Precipitating Factors Leading to Hospitalization and Mortality in Heart Failure Patients: Findings from Gulf CARE.

Aim: To investigate the precipitating factors that contribute to hospitalization and mortality in postacute heart failure (AHF) hospitalization in the Middle-East region.
Methods: We evaluated patient data from the Gulf AHF registry (Gulf CARE), a prospective multicenter study conducted on hospitalized AHF patients in 47 hospitals across seven Middle Eastern Gulf countries in 2012. We performed analysis by adjusting confounders to identify important precipitating factors contributing to rehospitalization and 90- to 120-day follow-up mortality.
Results: The mean age of the cohort (n = 5005) was 59.3 ± 14.9 years. Acute coronary syndrome (ACS) (27.2%), nonadherence to diet (19.2%), and infection (14.6%) were the most common precipitating factors identified. After adjusting for confounders, patients with AHF precipitated by infection (hazard ratio [HR], 1.40; 95% confidence interval [CI] 1.10-1.78) and ACS (HR-1.23; 95% CI: 0.99-1.52) at admission showed a higher 90-day mortality. Similarly, AHF precipitated by infection (HR-1.13; 95% CI: 0.93-1.37), and nonadherence to diet and medication (HR-1.12; 95% CI: 0.94-1.34) during hospitalization showed a persistently higher risk of 12-month mortality compared with AHF patients without identified precipitants.
Conclusion: Precipitating factors such as ACS, nonadherence to diet, and medication were frequently identified as factors that influenced frequent hospitalization and mortality. Hence, early detection, management, and monitoring of these prognostic factors in-hospital and postdischarge should be prioritized in optimizing the management of HF in the Gulf region. Copyright:

INTRODUCTION

Precipitating factors contributing to exacerbations of heart failure (HF) are associated with substantial morbidity and mortality. Understanding precipitants that contribute to rehospitalization and mortality is important and could have a positive influence on HF disease management. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry has identified ischemia and worsening renal function as precipitating factors for rehospitalization associated with increased risk of 60- to 90-day mortality after discharge.[1] However, to change the outcomes post-HF hospitalization, more research is needed for the early recognition of precipitating factors for rehospitalization and mortality. Identifying patients at early stages of HF would allow the implementation of more aggressive risk management strategies and should also decrease the progression to symptomatic disease. Several large registries such as Acute Decompensated Heart Failure National Registry, OPTIMIZE-HF, the American Heart Association's ongoing Get with the Guidelines – heart failure (GWTG-HF) registry and the most recent European Society of Cardiology Heart Failure Long-Term Registry demonstrated the clinical profiles and outcomes of HF patients from Western countries.[2345] All these registries helped the American and European cardiovascular communities frame competent HF guidelines. The GWTG-HF registry data reported the extent of inappropriate or underuse of medications or device therapy in patients with HF.[4]

The few available systematic data from Middle East countries suggest that the burden of patients with HF may be higher than that in Western countries.[678] However, variations in risk factors in patients with acute HF (AHF) in the Middle East populations remain unclear.

The Gulf Heart Association (GHA) initiated the first prospective, multinational, multicenter observational AHF registry (Gulf CARE) involving seven Middle East countries, including Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, the United Arab Emirates, and Yemen between February and November of 2012. Through this study, we aimed to investigate precipitating factors that contribute to hospitalization and mortality in post-AHF hospitalization in a large Gulf CARE cohort.

METHODS

Registry design

Gulf CARE registry design, methodology, and hospital characteristics have been previously described in detail.[9] Hospital-based registry patients admitted with AHF in participating hospitals in the 47 selected hospitals across seven Middle East regions were included.

Baseline demographics, comorbidities, risk factors, clinical presentations, in-hospital outcomes, management strategies, etiology, precipitating factors for worsening of HF (have persistent symptoms and signs of HF during treatment or pulmonary edema, or cardiogenic shock after stabilization and treatment of at least 24 h any of which requires rehospitalization) and other relevant data collected during admission and on follow-up were obtained from the Gulf CARE data using predefined inclusion and exclusion criteria.[9]

The registered patients were followed for 3 months to 1 year. To better understand the precipitating factors among Gulf population, we stratified the Gulf CARE registries into two groups based on their nationalities: Arab Gulf Corporation Council (GCC) that includes the United Arab Emirates, Bahrain, Saudi Arabia, Oman, Qatar and Kuwait, and nonGCC (Yemen and others). Six distinct classes of precipitating factors (acute coronary syndrome [ACS], nonadherence to medications, infection, uncontrolled arrhythmias, uncontrolled hypertension, and non-adherence to diet) for hospital admission were considered. Patients with these precipitating factors and the outcomes of the 90-day and 120-day all-cause mortality were investigated across the Gulf CARE cohort.

Ethical considerations

Institutional or national ethical committee or review board approval was obtained from 47 sites of the seven participating countries. The study protocol was registered at clinicaltrials.gov (NCT01467973). We strictly followed the 1975 Declaration of Helsinki's ethical guidelines. Written informed consent was obtained from each patient before their enrollment in the study. We used a custom-designed electronic case report form and entered the data online at the Gulf CARE website (www.gulfcare.org). Data characteristics and outcome variables were similar to that of previously published Gulf CARE studies.[10111213141516]

Patient and public involvement

Each patient who participated in the study was given a unique identification number. All the necessary information related to the research hypothesis, patient enrollment, and outcome measures were described in the study protocol.[9] The study was registered with clinical trials.gov (NCT01467973).

Statistical analysis

Descriptive statistics were used to summarize frequency tabulations (n, %) and distributions (mean, standard deviation). All results were summarized overall and by subgroup populations.

Multivariate logistic regression analysis was performed after adjustment for all confounders (age, sex, body mass index, history of HF, diabetes mellitus, coronary artery disease, systolic blood pressure, and heart rate at admission and impaired renal function, defined as estimated glomerular filtration rate (eGFR) mL/min/1.73 m2 using Cockcroft and Gault formula eGFR (mL/min)= ([140-age] × Weight/[0.814 × serum creatinine (SCr) in μmol/L]) × (0.85 if female) and to identify important precipitating risk factors for rehospitalization in patients with AHF across GCC countries. Univariate and covariate-adjusted Cox proportional hazards regression models were used to estimate the association between the presence of precipitating factors and the outcomes of the 90-day and 12-month risk of death. A p < 0.05 (two-tailed) was considered a cutoff value for statistical significance. SPSS 22.0 Statistical package (Chicago, IL, USA) was used for the analysis.

RESULTS

A total of 5005 patients were enrolled, and the mean age of the cohort was 59.3 ± 14.9 years. Around 50.8% of AHF patients were from GCC nations, and the majority were male (62.5%; P < 0.001). During 3- and 12-month follow-up, a significant 22.1% of the GCC nationalities in 3 months (P < 0.001) and 18.3% of the nonGCC nationalities in 12 months underwent rehospitalization due to AHF. The overall in-hospital mortality was 6.3%. A total of 18% (n = 903) and 21.4% (n = 1075) of the patients were rehospitalized during 3-month and 12-month follow-up. Table 1 shows baseline characteristics, adjusted for comorbidities, management, and follow-up data of the stratified population.

Table 1

Patient demographics and clinical characteristics in gulf acute heart failure registry cohort (n=5005)

	Whole cohort (n=5005), n (%)	GCC (n=2544), n (%)	Non-GCC (n=2461), n (%)	P
Age (mean±SD)	59.34±14.88	63.79±13.58	54.74±14.76	<0.001
Gender
Male	3131 (62.5)	1449 (57)	1682 (68.3)	<0.001
Female	1874 (37.4)	1095 (43)	779 (31.7)	<0.001
Coronary arterial disease	2337 (46.7)	1408 (55.3)	929 (37.7)	<0.001
Valvular heart disease	675 (13.5)	358 (14.1)	317 (12.9)	NS
Hypertension	3059 (61.1)	1929 (75.8)	1130 (45.9)	<0.001
Family history of cardiomyopathy	259 (5.1)	111 (4.4)	148 (6.0)	0.008
Atrial fibrillation	607 (12.1)	393 (15.4)	214 (8.7)	<0.001
Peripheral vascular disease	223 (4.4)	153 (6)	70 (2.8)	<0.001
Transient ischemic attack	404 (8.0)	284 (11.2)	120 (4.9)	<0.001
Type 1 diabetes mellitus	185 (3.7)	129 (5.1)	56 (2.3)	NS
Type 2 diabetes mellitus	2307 (46.1)	1508 (59.3)	799 (32.5)	<0.001
Hyperlipidemia	1799 (35.9)	1289 (50.7)	510 (20.7)	<0.001
Social habits
Alcohol use	176 (3.5)	69 (2.7)	107 (4.4)	<0.001
Occasionally	151 (3.0)	51 (2.0)	100 (4.1)	NS
Daily	25 (0.5)	18 (0.7)	7 (0.3)	NS
Khat use	891 (1.7)	16 (0.6)	875 (35.6)	<0.001
Tobacco user	1103 (22.0)	327 (12.9)	776 (31.5)	<0.001
Sheesha user	60 (1.2)	8 (0.3)	52 (2.1)	<0.001
Smoking/waterpipe/chewing tobacco	1103 (20.0)	327 (12.8)	776 (31.5)	<0.001
Management
Cardiogenic shock	402 (8.0)	177 (7.0)	225 (9.1)	0.004
Inotropes	783 (15.6)	325 (12.8)	458 (18.6)	<0.001
Preadmission
Diuretics	2882 (57.5)	1720 (67.6)	1162 (47.2)	<0.001
Beta-blockers	2208 (44.1)	1384 (54.4)	824 (33.5)	<0.001
ACE inhibitors	2132 (42.6)	1092 (42.9)	1040 (42.3)	NS
ARBs	647 (12.9)	501 (19.7)	146 (5.6)	<0.001
Aldosterone antagonists	840 (16.7)	538 (21.1)	302 (12.3)	<0.001
PCA	539 (10.8)	378 (14.9)	161 (6.5)	<0.001
CABG	366 (7.3)	250 (9.8)	116 (4.7)	<0.001
On-discharge
Diuretics	4464 (89.1)	2316 (91)	2148 (87.3)	<0.001
Beta-blockers	3362 (67.1)	1700 (66.8)	1662 (67.5)	NS
ACEI	2882 (58.6)	1337 (52.6)	1545 (62.8)	<0.001
ARB’s	802 (16.0)	503 (19.8)	299 (12.1)	<0.001
Aldosterone antagonists	2056 (41.0)	859 (33.8)	1197 (48.6)	<0.001
PCA	299 (5.9)	167 (6.6)	132 (5.4)	0.073
CABG	69 (1.3)	38 (1.5)	31 (1.3)	NS
Case process
Acute dialysis ultrafiltration	135 (2.7)	85 (3.3)	50 (2.0)	0.004
VT/VF requiring pharmacotherapy	222 (4.4)	80 (3.1)	142 (5.8)	<0.001
AF requiring therapy	311 (6.2)	200 (7.9)	111 (4.5)	<0.001
Major bleeding events	40 (0.8)	22 (0.9)	18 (0.7)	NS
Blood transfusion	254 (5.0)	135 (5.3)	119 (4.8)	NS
Stroke	68 (1.3)	32 (1.3)	36 (1.5)	NS
NYHA class
At admission				<0.001
NYHA I	2493 (49.8)	1254 (50.9)	1236 (48.5)	-
NYHA II	1865 (37.2)	1084 (44)	781 (30.7)	-
NYHA III	159 (3.1)	90 (1.7)	69 (2.7)	-
NYHA IV	302 (6)	40 (1.6)	262 (10.3)	-
12 months				<0.001
NYHA I	883 (17.6)	524 (20.6)	359 (14.6)	-
NYHA II	445 (8.9)	331 (13)	114 (4.6)	-
NYHA III	76 (1.5)	66 (2.6)	10	-
NYHA IV	3 (0.03)	2 (0.1)	1 (0.0)	-
In hospital mortality	313 (6.3)	134 (2.7)	179 (3.6)	<0.001
Follow-up
After 3 months
Alive	4301 (85.1)	2165 (85.1)	2136 (86.8)	0.018
Rehospitalization	903 (18.0)	562 (22.1)	341 (13.9)	<0.001
Died	316 (6.3)	185 (7.3)	131 (5.3)	0.005
After 12 months
Alive	3804 (76.0)	1826 (71.8)	1978 (80.4)	<0.001
Rehospitalization	1075 (21.4)	623 (24.4)	452 (18.3)	<0.001
Died	496 (9.9)	342 (13.4)	154 (6.2)	<0.001

GCC: Arab gulf cooperation council countries (United Arab Emirates, Bahrain, Saudi Arabia, Oman, Qatar, and Kuwait, Non-GCC countries: Yemen and others. ACE: Angiotensin convertase enzyme inhibitor, ARBs: Angiotensin-receptor blockers, CABG: Coronary artery bypass graft, PCA: Percutaneous coronary angioplasty, VT/VF: Ventricular tachycardia or ventricular fibrillation, NYHA: New York Heart Association, AF: Atrial fibrillation, NS: Not significant, SD: Standard deviation, GCC: Gulf corporation council

Prognostic and precipitating factors in the individual regions are summarized in Table 2 for AHF patients. The three most common precipitating factors of HF were ACS (n = 1365; 27.2%), nonadherence to diet (n = 964; 19.2%) and infection (n = 731; 14.6%).

Table 2

Gulf acute heart failure registry country-specific prognostic and precipitating factors for rehospitalization of heart failure patients (n=5005)

	Bahrain (n=58)	Kuwait (n=351)	Oman (n=943)	Qatar (n=131)	UAE (n=202)	Saudi Arabia (n=859)	Yemen (n=1613)	Others (n=848)	Whole cohort
Etiology of HF
Viral myocarditis	1	2	2	0	0	1	5	6	17
Pulmonary hypertension	0	8	9	3	1	17	76	14	128
Pulmonary valvular HD	6	14	42	7	18	83	218	73	416
IHD	27	185	561	95	117	443	755	480	2663
HHD	15	109	196	13	23	118	219	109	802
Congenital HD	1	1	3	0	0	3	6	4	18
Cardiomyopathy	8	32	129	13	43	194	334	162	915
CM
Toxic CM	0	1	4	1	1	14	11	7	39
Thyroid disease-related CM	0	0	1	0	1	2	4	2	10
Tachycardia-induced CM	1	0	6	0	5	0	7	12	31
Pregnancy-related CM	0	3	5	0	1	4	45	7	65
Infiltrative CM	0	0	1	0	0	6	4	2	13
Idiopathic DCM	7	22	76	12	24	156	224	118	642
HCM	0	2	1	0	3	2	11	3	22
Familial CM	0	0	5	0	0	1	2	1	9
Diabetic CM	0	4	27	0	8	9	26	10	84
Precipitating for worsening of HF
Worsening renal failure	1	16	36	8	24	52	31	53	221
Unknown	7	8	121	24	25	136	251	114	686
Uncontrolled hypertension	8	49	96	7	11	67	88	84	410
Uncontrolled arrhythmias	3	15	54	3	13	64	102	47	301
Salt retaining drugs (NSAIDs)	1	4	3	0	1	2	11	4	26
Pulmonary embolism	1	0	1	0	0	1	3	2	8
Nonadherence to diet	12	76	228	12	30	120	375	111	964
Infection	11	71	96	33	38	96	301	85	731
Anemia	1	15	20	4	7	18	67	22	154
Acute coronary syndrome	12	86	247	39	52	266	358	305	1365
Case process
Acute dialysis ultrafiltration	1	17	21	3	3	40	30	20	135
VT/VF requiring therapy	0	16	24	1	7	0.32	100	42	222
AF requiring therapy	4	32	58	6	10	90	57	54	311
Major bleeding events	1	1	3	0	2	15	6	12	40
Blood transfusion	4	34	26	7	15	49	78	41	254
Stroke	0	1	14	1	2	14	29	7	68

NYHA: New York Heart Association, HD: Heart disease, IHD: Ischemic heart disease, HHD: Hypertensive heart disease, DCM: Dilated cardiomyopathy, NSAIDs: Nonsteroidal anti-inflammatory drugs, VT/VF: Ventricular tachycardia or ventricular fibrillation, CM: Causes of cardiomyopathy, HF: Heart failure, AF: Atrial fibrillation, HCM: Hypertrophic cardiomyopathy

After adjustment of cofounders (demographic and clinical variables) that precipitate worsening of HF, in the spectrum of Gulf CARE participating countries, multivariate analysis for predictors of increased hospitalization demonstrated that uncontrolled hypertension, ACS, nonadherence to diet, and medications are significant precipitating factors for rehospitalization [Table 3]. For example, patients with uncontrolled hypertension showed 5.28 times and nonadherence to diet (4.20 times) increased the risk of rehospitalization among Kuwait patients. Furthermore, patients with ACS, uncontrolled hypertension, and nonadherence to diet were also more likely to be rehospitalized.

Table 3

Heart failure patient is precipitating factors for rehospitalization across gulf acute heart failure registry cohort

	Bahrain	Kuwait	Oman	Qatar	Saudi Arabia	UAE	Yemen
Acute coronary syndrome	1.04 (0.46-2.33)	2.94 (2.06-4.19)**	1.34 (1.04-1.72)*	0.67 (0.48-0.93)*	1.32 (1.05-1.66)*	0.89 (0.66-1.21)	1
Nonadherence to medications	0.86 (0.37-1.99)	2.09 (1.45-3.01)**	1.13 (0.88-1.46)	0.29 (0.19-0.43)**	0.51 (0.39-0.67)**	0.38 (0.26-0.55)**	1
Infection	0.72 (0.28-1.8)	1.81 (1.23-2.67)*	0.57 (0.42-0.78)**	0.60 (0.42-0.86)**	0.53 (0.40-0.70)**	0.61 (0.43-0.87)**	1
Uncontrolled arrhythmias	0.81 (0.22-2.99)	1.46 (0.85-2.52)	1.06 (0.72-1.55)	0.31 (0.16-0.61)**	1.01 (0.71-1.43)	0.99 (0.63-1.55)	1
Uncontrolled hypertension	1.78 (0.64-4.97)	5.28 (3.43-8.13)**	2.05 (1.45-2.90)**	0.88 (0.54-1.43)	1.04 (0.73-1.50)	1.11 (0.71-1.74)	1
Nonadherence to diet	0.98 (0.12-7.94)	4.20 (2.16-8.17)**	2.91 (1.72-4.90)**	0.52 (0.19-1.39)	1.88 (1.11-3.18)*	0.20 (0.48-0.87)*	1

*P<0.05, **P≤0.01. Adjusted cofounders: Age, sex, body mass index, history of HF, DM, coronary artery disease, systolic blood pressure, and heart rate at admission and impaired renal function. Adjusted odds ratio (95% CI). HF: Heart failure, DM: Diabetes mellitus, CI: Confidence interval

Among the patients with various precipitating factors, every prognostic determinant (age, gender, diabetes, history of HF, blood pressure, and heart rate at admission) was adjusted and was strictly associated with 3-month and 12-month mortality.

AHF patients precipitated by infection and ACS during hospitalization showed the higher 90-day hazard of mortality (hazard ratio [HR] 1.40, 95% CI 1.10–1.78; P < 0.001 and HR 1.23, 95% confidence interval [CI] 0.99-1.52; P < 0.001). Similarly, AHF precipitated by infection and non-adherence to diet and medications showed a persistently higher risk of 12-month mortality compared with AHF patients without identified precipitants. Moreover, hypertension and AF as a precipitating factor showed a reduced risk of death at 12-month posthospitalization compared with AHF without identified precipitants (HR 0.89, 95% CI 0.61–1.31 and HR 0.91, 95% CI 0.74–1.12), but not a significant association [Figure 1].

Figure 1

Precipitating factors and risk of death in 3-months and 12-months. HR: Hazard ratio, CI: Confidence interval

DISCUSSION

The Gulf CARE enrolled 5005 AHF patients admitted to 47 hospitals across 7 Middle Eastern countries and prospectively followed them for 12 months. This allowed us to assess patient outcomes and contributing factors associated with frequent hospitalization and mortality in these patients.

The main findings are: (i) 21.4% of AHF patients from NYHA classes I and II were rehospitalized during 12-months of follow-up, (ii) ACS (27.2%), nonadherence to diet (19.2%), and infection (14.6%) were most common precipitating factors of HF, (iii) nonadherence to medications, uncontrolled hypertension, and ACS significantly increase the risk of rehospitalization, (iv) there are significant differences between regions in precipitating risk factors for HF patients readmission, and (v) AHF patients precipitated by infection and ACS at readmission have the highest 90-day hazard of mortality, and nonadherence to diet and medications showed a persistently higher risk of 12-month mortality.

Numerous clinical factors can trigger a worsening of AHF, and one or more precipitating factors or comorbidities have been identified in a majority of patients admitted with acute decompensated HF (ADHF).[417181920] Any of these factors alone or in combination can initiate pathophysiological processes resulting in acute circulatory decompensation leading to hospitalization.[212223]

Identifying precipitating factors, relieving symptoms adequately, and following up on patients carefully can improve short- and long-term outcomes and can reduce frequent rehospitalization. AHF has several underlying etiologies, but ACS remained the most frequent precipitating factor in the Gulf CARE cohort, similar to OPTIMIZE-HF, French EFICA, and the recent intercontinental GREAT registry.[42223] The intercontinental GREAT registry highlighted that ACS increases the risk of death only transiently during the first week after hospitalization (HR 2.57, 95% CI 2.22–2.99, P < 0.001).[24]

Similarly, uncontrolled blood pressure also identified as an important precipitating factor (>90% of all AHF episodes are associated with normal or elevated blood pressure). There is overwhelming evidence that primary prevention of symptomatic HF strongly depends on blood pressure reduction[4181925] and systolic blood pressure >140 mmHg acts as a principal determinant of in-hospital morbidity and mortality.[82324252627] A large RCT demonstrated that targeting a significant reduction in systolic blood pressure in those at increased risk of cardiovascular disease is a novel strategy to prevent HF.[28] In our study, we identified that uncontrolled hypertension and nonadherence to medications as precipitants is associated with an increased risk of hospitalization. It is evident from the US study that the proportion of patients treated for hypertension was improved from 59.8% to 74.7%, and the proportion of adequate blood-controlled blood pressure improved from 53.3% to 68.9%.[29] These findings highlight the improvement in blood pressure control is likely to make a significant contribution to the decline in the incidence of hospitalization of HF patients. Furthermore, improved in-hospital and postdischarge systolic blood pressure control as a precipitant of HF admission is associated with better outcomes.[30] However, prognostic factors such as being more symptomatic, having lower systolic blood pressure, worse renal function, and higher troponins at baseline were some of the significant factors for HF hospitalization.[3132333435]

Identifying patients at high risk of developing symptomatic HF and other cardiovascular conditions is an important step to an effective preventive strategy for hospitalization.

Further studies should be designed to test interventions targeting these contributing factors in post-HF hospitalization prospectively. It should be noted that patients with ACS, infection and nonadherence to diet or medication as admission precipitants were at high adjusted risk of 90-day and 12-months postdischarge mortality. Patients identified with these precipitating factors should be counseled during the index hospitalization, and more emphasis should be given at discharge to improve postdischarge outcomes.

Several reviews and meta-analyses demonstrated that physical conditioning and training improve exercise tolerance, quality of life, and rate of hospitalization in patients with stable HF, in NYHA I-III functional class.[363738] Of note, a high number of patients in NYHA functional class I-II with stable HF were also readmitted within 12 months of the follow-up period. In general, data collected from clinical studies data rule out exercising in patients with AHF, however early mobilization and a personalized training program following hospitalization can prevent disability progress, and further investigation is required concerning cardiac rehabilitation in reducing rehospitalization among discharged HF patients.

Our study has some limitations. First, like any observational study, the possibility of selection bias could exist. Second, the 47 hospitals that participated may not be representative, and the results cannot be generalized. Finally, underreporting of comorbidities, especially subclinical disease, might have occurred, and this could have led to an overestimation of the impact of these comorbid conditions. We collected the data through a well-designed electronic system to obtain quality and complete data with only a few missing data.

CONCLUSION

Precipitating factors such as ACS, infection, nonadherence to diet, and medication were identified as influencing frequent hospitalization and risk of mortality. Hence, early detection, management, and approach monitoring of these prognostic factors in-hospital and postdischarge should be prioritized in optimizing the management of HF in our region.

Financial support and sponsorship

Gulf CARE is an investigator-initiated study conducted under the auspices of the GHA and funded by Servier, Paris, France; and-for centers in Saudi Arabia-by the Saudi Heart Association. Dr. Abi Khalil's lab is funded by the Biomedical Research Program (BMRP) at Weill Cornell Medicine Qatar, and partially by the pilot study 15-16, a program funded by Qatar Foundation. Dr. Al-Habib's lab is funded by the Saudi Heart Association and The Deanship of Scientific Research at King Saud University, Riyadh, Saudi Arabia (Research group number: RG-1436-013). All of the sources mentioned above did not have a role in the study's concept, analysis, and writing of the manuscript.

Conflicts of interest

There are no conflicts of interest.