The State of Cardiac Rehabilitation in Saudi Arabia: Barriers, Facilitators, and Policy Implications.

Cardiovascular disease (CVD) is a critical public health issue in Saudi Arabia, where it is the leading cause of death. The economic burden of CVD in the country is expected to triple by 2035, reaching $9.8 billion. This paper provides an overview of CVD in Saudi Arabia and its risk factors, impact on healthcare, and effects on patients' quality of life. The review emphasizes the potential of cardiac rehabilitation (CR) programs in addressing the CVD epidemic. CR programs have been shown to reduce morbidity, mortality, and hospital readmissions while improving patients' cardiovascular health and overall well-being. However, these programs are underutilized and inaccessible in Saudi Arabia. The paper highlights the urgent need for CR programs in the country and suggests key strategies for implementation. These include increasing patient referrals, tailoring programs to individual needs, enhancing patient education, and making CR accessible through home-based options. Fostering multidisciplinary collaboration and developing tailored guidelines for Arab countries can further enhance the impact of CR programs. In conclusion, this review underscores the vital importance of comprehensive CR programs in Saudi Arabia to combat the rising CVD burden, improve patient quality of life, and align with the goals of the Saudi 2030 Vision for a healthier society.

Prevalence of Caries among School Children in Saudi Arabia: A Meta-Analysis.

Introduction: Children's dental health has become the primary concern, because of the increase in the prevalence of caries amongst school children in Saudi Arabia. Therefore, a meta-analysis was conducted to assess the prevalence and severity of dental caries among school children in Saudi Arabia. Method: A systematic search of Scopus, ISI Web of Science, EMBASE, Saudi digital library, Google Scholar, and MEDLINE via Ovid for cross-sectional studies with healthy participants between 5and -15 years. Two authors independently extracted the prevalence of caries. With 95% confidence intervals (CIs) using a random-effects model, we calculated caries prevalence. Results: Dental caries prevalence data were extracted from 18 cross-sectional studies (n = 56,327 children). The pooled estimate for the caries prevalence among 5-7 years' children was 84% (95% CI: 0.81-0.87%; I2 = 91%) while among 12-15 years' children was 72% (95% CI: 0.63-0.79; I 2 = 96.2%). Discussion. In this systematic review, the summary estimate of the prevalence of dental caries among children of 5-7 years and 12-15 years were 84% and 72%, respectively. Further research is required to identify approaches for preventing and treating dental caries in schoolchildren.

N-terminal pro BNP and galectin-3 are prognostic biomarkers of acute heart failure in sub-Saharan Africa: lessons from the BAHEF trial.

AIMS: The relationship between N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and galectin-3 and outcomes has not been studied in African patients with acute heart failure (AHF). The current analysis sought to describe the association between plasma levels of NT-pro-BNP and galectin-3 and cardiovascular (CV) death or heart failure (HF) hospitalization, as well as their associations with symptoms and echocardiography markers of left and right ventricular remodelling among AHF patientsv in sub-Saharan Africa. METHODS AND RESULTS: In a subset of 80 patients with complete data in a study assessing the effects of hydralazine and nitrates in patients with AHF (BAHEF trial; NCT01822808), NT-pro-BNP and galectin-3 analyses were performed, and the association with various characteristics and outcome measures assessed. The mean age of the patients for whom the aforementioned biomarkers were measured was 52.6 years, with 52.5% women. Galectin-3 at baseline predicted changes (Week 24 to baseline) in left ventricular ejection fraction, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, and tricuspid annular plane systolic excursion. Biomarkers and their changes were not associated with changes in 6 min walk test at 24 weeks. Baseline galectin-3 and change in NT-pro-BNP were associated with improvements in dyspnoea at 24 weeks. Nine patients had an HF readmission or died of CV causes through 24 weeks (11.6%). Both biomarkers at baseline predicted combined CV death or HF hospitalization through Week 24 (P-values = 0.0328 and 0.0001, respectively). CONCLUSIONS: In a cohort of patients with AHF from sub-Saharan Africa, NT-pro-BNP and galectin-3 at baseline and their changes were associated with some changes in dyspnoea, echocardiographic remodelling, and CV death or HF hospitalization through Week 24. These tests have potential of being used for risk stratification of AHF patients in sub-Saharan Africa where resources are scarce.

Role of melatonin, melatonin receptors and STAT3 in the cardioprotective effect of chronic and moderate consumption of red wine.

We have recently discovered that melatonin, given acutely and directly to the isolated heart at the concentration found in wine, confers cardioprotection against ischemia-reperfusion (I/R). However, whether the presence of melatonin in wine contributes to the cardioprotective effect of chronic and moderate consumption of wine and its signalling mechanisms of protection are unknown. We therefore used both in vivo and in vitro models of I/R to investigate whether the presence of melatonin in red wine may contribute to the cardioprotective effect of chronic and moderate consumption of red wine. Wistar rats and C57black6 mice (WT) received drinking water supplemented daily with a moderate amount of red wine or melatonin given at the concentration found in the red wine. Rats were also pretreated with luzindole, a specific inhibitor of melatonin receptors 1 and 2 (2.3 mg/kg/day, intraperitoneally) or prazosin, a specific inhibitor of melatonin receptor type 3 (2.5 mg/kg/day, intraperitoneally). After 14 days, hearts were subjected to I/R in vivo or ex vivo. Red wine reduced the infarct size in both rats and WT mice (p < 0.001). Luzindole did not affect wine-induced cardioprotection, while prazosin reduced the infarct sparing effect of red wine (p < 0.05). Furthermore, red wine or melatonin failed to protect tumor necrosis factor alpha (TNF) receptor 2 knockout or cardiomyocyte specific signal transducer and activator of transcription 3 (STAT3) deficient mice (n.s. vs. control). Our novel findings suggest that the presence of melatonin in red wine contributes to the cardioprotective effect of chronic and moderate consumption of red wine against lethal I/R injuries. This effect is most likely mediated, at least in part, via melatonin receptor 3 and the activation of TNF and STAT3, both key players of the prosurvival and well described SAFE pathway.

Loss of cardioprotection with ischemic preconditioning in aging hearts: role of sirtuin 1?

The effectiveness of ischemic preconditioning (IPC) to protect the heart against ischemia/reperfusion injury (IRI) declines with age. The deacetylase protein sirtuin 1 (Sirt 1) confers myriad functions including longevity and cardioprotection against IRI. As such, Sirt 1 may be a potential candidate to explain the protective effect of IPC. We aim to explore the role of Sirt 1 in the loss of the cardioprotective effect of IPC with age. Isolated hearts from young (9 weeks) and older (12-18 months) Long-Evans rats were subjected to 30 minutes of global ischemia and 60 minutes of reperfusion. Preconditioning stimuli were applied with either 2 cycles of 5-minute ischemia/reperfusion or with the potent Sirt 1 agonist resveratrol (RSV, 10 µmol/L) for 15 minutes followed by a 10-minute washout before the sustained ischemia. Both IPC and RSV significantly enhanced the functional recovery of young hearts by 168% (P < .001 vs control) and 65% (P < .01 vs control), respectively, and concomitantly reduced the infarct size by 65% and 45%, but the effect was blunted in older hearts. Administration of the selective Sirt 1 inhibitor III to young hearts did not alter the protective effect of IPC. Following ischemia/reperfusion, higher Sirt 1 deacetylase activity was detected in older hearts compared to young hearts (0.48 ± 0.13 arbitrary units [AU] vs 0.17 ± 0.03 AU, P < .01) and IPC did not alter Sirt 1 deacetylase activity. In conclusion, although Sirt 1 deacetylase activity is increased with age during ischemia/reperfusion, our data suggest that the loss of the cardioprotective effect of IPC in older animals is likely to be independent of Sirt 1.

AMPK activation represses the human gene promoter of the cardiac isoform of acetyl-CoA carboxylase: Role of nuclear respiratory factor-1.

The cardiac-enriched isoform of acetyl-CoA carboxylase (ACCbeta) produces malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase-1. AMPK inhibits ACCbeta activity, lowering malonyl-CoA levels and promoting mitochondrial fatty acid beta-oxidation. Previously, AMPK increased promoter binding of nuclear respiratory factor-1 (NRF-1), a pivotal transcriptional modulator controlling gene expression of mitochondrial proteins. We therefore hypothesized that NRF-1 inhibits myocardial ACCbeta promoter activity via AMPK activation. A human ACCbeta promoter-luciferase construct was transiently transfected into neonatal cardiomyocytes+/-a NRF-1 expression construct. NRF-1 overexpression decreased ACCbeta gene promoter activity by 71+/-4.6% (p<0.001 vs. control). Transfections with 5'-end serial promoter deletions revealed that NRF-1-mediated repression of ACCbeta was abolished with a pPIIbeta-18/+65-Luc deletion construct. AMPK activation dose-dependently reduced ACCbeta promoter activity, while NRF-1 addition did not further decrease it. We also investigated NRF-1 inhibition in the presence of upstream stimulatory factor 1 (USF1), a known transactivator of the human ACCbeta gene promoter. Here NRF-1 blunted USF1-dependent induction of ACCbeta promoter activity by 58+/-7.5% (p<0.001 vs. control), reversed with a dominant negative NRF-1 construct. NRF-1 also suppressed endogenous USF1 transcriptional activity by 55+/-6.2% (p<0.001 vs. control). This study demonstrates that NRF-1 is a novel transcriptional inhibitor of the human ACCbeta gene promoter in the mammalian heart. Our data extends AMPK regulation of ACCbeta to the transcriptional level.

Upstream stimulatory factor 1 transactivates the human gene promoter of the cardiac isoform of acetyl-CoA carboxylase.

E-box cis-elements act as binding sites for upstream stimulatory factors (USFs), putative glucose-responsive transcriptional modulators. Since four E-boxes were identified on the human ACCbeta promoter, we hypothesized that USF1 induces ACCbeta expression in a glucose-dependent manner. Here, murine cardiac ACCbeta expression was significantly increased in response to high carbohydrate re-feeding after fasting. However, transfection studies showed no difference in ACCbeta promoter activity in neonatal cardiomyocytes and CV-1 fibroblasts after low (5.5mM) and high (25 mM) glucose exposure. USF1 overexpression significantly increased ACCbeta promoter activity in both cell lines under low glucose conditions. With high glucose exposure, USF1 further induced ACCbeta promoter activity only in CV-1 fibroblasts. USF1-induced ACCbeta promoter responsiveness was markedly attenuated when co-transfecting cardiomyocytes with a -93/+65 or -38/+65 promoter deletion construct (lacking E-boxes 1-3). Thus, USF1 transactivates the human ACCbeta promoter in the heart, likely through an E-box cis-element located close to the transcription start site.

Serine residues 338 and 339 in the carboxyl-terminal tail of the type II gonadotropin-releasing hormone receptor are critical for beta-arrestin-independent internalization.

Cloned mammalian type II GnRH receptors have a carboxyl-terminal tail in contrast to the mammalian type I GnRH receptors, which uniquely lack a carboxyl-terminal tail. Because this domain mediates internalization of many serpentine receptors, the internalization pathway of the marmoset monkey type II GnRH receptor and the functional role of the carboxyl-terminal tail in internalization was studied. The internalization pathway of the type II GnRH receptor was investigated in COS-1 cells by coexpressing G protein-coupled receptor kinases (GRKs), dynamin-1, and beta-arrestins. Internalization of the receptor requires GRKs and dynamin but does not require beta-arrestin. The type II GnRH receptor can also internalize via beta-arrestin in the presence of exogenous beta-arrestins, suggesting that the receptor can use two distinct internalization pathways. Receptor internalization appears to occur via clathrin-coated pits and caveolae because disruption of either structure inhibits internalization. Progressive truncations of the carboxyl-terminal tail identified a region containing serine residues 338 and 339 as critical for receptor internalization. Substitution of these serine residues with alanine residues inhibited internalization, whereas substitutions with glutamic acid residues rescued internalization. Furthermore, a dominant-negative GRK2 did not inhibit internalization of receptors having these serine substitutions, although it inhibited internalization of the wild-type receptor. These results together identify serine residues 338 and 339 in the carboxyl-terminal tail as critical for internalization of the type II GnRH receptor and suggest that these residues undergo phosphorylation by GRKs. However, neither of these residues, nor the carboxyl-terminal tail, is required for beta-arrestin-dependent internalization.