Nonischemic dilated cardiomyopathy (NIDCM) is a disease thatprimarily affects the cardiac muscle and is characterized by ventricularchamber dilatation and contractile dysfunction in the absence of significantcoronary artery disease or abnormal loading conditions 1. Left ventricularejection fraction (LVEF) should be less than 50% or fractional shortening ofless than 25 % with normal or near normal left ventricular (LV) wall thickness.These effects could extend to other cardiac chambers with the right ventricle(RV) and both atria may also be dilated and dysfunctional 2. The incidenceand prevalence of NIDCM is generally increasing, but this can be in part due toimproved recognition or other factors. Worldwide, NIDCM has a prevalence of atleast 1 in 2500 adults, affects males more than females, the third most commoncause of heart failure and the most frequent reason for heart transplantation3.
Despite having better prognosis than ischemic heart failure, NIDCM is stillassociated with significant morbidity and mortality either due to progressiveheart failure (HF) or sudden cardiac death (SCD). Despite therapeutic advancesin heart failure management, 5-year mortality remains as high as 20% 4. Onthe other hand, many of those patients have marked improvement in the LVsystolic function at follow-up and those patients have an excellent outcome. Therefore,Risk assessment in NIDCM is crucial for proper patient management withimplications on surveillance, treatment, and outcome. Currently, riskstratification is mainly dependent on the assessment of LVEF, as exemplified byits use as the key determinant of device implantation especially implantablecardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT)5,6 . Some of patients who had ICD implantation for primary prevention of SCDshowed significant improvement of the ejection fraction at follow-up to levelsthat may preclude implantation of these devices. LVEF is still an important prognostic factorin NIDCM, but effective risk stratification remains challenging, particularlywith respect to SCD, which calls for identification of more independentprognostic factors to enable clinicians to more accurately stratify patientswith NIDCM and subsequently tailor their management 7-10.
Data about NIDCM from the Middle East and Saudi Arabia is generallyscarce. In the HEARTS registry, which was the 1st heart failure registry inSaudi Arabia and Arab countries, NIDCM constituted 16 % of the causes of heartfailure in the acute setting and 38 % in the setting of high risk chronic heartfailure patients referred to tertiary care heart failure clinics. It wasconsidered the second most common cause of heart failure in both the acute andchronic setting after ischemic heart disease and before hypertension 11-13.The Gulf Acute Heart Failure Registry (Gulf CARE) is a multi-center,multi-national prospective study, comprising six Arab gulf countries plus Yemenand including 5005 patients, has reported that NIDCM constituted 18 % of heartfailure etiologies and was also the second cause of HF after coronary arterydisease 14. From the above registries and from our clinical observations,dilated cardiomyopathy in GULF countries needs more focus, attention andfurther studies due to the following:1- It is a common and prevalent morethan expected as shown from the HEARTS and GULF CARE registries and from ourclinical observations, at least in tertiary care hospitals.
2- It starts early in life with dismalimpact on survival, quality of life and productivity.3- The etiology is very diverse and notyet completely clear. While some causes are easy to identify like Peripartumcardiomyopathy for example, others are not like myocarditis, toxiccardiomyopathy, familial and idiopathic causes.4- High prevalence of use of illicitsubstances and drugs like Captagon (amphetamine like substance) and alcohol inyoung and middle aged HF patients may shed the light on these factors aspossible causes of cardiomyopathy in Saudi Arabia.5- Despite the rate of recovery of theejection fraction (EF) is high in these patients, it is very variable.
Whilesome patients have complete recovery of the EF and LV dimensions to normalparameters, others have either partial recovery or progressive worsening of theEF. We need to look at the rate and predictors of recovery of the ejectionfraction and subsequently explore the possible interventions that couldincrease the rate of recovery of the EF. 6- Some of the patients who had ICDimplantation for primary prevention of SCD had recovery of their ejectionfraction to levels that may preclude implantation of these devices. Thisobservation may mandate the importance of risk stratification that is notdependent only on the assessment of ejection fraction but also on otherparameters that my predict improvement of the systolic function.7- Despite the diagnostic and imagingfacilities (like CMR) are available in most of the tertiary care centers inSaudi Arabia, there is under usage of these facilities partially due to lack ofawareness of the treating physicians or absence of qualified readingphysicians.
With no doubt, NIDCM is a big and growing health burden in GULFregion and Saudi Arabia in particular, with many vague areas including thedetails of etiology, the clinical features and the rate and predictors ofrecovery of these cardiomyopathies, but this hypothesis needs to be tested. Aregistry able to capture all the relevant clinical information of patients withNIDCM would enable us to improve our knowledge on epidemiology and outcomes ofreal world patients with this clinical condition in this region. Further,specific questions of high clinical relevance could be answered using theinformation collected in the registry. Accordingly, our objective is to studythe clinical characteristics, diagnostic and management strategies and outcomesof patients with nonischemic dilated cardiomyopathy who are managed in theinpatient and outpatient setting..MethodsThis registry is a prospective, multicenter, observational study ofpatients with NIDCM in Saudi Arabia. We aim to collect data on the clinicalphenotypes, diagnosis, investigations, management strategies and outcomesincluding mortality, hospitalizations and recovery of EF across a wide varietyof patients with NIDCM seen by cardiologists, heart failure specialists andother specialists dealing with those patients.
NIDCM includes a large group of heterogeneous myocardial diseasesthat are characterized by ventricular dilation and hypocontractility of the myocardiumin the absence of coronary artery disease or abnormal loading conditions includinghypertension, valvular and congenital disorders. In clinical practice andmulticenter HF trials, the etiology of HF has often been categorized intoischemic or nonischemic cardiomyopathy. In the cardiology literature, the termDCM is being used interchangeably with nonischemic dilated cardiomyopathy but hisapproach fails to recognize that “nonischemic dilated cardiomyopathy” mayinclude cardiomyopathies due to volume or pressure overload, such ashypertension or valvular heart disease, which we usually do not accept them as NIDCM15. So we adopted the term NIDCM rather than DCM to include all the causes ofdilated cardiomyopathies other than ischemic, significant valvular diseases, congenitaldisorders or hypertension. Also we put ejection fraction of ? 40% as the cutoffto exclude any overlap with patients with heart failure and preserved ejectionfraction.Study designThe study is designed to be a prospective, multicenter,longitudinal observational study of the clinical, echocardiographic, imaging,laboratory, management and outcome features of patients with NIDCM presented tothe selected centers in the Kingdom. Data will be collected by using a webbased system and the CRF will be accessed online.
Inclusioncriteria- Patients above the age of 18 years.- Patient willing and able to give informed consent.- Patient is able to comply with all study requirements.- Signs and symptoms of heart failure.
– Documented evidence of LV dilatation and systolic dysfunctionwith EF ?40%.- Data collection is prospective and all patients enrolled in theregistry must be consecutively assessed in the study center.- Inpatients and outpatients are acceptable for enrollment.- New and follow-up patients are eligible.Exclusioncriteria- Patients with known significant coronary artery disease (priorMI, prior PCI or CABG, positive stress test for myocardial ischemia).
– Patients with known history of rheumatic heart disease.- Patients with known other significant valvular heart diseaseother than functional mitral regurgitation.- Patients with long standing hypertension. Enrolment dataThe following information will be captured for each enrolledpatient:- Demographic characteristics- Risk factors for cardiovascular diseases- Data on familial cardiomyopathy- Co-morbidities- Precipitating factors of HF- Clinical signs and symptoms- Blood tests performed- Use of invasive/ non-invasive diagnostic procedures- Use of pharmacological treatments- Use of non-pharmacological treatmentsFollow-up dataA follow-up visit after 6 and 12 months will be scheduled for alloutpatients and for patients discharged after an admission with NIDCM and HF.During the course of the year patients will be followed-up, according to theusual practice of the centers.Sample sizeWe aim to have a sample of at least 1000 patients, making it thelargest data collection on that disease in the region. Recruitment andenrolmentWe will recruit all consecutive patients with confirmed NIDCMassessed by a cardiologist taking part in the registry. Patients’ data will beexamined by the treating physician to check that they meet inclusion criteria.
Written or verbal versions of informed consent will be presented to the subjectdetailing no less than: the exact nature of the study; the implications andconstraints of the protocol; and any risks involved in taking part. It will beclearly stated that the patient is free to withdraw from the study at any time,for any reason, without any effect on future care, and with no obligation togive the reason for withdrawal. Centralvalidation of the diagnosisIt is imperative to ensure that patients in the registry have NIDCMrather than alternative diagnoses. Local Investigator should retain in theirdocumentation the discharge letters and the echocardiographic report of allenrolled patients.
The registry coordinating center will randomly select 20% ofenrolled patient for a central validation of the diagnosis. The coordinatingcenter will ask local investigators to send the documentation (dischargeletter, echocardiographic report and others) for centralized validation. Thedischarge or the medical report and echocardiogram report will be sent to 2members who will independently review the information provided. If they bothagree that NIDCM is present the case will be settled. If they disagree the casewill be discussed by 2 other members of the steering Committee. A consensusbetween these 4 members will be sought. Ruling out Ischemic etiologyIschemic heart disease is an exclusion criterion and should beruled out in this study. All patients with prior history of myocardialinfarction, acute coronary syndrome (ACS), PCI or CABG will be excluded.
Forother patients with risk factor (s) for CAD, coronary angiography should bepromoted to be the gold standard test to rule out CAD. For low risk patientsother noninvasive modalities like myocardial perfusion scans, stressechocardiography, CT angiography and cardiac magnetic resonance imaging can beconsidered. EchocardiographyEchocardiography is an accurate and reproducible method forassessing left ventricular size and function in normal-sized hearts withoutsegmental myocardial disease.
Directly measured and derived M-mode leftventricular parameters correlate well with invasively obtained data. MandatoryEchocardiography parameters: LVEDD, LVESD, EF, FS, presence of MR and TR. Moredetailed echocardiography parameters can be entered including details oftrans-thoracic, M-mode, 2-dimensional, and tissue Doppler echocardiography(TDI) will form part of the comprehensive assessment of patients, by anexperienced echo-cardiographer, at the intervals defined above.
The focus willbe on assessment of both the left ventricular dimensions and function. Cardiac MRI (CMR)Many tertiary care centers in Saudi Arabia have this imagingmodality. We will include CMR data related to tissue characterization and willencourage participating centers in the registry to request this test ifavailable. Outcome measurementsPrimary outcomes- Mortality at 1 year.- Cardiac transplantation or LVAD at 1 yearSecondary outcomes- Improvement in New York Heart Association Functional Class at oneyear.
– Readmission to hospital at 1 year.- Improvement in left ventricular function (ejection fraction) byechocardiographic evaluation at follow up visits.Medication andInterventionsData will be collected on:- Acute patient hospitalized (clinical course / medical treatmentin hospital).- For ambulant patients (medications and devices).
Statisticalconsiderations Statistical tests may be carried out for exploratory purposes, asappropriate. Continuous variables will be summarized using means or mediansbased on the normality; normally distributed variables will be summarized usingthe mean and standard deviation (SD), while the non-normally distributedvariables will be summarized using the median and interquartile range (IQR).Categorical variables will be summarized using frequencies and percentages.Multivariable analyses may be used to explore relationship between baselinecovariates and post-baseline outcomes, as appropriate. The study being fullyobservational, a formal sample size is not calculated. However, a sample of1000 enrolled patients has been estimated to be good enough to give us a goodview of the primary and secondary outcomes.Studyorganization The principle investigators are responsible for the formulation ofthe study protocol and to oversee its implementation.
The steering committeemembers are the sites principle investigators and they are key persons inresearch in cardiology and heart failure in Saudi Arabia. Center and participating centers coordinators are responsible forproper communication between different centers at all levels of datacollections and analysis. Persons assigned for data collections should beexperts in this field and include qualified nurses, physician assistants,clinical pharmacists and research assistants. The principal investigators andsteering committee team has to assure the constant quality control andcontinuity, necessary to ensure that the projects is completed on time andwithin the budget. The investigator centers are contacted and accepted on avoluntary basis.
A specific Case Report Form (CRF) will be distributed both inhard copy and web based to all centers with specific user name and password.Each center will have to fill in CRFs of consecutive patients. Eachparticipating hospital will have a local principle investigator (LPI) who hasbeen chosen by the study principle investigator (SPI). It is the responsibilityof the LPI to ensure the accuracy of the data collected, and the timely andcomplete entry of the data points into the e-CRF. In addition, the LPI willdesignate research assistants (RA) who will either collect or supervise thecollection of the Data.
Each patient will be assigned a unique study number, and allidentifiers will be encrypted. Qualitycontrol procedures for this study include source data verification by randomlyselecting 20% of registry participant records with comparison between the papercase report form (CRF) and the electronic database record of those samedata. If errors are common, data will becompletely checked prior to data analysis. Duration of thestudyIt is anticipated that approximately 1000 patients will be enrolledwithin 1 year.
There is no maximum number of patients per center. Follow-upwill be performed by the local investigators 6 and 12 months after enrolment.Ethical issuesSite investigators will be responsible for obtaining the approvalof the local review boards for this registry, if necessary. All patients willbe approached by local center investigators and will be asked for their writtenor verbal informed consent to participate in the registry (if necessary, i.e.based on local standards). This registry is an observational study that doesnot dictate the manner in which patients are evaluated or treated for NIDCM.Physicians may decide to evaluate and manage patients with NIDCM in the mostappropriate way, according to the local standard of care.
There is no selectionof patients and it is necessary to obtain patients’ agreement. In case ofrefusal, the patient will not be enrolled in the registry. Patients’identifiable data will be stored on local computers in order to facilitatesubsequent follow-up of patients. Patients who cannot provide the informedconsent at the time of admission due to very severe clinical conditions cangive their consent some hours/days after admission, when more favorableclinical conditions allow them to receive the appropriate information. Patients’data collected will be strictly confidential.
In order to maintain strictsecurity, each investigator/ study personnel will have a unique login andpassword to enter patient’s information. There will be no storage of clinicaldata outside of the data collection instrument, which will be a secure,web-based form. The main database will be secured according to currentstandards to ensure both ethical and integrity requirements of the data.
PublicationpolicyData will be published under the responsibility of the both theprincipal investigators and the steering committee. Requests for furtheranalyses to support further publications must be submitted to the principalinvestigator for approval. Any publications as a result of this study will beconsidered a joint publication by the principal and co-investigators.Contribution of the author to the study design, enrolment, data review, andmanuscript preparation and review will be considered when determining the orderof authorship. After the publication of the main paper, the database isavailable for further analyses to all participating Investigators. TheExecutive Committee must receive a copy of any presentation, manuscript, orabstract prior to dissemination.