common conduction defect of bundle branches (33.1%), atrio-ventricular block was recorded in 8 (0.97%) of the cohort.

The raised uric acid level was recorded in about 50% of the patients and about one-fifth had Hypocalcaemia. Hyperkalemia was more frequent than Hypokalemia. Hyponatremia was observed in 11.6%. The Beta-blockers and RAAS inhibitors were prescribed in about 80% and Mineralocorticoid receptor antagonists (MRA) in 76% of the cohort. The use of device-based treatment was recorded in a very small fraction of the cohort.

3.2. Outcomes

The details of incidences of outcomes are reported in Table 3. In brief, the Incidence of all cause mortality was 7 per 100 person years (6.8, 8.8 per 100 person years), with a cumulative incidence of 35% (30%, 40%) at 8 years of follow up. The incidence of HHF was 5 per 100 person years (4, 6 per 100 person years) and cumulative incidence of 25% (21.6%, 30%). The incidence of the composite of death, HHF, and stroke was 11 per 100 person years (10–13 per 100 person years) with a cumulative incidence of 49% (44%, 53%). Incidence of stroke was 0.3 per 100 person years (0.1–0.8 per 100 person years) with cumulative incidence of 1.7% (0.8%, 3%)

Table 3.

Incidence rate (per 100 person years) and cumulative incidence, percent (95% confidence interval) of Major adverse cardiovascular events (MACE), all cause death, hospitalization for heart failure (HHF), and stroke at a median follow up period of 3.0 years (range 1–8 years).

Outcomes	Incident cases	Person years	Incidence rate/100 person years (95% C.I.)	Cumulative incidence % (95% C.I.)
Composite of all cause death, HHF and or stroke) MACE	356	3018	11 (10, 13)	49 (44, 53)
All-cause death	234	3018	7 (6.8, 8.8)	35 (30, 40)
Hospitalization for heart failure (HHF)	167	3018	5 (4, 6)	25 (21.6, 30)
Stroke	10	3018	1.7 (0.8, 3)	3 (1,6)

3.3. Risk predictors of outcomes

The details of adjusted predictors of all-cause death and composite of all-cause death, hospitalization of heart failure (HHF), and or stroke as major adverse cardiac events (MACE) are reported in Table 4. The risk of mortality was significantly higher in males and the elderly population. Patients with a history of Hypertension and higher systolic blood pressure and those who were overweight at baseline had significantly lower mortality rates. The risk of mortality was significantly higher in patients with a history of diabetes, symptoms of advanced heart failure, CKD, hyperuricemia at baseline. The predictors of MACE were similar as for mortality risk.

Table 4.

Adjusted predictors of all-cause deaths and composite of all-cause death, hospitalization of heart failure, and or stroke (MACE).

	All-cause death	MACE
Risk factors	H.R. (95% C.I.)	H.R. (95% C. I.)
Age	1.01 (1.00–1.02)	1.01 (1.00–1.01)
Sex (male)	1.33 (1.02–1.73)	1.13 (0.91–1.39)
Hypertension	0.72 (0.55–0.95)	0.92 (0.74–1.13)
Diabetes	1.60 (1.16–2.20)	1.39 (1.06–1.82)
NYHA class III/IV	1.55 (1.19–2.01	1.48 (1.19–1.83)
Right Heart Failure	1.76 (1.32–2.32)	1.74 (1.38–2.19)
BMI category
≤25	Reference	Reference
25.1–29.9	0.61 (0.41–0.92)	0.79 (0.58–1.06)
≥30	1.19 (0.75–1.91)	1.18 (0.80–1.73)
SBP	0.99 (0.98–0.99)	0.99 (0.98–0.99)
CKD (≥stage III)	2.11 (1.29–3.43)	1.41 (0.91–2.2)
Hyperuricemia	1.95 (1.44–2.65)	1.59 (1.25–2.03)
LVEF	0.99 (0.97–1.00)	0.99 (0.98–1.00)
MRA	0.76 (0.56–1.02)	0.98 (0.75–1.26)
RAAS inhibitors	0.86 (0.62–1.21)	0.96 (0.72–1.28)
Beta blockers	0.75 (0.54–1.04)	0.83 (0.63–1.09)

Abbreviations: NYHA; New York Heart Association, BMI; body mass index, SBP; systolic blood pressure, CKD; chronic kidney disease, LVEF; left ventricular ejection fraction, MRA; Mineralocorticoid receptor antagonist, RAAS; rennin angiotensin Aldosterone system.

4. Discussion

The patients of HFrEF of non-ischemic etiology are middle age population without significant gender predilection, with frequent symptoms of advanced heart failure and severely depressed LV systolic function. Hypertension, Diabetes, obesity, valvular heart disease, and harmful alcohol consumption were the most frequent risk factors. Toxins, infections, hereditary, hormonal, and tachycardia-induced cardiomyopathy formed a small percentage of the attributable risk factors. The use of guideline directed drugs was higher and annual incidence of all cause mortality was lower than reported in other registries ^1,4,25.

The data on risk factors recorded systematically in patients with HFrEF of non-ischemic etiology is lacking. Hypertension and Diabetes were also observed to be common risk factors associated with Heart failure of non-ischemic etiology ^{2, 3.}

In a study population of patients with HFrEF enrolled in the PARADIGM-HF trial, dilated cardiomyopathy (DCM) constituted about 19% of the overall study population and 47% of non-ischemic HFrEF.⁶ Significant geographical variations in the prevalence of non-ischemic DCM have been reported with the highest prevalence of 28% in the Asian Pacific region and lowest in Europe and Northern America (14%).6, 7 In the present registry, about one-third of the cohort had DCM without any apparent risk factors.

The LV systolic function is severely depressed in a cohort of patients with non-ischemic systolic heart failure.2, 8, 9 In the present registry, about 50% of the study cohort had LVEF less than 30%. The Right ventricular dysfunction was recorded in about one-third of the study cohort and about one-fourth had clinical signs of Right heart failure. Patients of HFrEF with Right heart failure are a high-risk population for adverse outcomes.¹⁰

The patients of HFrEF are often complicated with pulmonary arterial hypertension (PAH). The prevalence of PAH has been reported variably; ranging from 14% to 18% in large studies mostly from outpatient clinics to 54–73% in smaller cohorts comprised of DCM with advanced heart failure.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 In the present registry, 44% had PAH among those with tricuspid regurgitation.

The significant geographical variations in the prevalence of His bundle conduction defects and atrial fibrillation have been reported in patients of HFrEF.^15,22,23,25 In the present registry, LBBB was the most common conduction defect (31%) followed by RBBB (7.1%). LBBB was also reported to be the commonest His bundle conduction defect in patients with HFrEF in South Asian patients (20.3%) compared to North-East Asian (11.9%) and Southeast Asians (11.2%).¹ In a study population of non-ischemic HFrEF from Latin America enrolled in PARADIGM-HF and ATMOSPHERE Trial 31% had LBBB and 21.8% had atrial fibrillation.⁶ The prevalence of atrial fibrillation in patients with HFrEF reported from Northern European countries is higher compared to the present registry (27.0% vs. 13.6%) ^22. The Asian HF registry reported variable prevalence of atrial fibrillation; the lowest in South Asians (4.2%) compared to North-East Asian (30.2%) and Southeast Asian (17.6%) patients with HFrEF.¹

The incidence of mortality was significantly lower in the present cohort of patients with NISHF compared to mortality rates reported in inpatients with HFrEF from southern India ^{4, 25.} The incidence of all cause death and the composite of all cause deaths and or HHF was 10.8 per 100 person years and 12.5 per 100 person years respectively in the Latin American cohort of non-ischemic HFrEF.1, 2 The one-year mortality rate was higher in both inpatients and outpatients of the Indian cohort of heart failure enrolled in the INER-CHF registry compared to the present registry.¹ The all-cause death was similar to the cohort of HFrEF from the South Asian region in the Asian HF registry (7.5%).²⁴ The cumulative incidence of mortality in the present registry at 8 years was lower compared to patients with HFrEF reported at 3 years (35% vs. 46.2%) reported in the Trivandrum heart failure registry (THFR) from south India.²⁵ The THFR was a cohort of in-patients with acute heart failure unlike present registry thus was high risk patients having higher mortality rate.

The use of beta-blockers (55.9% vs.81.3%) and Rennin Angiotensin Aldosterone system (RASS inhibitors) (47.2% vs. 80.0%) were significantly lower in THFR compared to the present registry. The use of beta-blockers and RAAS inhibitors was similar to the Asian HF registry cohort however use of Mineralocorticoid receptor antagonist (MRA) was lower in the present registry.

Although a substantial proportion of the patients had LBBB, numbers receiving cardiac resynchronization therapy (CRT) were dismal. This probably is related to affordability issues and a higher threshold for CRT implantation by treating Cardiologists.

Present registry substantiates the prognostic value of LVEF, NYHA functional class III/IV, RHF, associated co-morbidities; CKD, Diabetes, and elevated uric acid levels as independent risk predictors of mortality reported in previous registries in patients with HFrEF.^1,10,24,26 The mortality rate was lower in patients with a history of Hypertension and higher baseline SBP and those with overweight compared to cohort with BMI ≤25 kg/M².

The findings of present registry data of patients with HFrEF of non-ischemic etiology reported from the northern state of India have important implications. Early detection and risk management of the modifiable risk factors identified and optimization of guideline directed treatment may reduce the incidence of NISHF and associated morbidity and mortality.

5. Limitations

This was a single-center registry data and 136 patients were lost to follow up, thus there is an element of selection bias. However, this is the only registry study with a large sample size reported to date in patients with NISHF from India.

6. Conclusion

Patients of NISHF are the middle-aged population with severely depressed LV systolic function and frequent symptoms of advanced heart failure. About two-thirds had associated modifiable risk factors. The use of guideline directed treatment is sub-optimum. The incidence of mortality is lower than reported from registry studies from India and other low-income and middle-income countries. Patients with severe heart failure, RHF, the elderly population, Diabetics, and those with CKD were at higher risk of mortality.

Funding source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Credit author statement

PCN was involved in the conception and design of the study. AG, MR, SA, NG, RM, RS and AK helped in acquisition of data. PCN, MR analyzed the data, reviewed the literature and wrote the manuscript. All the authors read and approved the final manuscript.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.