Toward a Universal Definition of Etiologies in Heart Failure: Categorizing Causes and Advancing Registry Science.

Heart failure (HF) is a well-described final common pathway for a broad range of diseases however substantial confusion exists regarding how to describe, study, and track these underlying etiologic conditions. We describe (1) the overlap in HF etiologies, comorbidities, and case definitions as currently used in HF registries led or managed by members of the global HF roundtable; (2) strategies to improve the quality of evidence on etiologies and modifiable risk factors of HF in registries; and (3) opportunities to use clinical HF registries as a platform for public health surveillance, implementation research, and randomized registry trials to reduce the global burden of noncommunicable diseases. Investment and collaboration among countries to improve the quality of evidence in global HF registries could contribute to achieving global health targets to reduce noncommunicable diseases and overall improvements in population health.

Heart failure, the global pandemic: A call to action consensus statement from the global presidential conclave at the platinum jubilee conference of cardiological society of India 2023.

Heart failure (HF) is emerging as a major public health problem both in high- and low - income countries. The mortality and morbidity due to HF is substantially higher in low-middle income countries (LMICs). Accessibility, availability and affordability issues affect the guideline directed therapy implementation in HF care in those countries. This call to action urges all those concerned to initiate preventive strategies as early as possible, so that we can reduce HF-related morbidity and mortality. The most important step is to have better prevention and treatment strategies for diseases such as hypertension, ischemic heart disease (IHD), type-2 diabetes, and rheumatic heart disease (RHD) which predispose to the development of HF. Setting up dedicated HF-clinics manned by HF Nurses, can help in streamlining HF care. Subsidized in-patient care, financial assistance for device therapy, use of generic medicines (including polypill strategy) will be helpful, along with the use of digital technologies.

Prevalence of Brugada electrocardiographic pattern in adult population - A community-based study from Kerala, South India.

There is no data for Brugada electrocardiographic pattern (BrEP) from India. In a cross-sectional study of men and women between the ages 20-79 years, electrocardiograms were analyzed following the 2002 consensus. The overall prevalence of BrEP was 1.06 % (95 % CI 0.76, 1.35). There were two cases type I (0.04 %; 95 % CI 0.01, 0.06) and forty-seven type II/III (1.01 %; 95 % CI 1.02, 1.35); the pattern was markedly higher in men. In this study, BrEP was slightly less prevalent compared to South Asia but more than in the west.

Identification of novel endogenous control miRNAs in heart failure for normalization of qPCR data.

MicroRNAs (miRNAs), a class of non-coding RNAs, are utilized as biomarkers for a wide range of disorders. Circulating miRNAs are proposed as potential markers in the clinical identification of heart failure (HF). However, identifying miRNA biomarkers in HF requires identification of robust endogenous control miRNAs for normalization in differential expression analysis. Hence, this study aimed to identify circulating miRNAs that can be utilized as endogenous controls in HF. We evaluated the expression of eight miRNAs, which were previously reported as endogenous controls in different pathological conditions. Total RNA, including miRNA, was extracted from the serum samples of 30 HF patients (15 HFrEF and 15 HFpEF) and their matched controls (n = 15). We used quantitative PCR to determine the miRNA expression. The stability of the selected endogenous miRNAs was assessed and compared using a standard set of criteria with the RefFinder software. Six of the eight miRNAs analyzed showed consistent expression among all sample groups. Stability analysis ranked hsa-let-7i-5p, hsa-miR-148b-3p, and hsa-miR-484 as the most stable miRNAs, indicating their potential as reliable endogenous controls.

Tricuspid Annular Plane Systolic Excursion (TAPSE) for the Assessment of Right Ventricular Function in Adult and Pediatric Cardiac Surgery: Modified Two-dimensional and M-mode TAPSE by Transesophageal Echocardiography Compared to M-mode TAPSE by Transthoracic Echocardiography.

OBJECTIVES: To compare transesophageal echocardiography-guided 2-dimensional and M-mode tricuspid annular plane systolic excursion (TAPSE) to transthoracic echocardiography (TTE)-guided M-mode TAPSE in terms of accuracy, interobserver, and intra-observer variability. DESIGN: A prospective, observational study. SETTING: Adult and pediatric operating rooms. PARTICIPANTS: Adult and pediatric patients (42 each) undergoing cardiac surgeries. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Modified midesophageal (Mod-ME), deep transgastric, and transgastric TAPSEs were analyzed for reliability and were compared to TTE TAPSE in both adult and pediatric groups. Modified ME TAPSE showed good method agreement with TTE TAPSE (bias = -0.97, p = 0.08 (adult); bias = 0.17, p = 0.71 [pediatric]), and showed a moderate correlation with right ventricular (RV) fractional area change (FAC) (r = 0.41, p = 0.006, [adult]; r = 0.57, p < 0.001, [pediatric]), with acceptable interobserver variability (percentage error =10.56 [adult]; 4.42 [pediatric]) and intraobserver variability (percentage error = 13.1 [adults]; 12.24 [pediatric]). Transgastric TAPSE poorly agreed with TTE TAPSE and had higher interobserver and intraobserver variability. Deep transgastric TAPSE had good method agreement with TTE TAPSE and had acceptable interobserver and intra-observer variability. CONCLUSIONS: Modified ME TAPSE is a reliable and reproducible measure of RV function before pericardiotomy in both adult and pediatric cardiac surgery. Right ventricular FAC values reflected the RV systolic function better than TAPSE after pericardiotomy. Deep transgastric TAPSE is reliable and reproducible but is less accurate than Mod-ME TAPSE.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

Charting a roadmap for heart failure research in India: Insights from a qualitative survey.

Background & objectives: Heart failure (HF) is emerging as a major health problem in India. The profile of HF in India is divergent from elsewhere in the world. While cardiologists must equip themselves with the requisite clinical management tools, scientists and health policymakers would need epidemiological data on HF and information on the resources required to meet the challenges ahead. The aim of this study was to identify the lacunae and to suggest recommendations to improve HF research. Methods: We surveyed a multidisciplinary group of HF experts using a two stage process. An email-based survey was conducted using a structured questionnaire, followed by an online discussion. The experts prioritized the major challenges in convergence research in India and inter-rater agreement values were calculated. In addition, they enlisted potential research gaps and barriers in the domains of epidemiology, diagnostics, management and technology and suggested recommendations to overcome those barriers. Results: The experts identified a paucity of data on HF burden, lack of state-of-the-art diagnostic facilities and trained personnel, overt dependence on imported devices/equipment/reagents, lack of interaction/awareness/information among stakeholders and lack of biobanks, as major barriers in HF research. Three fourths of the experts agreed that lack of interaction among stakeholders was the major challenge with the highest inter-rater agreement in both stages (19 out of 25 and 11 out of 17, respectively). The experts recommended the creation of multidisciplinary taskforces dedicated to population sciences, data sciences, technology development and patient management with short-, intermediate- and long-term strategies. Interpretation & conclusions: The study generated a wish list for advances in HF research and management, and proposed recommendations for facilitating convergence research as a way forward to reduce the burden of HF in India.

Sarcomeric gene variants among Indians with hypertrophic cardiomyopathy: A scoping review.

Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that frequently causes sudden cardiac death (SCD) among young adults. Several pathogenic mutations in genes encoding the cardiac sarcomere have been identified as diagnostic factors for HCM and proposed as prognostic markers for SCD. The objective of this review was to determine the scope of available literature on the variants encoding sarcomere proteins associated with SCD reported among Indian patients with HCM. The eligibility criteria for the scoping review included full text articles that reported the results of genetic screening for sarcomeric gene mutations in HCM patients of Indian south Asian ancestry. We systematically reviewed studies from the databases of Medline, Scopus, Web of Science core collection and Google Scholar. The electronic search strategy included a combination of generic terms related to genetics, disease and population. The protocol of the study was registered with Open Science Framework (https://osf.io/53gde/). A total of 19 articles were identified that reported pathogenic or likely pathogenic (P/LP) variants within MYH7, MYBPC3, TNNT2, TNNI3 and TPM1 genes, that included 16 singletons, one de novo and one digenic mutation (MYH7/ TPM1) associated with SCD among Indian patients. Evidence from functional studies and familial segregation implied a plausible mechanistic role of these P/LP variants in HCM pathology. This scoping review has compiled all the P/LP variants reported to-date among Indian patients and summarized their association with SCD. Single homozygous, de novo and digenic mutations were observed to be associated with severe phenotypes compared to single heterozygous mutations. The abstracted genetic information was updated with reference sequence ID (rsIDs) and compiled into freely accessible HCMvar database, available at https://hcmvar.heartfailure.org.in/. This can be used as a population specific genetic database for reference by clinicians and researchers involved in the identification of diagnostic and prognostic markers for HCM.

Utility of 3D Echocardiography for Device Sizing During Transcatheter ASD Closure: A Comparative Study.

BACKGROUND: Two-dimensional (2D) transesophageal echocardiography (TEE) is commonly used for assessing patients undergoing transcatheter atrial septal defect (ASD) device closure. 3D TEE, albeit providing high resolution en-face images of ASD, is used in only a fraction of cases. We aimed to perform a comparative analysis between 3D and 2D TEE assessment for ASD device planning. METHODS: This was a prospective, observational study conducted over a period of one year. Patients deemed suitable for device closure underwent 2D and 3D TEE at baseline. Defect characteristics, assessed separately in both modalities, were compared. Using regression analysis, we aimed to derive an equation for predicting device size using 3D TEE parameters. RESULTS: Thirty patients were included in the study, majority being females (83%). The mean age of the study population was 40.5 ± 12.05 years. Chest pain, dyspnea and palpitations were the common presenting complaints. All patients had suitable rims on 2D TEE. A good agreement was noted between 2D and 3D TEE for measured ASD diameters. 3D TEE showed that majority of defects were circular in shape (60%). The final device size used had high degree of correlation with 3D defect area and circumference. An equation was devised to predict device size using 3D defect area and circumference. The mean device size obtained from the equation was similar to the actual device size used in the study population (p = 0.31). CONCLUSIONS: Device sizing based on 3D TEE parameters alone is equally effective for transcatheter ASD closure as compared to 2D TEE.

Team based collaborative care model, facilitated by mHealth enabled and trained nurses, for management of heart failure with reduced ejection fraction in India (TIME-HF): design and rationale of a parallel group, open label, multi-centric cluster randomised controlled trial.

Background: Heart failure (HF) is a debilitating condition associated with enormous public health burden. Management of HF is complex as it requires care-coordination with different cadres of health care providers. We propose to develop a team based collaborative care model (CCM), facilitated by trained nurses, for management of HF with the support of mHealth and evaluate its acceptability and effectiveness in Indian setting. Methods: The proposed study will use mixed-methods research. Formative qualitative research will identify barriers and facilitators for implementing CCM for the management of HF. Subsequently, a cluster randomised controlled trial (RCT) involving 22 centres (tertiary-care hospitals) and more than 1500 HF patients will be conducted to assess the efficacy of the CCM in improving the overall survival as well as days alive and out of hospital (DAOH) at two-years (CTRI/2021/11/037797). The DAOH will be calculated by subtracting days in hospital and days from death until end of study follow-up from the total follow-up time. Poisson regression with a robust variance estimate and an offset term to account for clustering will be employed in the analyses of DAOH. A rate ratio and its 95% confidence interval (CI) will be estimated. The scalability of the proposed intervention model will be assessed through economic analyses (cost-effectiveness) and the acceptability of the intervention at both the provider and patient level will be understood through both qualitative and quantitative process evaluation methods. Potential Impact: The TIME-HF trial will provide evidence on whether a CCM with mHealth support is effective in improving the clinical outcomes of HF with reduced ejection fraction in India. The findings may change the practice of management of HF in low and middle-income countries.

Development and validation of heart failure-specific quality-of-life measurement tool in India.

Objective: To develop and validate a sensitive tool for assessment of quality of life (QoL) in heart failure (HF) patients in Indian settings. Methods: The authors conducted literature review, in depth interviews, clinical observations and designed the first draft of the QoL tool. The tool was validated using content and face validity by a panel of experts. For internal consistency reliability, the questionnaire was administered among 270 HF patients. Test-retest reliability was assessed in 20 HF patients. Principal component factor analysis with varimax rotation was employed to assess the dimensionality and to reduce the number of items. Cronbach's alpha, and Intra-class correlation coefficients (ICCs) were employed to investigate reliability of questionnaire. The responsiveness data were collected 6 months after the baseline data collection from 30 HF patients. IBM® SPSS® Statistics Version 21 was used for statistical analysis. Results: The principal component factor analysis revealed mainly 5 domains. The final tool included 25 items. Cronbach's alpha (α) for the overall tool was 0.915. Intra-class correlation coefficients (ICCs) based on test-retest was 0.734. The final tool showed good responsiveness to changes with a mean ± SD of the change in response of 46 ± 12.4 and a standardized mean response of 3.7 within six-months. Conclusion: The HF specific QoL tool developed for Indian patients is a valid and reliable instrument and it can be applied in daily clinical practice, and research. Short summary: We had developed and validated a quality-of-life tool for heart failure patients in India. This is the first ever attempt to develop a measure for heart failure patients in India. We had used a mixed methodology approach to identify all the domains in the tool. The newly developed tool is a valid, reliable, sensitive and responsive tool to measure quality of life in HF patients in India. This tool can be applied in daily clinical practice, research and health system for patients with HF in India.

Prevalence and Risk Factors of Periodontal Disease among Rural and Urban Residents of a South Indian City: A Cross-Sectional Study.

Background: The prevalence of oral diseases has been increasing alarmingly in the state of Kerala. Screening for periodontal disease (PD) is crucial due to its negative impact on oral and overall health. Since the occurrence and severity of PD depend on its risk factors, a structured survey in randomly selected districts in the state can be a valuable tool for policymakers to envisage strategies to enhance oral health care and control shared systemic illnesses. Data on the prevalence and risk factors of PD among the residents of the Thiruvananthapuram district of Kerala is not currently available in the public domain. This data could also be representative of the other 13 districts with more or less similar topographical, cultural, and lifestyle characteristics. Aim: To study the prevalence of PD and its risk factors among the residents of the Thiruvananthapuram district of Kerala and to compare the urban-rural differences. Materials and Methods: In this community-based cross-sectional study, a multistage cluster random sampling method was used to select the participants. Among the 1285 participants, 560 were from urban areas, and 725 were from rural areas. A modification of the Ramfjord PD index was used to assess periodontal health. The epidemiological risk factors were evaluated using sociodemographic data, personal histories, and physical and biochemical parameters. Multivariate logistic regression was used to determine the relationship of PD with independent variables. Mediation analysis was performed to examine the mediating effects of independent factors. Results: The rural population (61.4%) had a higher frequency of PD than the urban (35.5%) and an overall prevalence of 50%. Aging, poor oral hygiene, and low educational level (EL) were significant risk factors for PD in urban and rural settings, with hypertension only being significant in the latter. A higher odds ratio (9.07-29.68) with a confidence interval of (5.45-48.94) for poor oral hygiene was noted. Poor oral hygiene and tobacco use had mediating effects between low EL and PD. Conclusions: In this study, the overall prevalence of PD was 50%, with the rural population being more afflicted. Poor oral hygiene has been identified as a modifiable risk factor for PD in urban and rural populations. Poor oral hygiene and tobacco use have been demonstrated to be mediators of the strong link between low EL and PD. Therefore, this study reiterates the need for better oral health awareness and treatment facilities to minimize the impact of the above risk factors on the periodontium. A shared risk relationship between PD and hypertension in the rural population emphasizes the need for an integrated approach to public health by including oral health as part of noncommunicable disease prevention and intervention programs.

Clinical profile and 90 day outcomes of 10 851 heart failure patients across India: National Heart Failure Registry.

AIMS: Limited data on the uptake of guideline-directed medical therapies (GDMTs) and the mortality of acute decompensated HF (ADHF) patients are available from India. The National Heart Failure Registry (NHFR) aimed to assess clinical presentation, practice patterns, and the mortality of ADHF patients in India. METHODS AND RESULTS: The NHFR is a facility-based, multi-centre clinical registry of consecutive ADHF patients with prospective follow-up. Fifty three tertiary care hospitals in 21 states in India participated in the NHFR. All consecutive ADHF patients who satisfied the European Society of Cardiology criteria were enrolled in the registry. All-cause mortality at 90 days was the main outcome measure. In total, 10 851 consecutive patients were recruited (mean age: 59.9 years, 31% women). Ischaemic heart disease was the predominant aetiology for HF (72%), followed by dilated cardiomyopathy (18%). Isolated right HF was noted in 62 (0.6%) participants. In eligible HF patients, 47.5% received GDMT. The 90 day mortality was 14.2% (14.9% and 13.9% in women and men, respectively) with a re-admission rate of 8.4%. An inverse relationship between educational class based on years of education and 90 day mortality (high mortality in the lowest educational class) was observed in the study population. Patients with HF with reduced ejection fraction and HF with mildly reduced ejection fraction who did not receive GDMT experienced higher mortality (log-rank P < 0.001) than those who received GDMT. Baseline educational class, body mass index, New York Heart Association functional class, ejection fraction, dependent oedema, serum creatinine, QRS > 120 ms, atrial fibrillation, mitral regurgitation, haemoglobin levels, serum sodium, and GDMT independently predicted 90 day mortality. CONCLUSION: One of seven ADHF patients in the NHFR died during the first 90 days of follow-up. One of two patients received GDMT. Adherence to GDMT improved survival in HF patients with reduced and mildly reduced ejection fractions. Our findings call for innovative quality improvement initiatives to improve the uptake of GDMT among HF patients in India.

A multicentric, 2 × 2 factorial, randomised, open-label trial to evaluate the clinical effectiveness of structured physical activity training and cognitive behavioural therapy versus usual care in heart failure patients: a protocol for the PACT-HF trial.

Background: Heart failure (HF) is a multi-morbid chronic condition, which adversely affects the quality of life of the affected individual. Engaging the patient and their caregivers in self-care is known to reduce mortality, rehospitalisation and improve quality of life among HF patients. The PACT-HF trial will answer whether clinical benefits in terms of mortality and hospitalisation outcomes can be demonstrated by using a pragmatic design to explore the specific effects of physical activity, and cognitive behavioural therapy in HF patients in India. Methods: We will conduct a 2 × 2 factorial, randomized, open-label trial, which aims to see if rehabilitation strategies of structured physical activity training and cognitive behavioural therapy for depression and self-management reduce the risk of repeat hospitalisation and deaths in HF patients in India. Patients will be randomised to (1) physical activity + usual care (2) cognitive behaviour therapy + usual care, (3) physical activity + cognitive behaviour therapy + usual care, and (4) usual care at 1:1:1:1 ratio. Time to mortality will be the primary outcome. A composite of mortality and hospitalisation for HF will be the main secondary outcome. Additional secondary outcomes will include 'days alive and out of hospital', cumulative hospitalisation, quality of life, Minnesota Living with Heart Failure questionnaire score, depression score, six minutes walking distance, handgrip strength, and adherence to medicines and lifestyle.  The effects of intervention on the primary outcome will be estimated from Cox proportional hazard models. For the continuous secondary outcome variables, differences between randomised groups will be estimated from linear mixed models or generalised estimating equations (GEE) as appropriate. Discussion: PACT-HF is designed to provide reliable evidence about the balance of benefits and risks conferred by physical activity and cognitive behavioural therapy-based cardiac rehabilitation for those with HF, irrespective of their initial disease severity.

A community-based study on electrocardiographic abnormalities of adult population from South India - Findings from a cross sectional survey.

BACKGROUND: There are no data on electrocardiographic (ECG) findings from general population of Indian subcontinent. We analyzed ECG abnormalities of in adults as part of a community survey of prevalence of coronary artery disease and risk factors from South India. METHODS AND RESULTS: In this cross-sectional study of men and women between the ages 20 to 79 years, ECGs recorded digitally were analyzed using the Minnesota code. Electrocardiograms were analyzed for abnormalities in 4630 participants (women 59.6%). The overall prevalence of ECG abnormalities (39.9%) was higher in men (47.24% vs. 34.9% p <0.0001). QRS axis deviation, first degree AV block, fascicular blocks, incomplete right bundle branch block, sinus bradycardia and ST elevation in the anterior chest leads were markedly higher in men. Sinus tachycardia and low voltage QRS occurred more often in women. The overall prevalence of atrial fibrillation was 0.32% which was markedly lower than the western data. Brugada and early repolarisation patterns occurred in 1.06% and 1.56% respectively, equal in both age groups, but markedly higher in men. Brugada pattern occurred more often than in the west, but much less than the Far East population. Early repolarisation pattern was similar to rest of Asian population, but significantly less than the Caucasian population CONCLUSION: In this community-based study, prevalence of major electrocardiographic abnormalities was high. Overall, men had significantly higher ECG abnormalities.

Assessment of the impact of heart failure on household economic well-being: a protocol.

Background: Heart failure (HF), which is an emerging public health issue, adversely affects the strained health system in India. The adverse impact of HF on the economic well-being has been narrated in various anecdotal reports from India, with affected individuals and their dependents pushed into the vicious cycle of poverty. There is limited research quantifying how HF impacts the economic well-being of households from low- and middle-income countries. Methods: We describe the methods of a detailed economic impact assessment of HF at the household level in India. The study will be initiated across 20 hospitals in India, which are part of the National heart Failure Registry (NHFR). The selected centres represent different regions in India, stratified based on the prevailing stages of epidemiological transition levels (ETLs). We will collect data from 1800 patients with acute decompensated HF and within 6-15 months follow-up from the time of initial admission. The data that we intend to collect will consist of a) household healthcare expenditure including out-of-pocket expenditure, b) financing mechanisms used by households and (c) the impoverishing effects of health expenditures including distress financing and catastrophic health expenditure. Trained staff at each centre will collect data by using a validated and structured interview schedule. The study will have 80% power to detect an 8% difference in the proportion of households experiencing catastrophic health expenditures between two ETL groups.  After considering a non-response rate of 5%, the target sample size is approximately 600 patients from each group and the total sample size is 1800 patients. Potential Impact: Our study will provide information on catastrophic health spending, distress financing and household expenditure in heart failure patients. Our findings will help policy makers in understanding the micro-economic impact of HF in India and aid in allocation of appropriate resources for prevention and control of HF.

The traditional and modifiable risk factors of coronary artery disease - a community-based cross-sectional study among 2 populations.

ABSTRACT: A community-based cross-sectional study was undertaken by the Cardiology Society of India (Kerala Chapter) to determine the prevalence of coronary artery disease (CAD) and its risk factors. The periodontal health status of the rural and urban participants in the Thiruvananthapuram district of Kerala was evaluated to document any association between periodontal disease (PD) and CAD and to describe any shared risk factors.The participants were selected using a multistage cluster random sampling method. Socio-demographic data and personal histories were collected using a structured interview schedule and validated tools. Body mass index, blood pressure, electrocardiogram, and biochemical investigations were recorded and analyzed using standard protocols. A modification of the Ramfjord periodontal disease index was used to assess periodontal health.PD was more frequent among rural (61.4%) than in the urban population (35.5%). The frequencies of CAD associated with PD in the rural and urban populations were 82.6% and 40.5%, respectively. PD was not found to be a significant risk factor for CAD in the univariate regression analysis of urban populations. In the rural population, the odds of PD as a risk factor for CAD were found to be 3.08 (95% CI [1.38-8.38]) and significant (P = .043) in univariate regression analysis and 1.54 (95% CI: 0.44-5.4) and non-significant (P = .503) in the multivariate regression analysis.In rural areas, male sex and dyslipidemia demonstrated borderline significance as risk factors for CAD. PD was not found to be an independent risk factor after adjusting for age, sex, tobacco use, hypertension, sedentary lifestyle, and dyslipidemia. Male sex and dyslipidemia were identified as shared risk factors between PD and CAD, which could have confounded the significant association between the latter. In urban areas, age, male sex, and dyslipidemia demonstrated an independent association with CAD. This study could not establish an independent association between PD and CAD in either community. Future epidemiological studies should identify and recruit novel environmental factors to understand the interrelationships between PD and CAD and focus on the role of effect modifiers that may have a protective role against PD colluding with CAD.