Explaining Heart Failure Hyper-mortality in Sub Saharan Africa: Global Genomic and Environmental Contribution Review.

The annual heart failure (HF) mortality rate in Africa is 34% according to the INTERHF study. This is twice the world average of 16.5% and 3.7 times that of South America, 9%. We review evidence-based explanations for the Hyper-mortality of HF, by comparison of North American, Caribbean, Afro-Brazilian with Sub-Saharan African (SSA) nations profiles, and suggest amelioration. 1 year HF mortality rates in SSA ranged from 29% to 58%, and intra-hospital mortality rate from 8 to 26% (n = 8). A clustering of adverse genetic single nucleotide polymorphisms (SNP) predisposing to hypertension and/or left ventricular hypertrophy (LVH) in the black diaspora may contribute. A higher prevalence of HF with reduced Ejection Fraction (HF r EF) phenotype, which is associated with greater mortality is more common in SSA nations. Additionally, a worse co-morbidity burden, especially valvular regurgitations causing LV remodeling (LVR), chronic kidney disease (CKD), anemia, lung disease, infections, late presentation in NYHA III/IV, right ventricular disease (RVD) were also common in SSA. Geographic variation in SSA, HF risk factors and co-morbidity was observed. There was sub-optimal use of guideline directed medical therapy (GDMT) and intracardiac device (ICD) unavailability. Gross Domestic Product -per purchasing power parity (GDP-PPP), which is low in SSA, was inversely correlated both to higher intra-hospital mortality rate % (r = -0.73, r 2 = 0.54 p = 0.038) and higher 1 year HF mortality rate % (r = -0.62, r 2 = 0.38, = 0.098). Localized primary prevention, early detection and prompt treatment of hypertension, diabetes, rheumatic fever, early cardiac valve repair and use of cardiovascular polypill, optimal use of GDMT, national health insurance scheme are advocated to stem the dismal mortality and cost burden of HF.

Itching, chloroquine, and malaria: a review of recent molecular and neuroscience advances and their contribution to mechanistic understanding and therapeutics of chronic non-histaminergic pruritus.

Chloroquine (CQ) is an antimalarial drug that elicits severe pruritus in black Africans with malaria fever. This acute itching (2-7 days duration) exhibits age dependency and a racial and genetic predilection. CQ itch is non-histaminergic, which makes it both a good model and a tool to probe the mechanisms of chronic itch. This review focuses on recently discovered mechanisms, neuroscience, mediators, and receptors that are implicated in molecular studies of CQ pruritus. CQ pruritus mechanisms are also compared to that of itching following other systemic diseases, such as chronic kidney disease, chronic liver disease, skin disorders, and burns. There are striking similarities between CQ itching pathways and other chronic itch secondary to systemic disease with or without skin lesions, which have not been previously highlighted. Prominent among these are the shared roles of skin, neural and spinal µ opiate receptors, kappa opiate receptor, nitric oxide, serotonin via 5HT1B/D receptors, cytokines, especially interleukins, and tumor necrosis factor. There is elaborate "cross talk" among the diverse mediators and receptors involved in CQ-induced pruritus. CQ also binds to the mas-related G protein coupled receptors MrgprA3/MrgprX1 present in a small proportion (4-5%) of dorsal root ganglion neurons and skin. The mrgprA3 CQ receptors are coupled to PLC-ß3 and a chloride channel to initiate skin itch action potentials in C nerve fibers. Mrgpra3/X1 couples to TRPA1 for calcium influx into neuronal cells at noncutaneous sites. Central CQ itch occurs via gastrin-related peptide (GRP) and its receptor (GRPR) in the dorsal spinothalamic tracts, as well as glutamic mediated GRP projection to parabrachial nucleus. The possibility of chronic itch therapy based on personalized medicine, genetics, and transcriptomics or the use of itch "polypill/polycream" are discussed.

Influence of West African Ethnicity and Gender on Beta-Cell Function and Insulin Sensitivity in Essential Hypertensives Treated with Hydrochlorothiazide and Hydrochlorothiazide-lisinopril Combination.

OBJECTIVE: To assess the effects of hydrochlorothiazide (HCT) given alone and in combination with an angiotensin-converting enzyme inhibitor (ACEI) on beta-cell function in a negroid population to further explore possible ethnic differences in the effect of antihypertensive drugs on homeostasis model assessment - insulin resistance (HOMA-IR). MATERIALS AND METHODS: A total of 80 newly diagnosed Nigerian essential hypertensive patients were assigned to receive either HCT 25 mg daily or both HCT and lisinopril (Lis; 25/10 mg daily) in an open-label study for 12 weeks. The treatment groups were well matched in clinical and demographic baseline features. Changes in HOMA-IR from baseline to end of study (week 12), fasting plasma glucose (FPG), serum potassium, serum insulin, and blood pressure over the same period were also evaluated. RESULTS: After 12 weeks, mean delta HOMA-IR (and %) was higher in the HCT monotherapy group; although, this change did not reach statistical significance in both groups -0.1 ± 7.1, P = 0.538 (HCT) and 0.6 ± 4.2 P = 0.913 (HCT + Lis); an insignificant increase was observed in FPG and serum insulin in both groups, whereas serum potassium decreased in similar fashion. Blood pressure reduction was similar in both groups. Analysis of HOMA-IR change according to gender in response to HCT mono- or combination therapy with Lis showed no significant difference. CONCLUSIONS: HCT monotherapy in hypertensive indigenous Nigerians, was not associated with worse metabolic effects when compared with combination therapy using Lis, an ACEI after 12 weeks. Low-dose thiazide diuretic as first-line antihypertensive medication may be safe in the short-term, further larger and long-term studies are needed to corroborate this finding.

Pattern of arrhythmias among Nigerians with congestive heart failure.

BACKGROUND: In patients with heart failure, death is often sudden due to life-threatening arrhythmias. This work was carried out to evaluate the pattern of arrhythmias in Nigerians with heart failure. MATERIALS AND METHODS: Thirty subjects with congestive heart failure (CHF), 30 subjects with hypertensive heart disease, and 15 normal subjects with no obvious features of heart disease were evaluated with resting and 24-hour electrocardiographic monitoring and transthoracic echocardiography. Data were analyzed with one-way analysis of variance with post hoc Duncan's analysis, Fisher's exact test, and linear regression analysis using SPSS version 16. RESULTS: CHF subjects had more instances of supraventricular tachycardia (P=0.005), ventricular extrasystoles (P<0.001), bigeminy (P<0.001), trigeminy (P<0.001), couplets (P<0.001), triplets (P<0.001), and nonsustained ventricular tachycardia (VT) (P=0.003) than the other two control groups. They also showed a significantly longer VT duration (4.6±5.6 seconds) compared with the other groups (P<0.001). Linear regression analysis showed a significant direct relationship between VT and the maximum number of ventricular extrasystoles per hour (P=0.001). CONCLUSION: Cardiac arrhythmias are common in subjects with CHF and are more frequent when compared with patients with hypertensive heart disease and normal subjects.

Valvular regurgitations may increase risk of arrhythmias in Nigerians with hypertensive heart failure.

BACKGROUND: Hypertensive heart disease (HHD) is the commonest cause of sudden cardiac death among Nigerians. A high frequency and early onset of valvular regurgitations (VHD) in hypertensives, and greater concentric hypertrophy are also common in that population. AIMS AND METHODS: To further investigate the relationship between VHD and cardiac arrhythmias and their correlates seen in the hypertensive spectrum and to test the hypothesis that VHD predisposes to cardiac arrhythmias in hypertensive heart failure (HHF). HHF patients (n = 14), HHD patients n = 23, and normotensive controls (n = 9) all underwent 24 h electrocardiogram Holter monitoring as well as two-dimensional and Doppler echocardiography. Participants in each patient category were classified according to the presence and severity of VHD or its absence (NVHD). RESULTS: There were statistically significant differences in the mean supraventricular tachycardia (SVT) (P < 0.001 analysis of variance; ANOVA), the mean and median frequency of ventricular tachycardia episodes (P < 0.02 ANOVA), and couplets (P = 0.0002 ANOVA) between groups. HHF-VHD always had more SVT (81/24 versus 4.4/24 h; P = 0.016) and ventricular arrhythmias 69/24 versus 34/24 h (P < 0.02) than HHF-NVHD. Multivalvular regurgitations (three or more valves), higher left ventricular mass index (g/m2) [274 (24) versus 191(19); P < 0.001 ANOVA], and lower ejection fraction (EF; %) [29(3) versus 53(14)] in HHF-VHD were arrhythmogenic. Mean ventricular tachycardia/triplet frequency/24 h were HHF-VHD 69, HHF-NVHD 39, HHD-VHD 0.3, HHD-NVHD 6, and controls 0.2 (P < 0.02 ANOVA). Compared with 35% (10/27) of all VHD, 15.7% (3/19) of all NVHD participants had nonsustained ventricular tachycardia. The number of regurgitant valves was positively correlated with the frequency of the Lown class of the arrhythmias 0-IVB (r = 0.42, P = 0.003) and to ventricular tachycardia (r = 0.3, P = 0.04) (both n = 46). CONCLUSION: Left ventricular hypertrophy (LVH) increased arrhythmias. But multivalvular regurgitations predisposes to greater SVT and complex ventricular arrhythmias, especially in HHF. Low EF and concentric LVH are correlates.

Valvular regurgitation impact on left ventricular 2-dimensional and Doppler echocardiographic indices in patients with essential hypertension.

BACKGROUND: Blacks have both a higher hypertension prevalence and accelerated cardiac end organ damage. Because blacks also have a higher prevalence of valvular heart disease, which occurs at a younger age than for whites, we further examined the contribution of valvular regurgitation to the severity of hypertensive heart disease in Nigerians. METHODS: We evaluated and compared echocardiographic indexes in 75 essential hypertensive Nigerians with (n=48) and without (n=27) valvular regurgitations. Demographic and echocardiographic indices, as well as the types and severity of valvular lesions were compared between the groups using bivariate logistic regression and analysis of variance. RESULTS: The 2 groups were of similar demographics, but those with regurgitations had larger cardiac size (p < .05), greater mass (147 +/- 31 vs. 122 +/- 32 g/m2, p = .01) higher volume (p < .01), and left atrial size (35.6 +/- 4.6 vs. 33.3 +/- 4.6 mm, p < .05). Atrial size, cardiac volume, and dimension were independent correlates/predictors of regurgitation occurrence. Relative wall thickness of at least 0.6 was more common in regurgitation patients. Cardiac mass was correlated to increasing age (r = 0.23, p = .043). The valvular lesions frequencies were aortic regurgitation, 8; mitral regurgitation, 22; and mixed, 18. The aortic orifice dimension was significantly different among the regurgitant cases, highest in aortic regurgitation (p = .001). Aortic orifice dimension increased with hypertension duration (p = .028). CONCLUSIONS: Regurgitant lesions are common and occur early in hypertensive Africans. Apparently mild valvular regurgitation may accentuate preclinical concentric hypertrophy in hypertensive blacks.

Left Ventricular Diastolic Function in Nigerian Patients with Essential Hypertension: A Retrospective Study to Compare Angiotensin Converting Enzyme Inhibitors, Calcium Channel Blockade or Their Combination.

BACKGROUND: Hypertension in blacks imposes a greater left ventricular hypertrophy, and accelerated heart failure onset. We evaluated and compared the echocardiographically determined systolic and left ventricular diastolic functional indices in Nigerian hypertensive patients, associated with the chronic use of ACE inhibitors, Calcium channel blockers (CCB) or their combinations. METHODS: Ejection fraction -EF, intraventricular relaxation time (IVRT), E/A peak velocity ratio, E wave deceleration time] as well as the left ventricular mass index (LVMI) was undertaken among 41 Nigerian patients with essential hypertension only, on treatment for 4-6 months prior. The 41 patients (aged 59 +/- 10 years, 40% females) were divided into three groups; those receiving (i) ACE inhibitors; or (ii) CCB or (iii) combination of ACEI and CCB. All the three groups had a background of diuretic treatment for optimal blood pressure control. RESULTS: There were no statistically significant differences in the mean LVMI or sitting blood pressure between treatment groups. E/A ratio for ACEI treatment was 1.06 +/- 0.44, CCB 0.74 +/- 0.19, and for ACEI + CCB 0.87 +/- 0.26 (F = 3.29, P = 0.048 anova). The 95% confidence interval for the E/A ratio on ACEI was 0.8 to 1.33. The A wave duration time integral (AVVTi) were all abnormally large, but showed a significant between treatment group difference (P = 0.037, anova). The values were 21.9 +/- 4.7 for ACEI, 25.3 +/- 6.3 for CCB, and least at 20.1 +/- 3.6 cm for the ACE + CCB combination. Similarly, the IVRT was lowest and <100 ms with ACEI + CCB being 93 +/- 18 ms, ACEI 115 +/- 23 ms, and CCB being 117 +/- 22 ms (F = 4.92, P = 0.01, anova). The 95% CI for IVRT on ACEI + CCB was 82 to 104 ms. There were no between treatment group differences in systolic contractility, (fractional shortening or EF). CONCLUSIONS: The results indicate that use of an antihypertensive drug regime inclusive of an ACE inhibitor (+/-CCB) may be associated with greater salutary effect on indices of diastolic function, (E/A > 1, lower AVVTi, IVRT < 100 ms) even in the presence of an equivalent effect on systolic function and blood pressure.

The effect of flutamide on systemic and renal hemodynamics in Zucker diabetic rats: paradoxic renal vasodilator response to endothelin-1 and TXA2 receptor activation in female sex.

BACKGROUND: There is increasing evidence that endogenous sex hormones regulate vascular reactivity, and testosterone may contribute to the worse prognosis for renal disease in men. Male Zucker diabetic rats exhibit improved renal hemodynamic responses after castration. It is, however, unclear whether endogenous testosterone affects renal and systemic microcirculatory responses in the female sex, especially in type 2 diabetes. AIM: To test the hypothesis that endogenous testosterone in the female Zucker diabetic rat exerts a pathophysiologically relevant modulation of endothelial and renal microvascular function. METHODS: Female Zucker diabetic rats (FZDR) aged 5-6 weeks and from the same litter were divided into 2 groups (n = 6-8 each). The experimental group received the androgen receptor blocker flutamide, dissolved in alcohol and added to their drinking water (500 mL) at 20 mg/rat/week. The control FZDR received only the alcohol vehicle added to the same volume of drinking water. Both FZDR groups were treated for 3 months before undergoing the hemodynamic studies. A sex comparison control group of male Zucker diabetic rats (MZDR), also aged 5-6 weeks, was studied, following same protocol. Mean arterial pressure (MAP) and renal cortical blood flow (RCF) response to phenylephrine, acetylcholine, TXA2-mimetic U46619, endothelin-1 (ET-1), angiotensin II, and L-NG-nitro arginine methyl ester were studied. Furthermore, the role of protein kinase C in the responses was assessed using phorbol-12,13 dibutyrate 10(-4) M. The impact of flutamide on body weights and blood glucose of the rats were also determined. RESULTS: Flutamide-treated FZDR had a significant reduction in body weight/adiposity to 432 +/- 44 g, compared to controls at 553 +/- 37 g (P = 0.045), and random blood glucose concentration of 185 +/- 44 g/dL, compared to the control FZDR at 475 +/- 34 g/dL (P = 0.002). Vehicle-treated FZDR (n = 6-8), exhibited little or no systemic or renal response to any of the agonists. By contrast, flutamide treatment of FZDR (n = 5-7) caused a normalization of the dose-dependent MAP and RCF pressor response to phenylephrine [P < 0.005, analysis of variance (ANOVA)] and the vasodilator response to acetylcholine (P <. 0.01, ANOVA). Flutamide-treated FZDR showed enhanced pressor response to U46619 (P = 0.024, ANOVA), ET-1, and angiotensin II (P < 0.03, ANOVA). Surprisingly, the augmented systemic pressor action of U46619 and ET-1 was accompanied by a renal vasodilator action, with paradoxic RCF increases to U46619 (P < 0.003, ANOVA) and to ET-1 (P < 0.001, ANOVA) only in flutamide-treated FZDR. By contrast, flutamide-treated MZDR exhibited no significant change in body weight and an attenuation of the vasoconstrictor responses and enhanced nitric oxide-mediated dilatation compared with male controls. However, no specific effect on ET-1 or TXA2 receptor-mediated renal perfusion was discernible. Both L-NG-nitro arginine methyl ester and the protein kinase C agonist phorbol-12,13 dibutyrate [10(-4)M] significantly increased MAP and reduced RCF (P < 0.03) in the experimental FZDR compared with their controls. CONCLUSION: Flutamide administration to FZDR resulted in the reversal of abnormal systemic and renal alpha-1-mediated vasoconstriction and enhanced nitric oxide-mediated vasodilation. Flutamide caused a paradoxic but specific increase in renal perfusion during ET-1 and TXA2 receptor activation, which could be renoprotective in females. The salutary effects of flutamide on vascular reactivity in the FZDR may be mediated by a protein kinase C-dependent mechanism. These results are compatible with the notion that endogenous testosterone may regulate systemic and renal microcirculation in the female sex and in the type 2 diabetic state.

Adjunctive sympathoplegic therapy to ACE inhibition in Blacks with congestive heart failure: a comparison of alpha-1 with beta-1 blockade on exercise tolerance and cardiac sympathovagal reflex activity.

OBJECTIVES: Congestive heart failure (CHF) is characterized by an initial compensatory, but subsequently deleterious, activation of both the renin-angiotensin (RAS) and the sympathetic nervous system (SNS). Incomplete suppression of the SNS may contribute to the residual mortality during optimal ACE inhibitor therapy in CHF. Carvedilol, a mixed alpha and beta-blocker with antioxidant properties, and other pure beta-adrenoceptor blockers reduce morbidity and mortality in Caucasians with CHF. However, beta-blocker monotherapy is of poor efficacy in Blacks with essential hypertension or in the treatment of glaucoma. The efficacy of beta-blockers in the treatment of African Americans with congestive heart failure is a controversial issue with conflicting findings. The aims of the present study were to examine and compare the cardiovascular, autonomic, and clinical effects of additional alpha-1, or beta-1 blockade in ACE-inhibitor treated Black patients with moderate to severe CHF. METHODS: Twenty-eight Nigerian patients with chronic CHF stabilized on digoxin and diuretics, were randomized to 3 groups of similar demographics according to a single blind, parallel group design. The patients were aged 53 +/- 6 years, and comprised 14 men and 14 women, with a mean cardiothoracic ratio of 0.66 +/- 0.03, and ejection fraction of 0.38 +/- 0.10, 60% hypertensive etiology. Group 1 patients received 5 mg enalapril alone, group 2 received 5 mg enalapril + 1 mg prazosin, and group 3 received 5 mg enalapril + 50 mg atenolol. All medication was taken daily for 4 weeks. Blood pressure, heart rate, pressure rate product, 6-minute walk test, NYHA class, and cardiac autonomic reflexes were measured at baseline and again at 2 and 4 weeks of treatment. Two-way repeated measures ANOVA, and a one-way ANOVA were used in data analysis. RESULTS: The 3 treatments caused significant (P<.001 ANOVA) and similar improvements for the NYHA class (-1.0 to -1.6), and increased the 6-minute distance covered (+130 m to +205 m). Although no treatment differences were observed, a trend suggesting a greater improvement with enalapril + atenolol became apparent. By the fourth week, the sympathoplegic treatments, enalapril + atenolol, and enalapril + prazosin, caused significant reductions in the pressure rate product (-3726 +/- 1885 mm Hg x beats/min; -3498 +/- 396 mm Hg beats/min, respectively), (compared to enalapril alone (-1349 +/- 894 mm Hg x beats/min) (P<.001 ANOVA). During the Valsalva maneuver, the phase IV bradycardia were significantly greater after treatment with enalapril + atenolol (944 +/- 66 msec) or with enalapril + prazosin (825 +/- 48 msec), compared to enalapril alone (760 +/- 45 msec) (P<.001 ANOVA). The phase II Valsalva tachycardia were similar between treatments. The respiratory sinus arrhythmia ratio increased significantly (P<.005 ANOVA) and equally on all treatments. However, the pressor and chronotropic responses to forearm isometric handgrip increased significantly on the enalapril + prazosin combination (P<.02), compared to the other treatments. CONCLUSIONS: Our findings demonstrated not only the safety of providing additional therapy with alpha-1 or beta-1 receptor blockade concurrent with ACE inhibition in Blacks with CHF, but also the resultant improvement in exercise tolerance and NYHA class. Compared to using ACE inhibition alone, the combined therapies caused a marked reduction in the pressure rate product, an index of myocardial oxygen consumption, and a greater enhancement of cardiac parasympathetic activity. Selective beta-1 blockade caused a greater enhancement of central baroreceptor vagal activity compared to alpha-1 blockade. Conversely, the pressor and chronotropic abnormalities during forearm isometric handgrip in CHF, were normalized by alpha-1, but not beta-1, blockade. Thus, the combined reflex cardiac vagal augmentation following selective beta-1 blockade, and the hemodynamic effects of alpha-1 antagonism with concurrent ACE inhibition, may be of major therapeutic and prognostic benefit in Blacks with non-ischemic (hypertensive) CHF stabilized on digoxin and diuretics.