V)] and electromechanical coupling are two promising approaches in acute circulatory failure. However, validation of the parameters of electromechanical coupling in critically ill patients is ongoing. Furthermore, a unifying link between VA and electromechanical coupling may exist, as EV is correlated with different times of the cardiac cycle.Two parallel paradigms of cardiovascular efficiency and haemodynamic optimisation coexist in haemodynamic research. Targeting ventriculo-arterial (VA) coupling , VA coupling , and SWI/PVA . Patients without baseline dyssynchrony showed no statistically significant results. The improvement in VA coupling was mediated by an amelioration of EV. All patients improved their arterial pressure and cardiac index with treatment. The haemodynamic treatment group exhibited no effect on changing t-IVT.We included 54 patients; 39 (72.2%) were classified as having intraventricular dyssynchrony at baseline. These patients with baseline dyssynchrony showed a statistically significant amelioration of t-IVT . This study was the first to demonstrate a possible link between cardiac electromechanical coupling and VA coupling in patients with acute circulatory failure. A) and left ventricular elastance (EV)  . Severalnce (EV) –9.V is linked with the LV ejection fraction (LVEF). In a study underlying the limits of LVEF in heart failure, EV was found to be strongly correlated with different times of the cardiac cycle , were aged 18 years or above, and were under controlled positive ventilation. For these patients, the intensivist decided to perform a haemodynamic therapeutic intervention  in accordance with the unit's care protocol. The non-inclusion criteria were those who had low echogenicity, a pacemaker, bundle branch block, permanent atrial fibrillation, more than mild aortic regurgitation, or mitral regurgitation, and right heart dysfunction.−2). Cardiac index (CI) (L min−1 m−2) was calculated as SVi × heart rate (HR). The indexed systemic vascular resistance (SVRi) (mmHg mL−1 m−2) was obtained using the formula SVRi = MAP–central venous pressure/CI. Total arterial compliance (mL mmHg−1) was calculated as the ratio between the SV and the arterial pulse pressure.Systolic blood pressure (SAP), diastolic blood pressure (DAP), and mean blood pressure (MAP) were measured using an invasive arterial catheter. Transthoracic echocardiography  was performed by a physician blinded to the results of the study. The echocardiographic parameters were calculated as the average of five measurements (regardless of the respiratory cycle). The data were acquired and stored for further analysis. LVEF, end-systolic volume (ESV), and end-diastolic volume (EDV) were calculated using Simpson's method on a four-chamber view. The diameter of the left ventricular outflow tract was measured on a long-axis parasternal view at the time of patient inclusion. The aortic velocity time integral (VTIAo), pre-ejection time and systolic time were measured using a pulsed Doppler on a five-chamber apical view. Stroke volume (SV) (mL) was calculated as VTIAo × aortic area and was expressed as indexed SV (SVi) = SV/body surface area  was calculated as end-systolic pressure (ESP) × SV. The pressure–volume area (PVA), which corresponds to the total energy generated by each cardiac contraction, was calculated using the formula PVA = SW + PE, where PE is the potential energy stored at the end of systole (0]/2), assuming that V0 is negligible compared to the ESV. Using these variables, the SW index/pressure–volume area (SWI/PVA) ratio was further calculated, corresponding to the mechanical efficiency of converting the total mechanical energy  available to the left ventricular SW , where t-ET is the total ejection time, and t-FT is the total filling time . A t-IVT2O. Ventilator settings  and propofol infusion rate were not modified during the study period.General demographic parameters were collected at the moment of inclusion . Patients were evaluated at two consecutive steps: (1) at the baseline and after therapeutic intervention and (2) after 15 min of haemodynamic stability, which is a change in MAP of <10%. The indication for haemodynamic treatment with fluid expansion, norepinephrine, or dobutamine infusion was left at the discretion of the physician in charge of the patient. All patients were sedated by continuous infusion of propofol and were fully adapted to volume-controlled mechanical ventilation. All patients were mechanically ventilated in a pressure-controlled mode with a positive end-expiratory pressure (PEEP) of 5 cm HThe database was complete; thus, no imputation strategy for missing data was necessary. The normal distribution of variables was assessed using histograms and the Shapiro-Wilk test. Data were expressed as numbers, proportions (in percent), medians [25–75% interquartile range], or as means (± standard deviation), as appropriate. The correlation was assessed using Pearson's or Spearman's tests, as appropriate. Paired data were compared using the Wilcoxon signed rank test.Logistic regression models were performed to evaluate the relation between the baseline characteristics, the type of hemodynamic intervention, and baseline dyssynchrony status. Logistic regression models were further performed to evaluate the relation between the baseline characteristics, the type of hemodynamic intervention, and the response to the treatment. The responsive patients were defined as those with a decrease of at least 10% of baseline total isovolumic time after treatment. The conditions of validity for the logistic regression were verified, in order to have at least 5–10 events for each independent variable included in the model.A/EV higher than 0.4 using Spearman's correlation coefficient with a risk alpha of 5% and a power of 80%. Considering a 10% risk of loss or missing data, we decided to include 54 patients.In the absence of previous data, we estimated that a sample size of 40 patients would allow us to demonstrate a correlation between t-IVT and CI or Ep-value of 0.05 was considered statistically significant.Statistical analyses were performed using RStudio  and SPSS® . A bilateral Fifty-four patients were included in the study. Their general characteristics are summarized in V, cardiac power, or VA-coupling. The MAP, SVi, CI, and LVEF significantly changed with treatment in all cohorts, without modifying peripheral resistances and HR. The patients with intraventricular dyssynchrony had an indexed EDV of 56 (44–81) ml/m2, and the patients without baseline dyssynchrony had an index EDV of 62 (52–96) ml/m2, without a statistically significant difference (p = 0.161).The haemodynamic parameters before and after therapeutic intervention for all cohorts are presented in p > 0.05, p < 0.001) and the ejection time being similar between the two groups . The baseline ratio of ejection time to filling time was high in patients with intraventricular dyssynchrony .The haemodynamic parameters are presented in p = 0.906). Patients with intraventricular dyssynchrony significantly improved EV, ventriculo-arterial coupling . The decrease was highly statistically significant in the group with baseline intraventricular dyssynchrony. The Tei-index was correlated with t-IVT at baseline  and after treatment . The changes in the Tei index were different between the treatment subgroups (p = 0.03). The Tei index response seemed higher in the norepinephrine subgroup [−32% ] compared with that in the fluid expansion subgroup [−8% ] and dobutamine subgroup [−3% ].The Tei index decreased with haemodynamic treatment  and after treatment . The type of haemodynamic treatment was not associated with I/H index changes (p = 0.875).The I/H index did not change with treatment in the cohort as a whole. Nevertheless, it significantly improved in patients with intraventricular dyssynchrony, whereas it worsened in patients without intraventricular dyssynchrony. I/H index and t-IVT were correlated at baseline  patients suffering from acute circulatory failure exhibited cardiac electromechanical uncoupling, independently of the macro-hemodynamic status, type of shock, and patient's characteristics, (2) the cardiac electromechanical coupling was improved by haemodynamic treatment only if altered at baseline , and (3) the improvement of cardiac electromechanical coupling was associated with improvement of markers of cardiocirculatory efficacy and efficiency .V. The increase in EV with a steady EA induced the improvement of ventriculo-arterial coupling.Ventriculo-arterial coupling considers the complex relationship between ventricular and arterial system elastances, and it exhibits a strong link with cardiac energetics and cardiac efficiency , 30, 31.An association between t-IVT and macro-haemodynamic parameters  was observed in patients in the general ICU . BaselinV. Tavazzi et al.  our results, and the fact that during acute phase of shock the main determinant of ventricular dyssynchrony may be heart blood perfusion and cardiovascular interactions. The sample size of the present study may be limited but we performed a sample size calculation based on the study of Tavazzi et al. . PreviouAcute circulatory failure is associated with electromechanical dyssynchrony . Patients with electromechanical dyssynchrony are those who further benefit from haemodynamic treatment in terms of cardiac efficacy and efficiency. T-IVT may represent a potential target for haemodynamic monitoring and optimisation in patients suffering from acute circulatory failure.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Comité de Protection des Personnes Nord-Ouest II CHU - Place V. Pauchet, 80054 AMIENS Cedex 1. The patients/participants provided their written informed consent to participate in this study.SA and P-GG conceived the study, analyzed the data, and drafted the manuscript. VC and P-GG collected the data. BP, MN, and BB provided a critical revision of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Diabetic kidney disease (DKD) is the leading cause of chronic and end-stage kidney disease worldwide. Its pathogenic mechanism is complex, and it can affect the entire structures of the kidneys such as the glomerulus, tubules and interstitium. Currently, the urinary albumin excretion rate and the estimated glomerular filtration rate are widely accepted as diagnostic criteria. However, some studies have reported a different or non-classical clinical course of DKD, with some patients showing declined kidney function with normal levels of albuminuria, known as the ‘non-albuminuric DKD’ phenotype. The pathogenesis of this phenotype remains unclear, but some clinical and pathological features have been postulated. This review explores the evidence regarding this topic. Currently, the urinary albumin excretion rate and the estimated glomerular filtration rate (eGFR) are widely accepted as diagnosis criteria, and the presence of microalbuminuria has been recommended as the first clinical sign of DKD.3Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide.9 Recent evidence has shown that around 20–40% of patients with type 2 diabetes mellitus (T2DM) have declining kidney function without the presence of albuminuria.11 Currently, the pathogenesis of NA-DKD remains unclear, but some clinical and pathological features of this phenotype have been postulated. Here, we review the evidence regarding this topic.Beyond this classical clinical course, some studies report a non-classical clinical course of DKD, where kidney function declines but albuminuria levels are normal. This group of patients is recognized as having the ‘non-albuminuric DKD’ (NA-DKD) phenotype.1The rapid increase in the prevalence and incidence of diabetes has led to a rising prevalence of diabetes-related complications. DKD, a common microvascular complication of diabetes, has become a worldwide public health problem.12 In the UK Prospective Diabetes Study, which followed 9,063 patients with T2DM for 15 years, 61% of patients who developed CKD did not have albuminuria during the follow-up period.13 In Korea and Japan, the reported prevalence of NA-DKD among patients with T2DM is 29.1% and 52.7%, respectively.15 According to other studies, approximately 9.3–71.1% of patients with an eGFR <60 mL/min/1.73 m2 had normal albuminuria.16 Finally, a Chinese study showed that the prevalence of normal albuminuria but reduced eGFR was 8.3% in all patients with diabetes, and 63.3% in those who had an eGFR decline.17The reported prevalence of NA-DKD varies between regions. The Third National Health and Nutrition Examination Survey (NHANES III) data indicated that albuminuria and retinopathy were both absent in 30% of adults with T2DM and CKD among US civilians.Currently, the causes of the increased prevalence of NA-CKD and NA-DKD could be related to the widespread use of renin-angiotensin system blockers and their combinations with the new classes of hypoglycaemic agents, including sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP1-RAs). This situation would increase the proportion of NA-CKD among subjects with T2DM and renal failure.18Regarding cardiovascular outcomes, patients with albuminuric DKD had the highest risk of adverse outcomes compared with patients without DKD. However, results were conflicting when comparing patients with albuminuric versus NA-DKD.6Therefore, albuminuric and NA-DKD patterns significantly differ in their natural history and outcomes. Although NA-DKD is a more favourable condition regarding ESKD risk, it is associated with cardiovascular disease and its risk factors. Both increased albuminuria and reduced eGFR are predictors of ESKD and cardiovascular events in patients with T2DM.19 In classical DKD, retinopathy usually precedes albuminuria as a microvascular complication; however, without albuminuria, the presence of retinopathy supports a pathway of DKD progression distinct from that of the classical phenotype.9 In patients without diabetes with moderate CKD, any type of proteinuria  is present in around 22%.20 As in NA-DKD, tubular damage is associated with the presence of inflammatory markers in CKD.20Although there are few studies addressing this atypical presentation of DKD, factors associated with risk for NA-DKD include female sex, hypertension, active smoking, the absence of diabetic retinopathy and the use of renin–angiotensin–aldosterone system (RAAS) inhibitors.6 However, some intercurrent factors are associated with worse clinical outcomes in patients with NA-DKD.6 Factors such as increasing age, macrovascular complications and interstitial nephritis could modify the course of the disease.17 Overall, NA-DKD tends to be associated with more advanced tubulointerstitial and vascular lesions, but milder typical glomerular damage compared with patients with albuminuric DKD.17 Further exploration of the factors other than albuminuria that contribute to disease progression will help elucidate the mechanisms of NA-DKD.Of note, NA-DKD appears to have a better clinical course than classical DKD, with a slower decline in eGFR and a lower risk of CKD progression.2; however, in patients with T2DM, the median eGFR slope varied from -1.5 mL/min/1.73 m2/year to -4.0 mL/min/1.73 m2/ year.21 In healthy individuals, this decline is attributed mainly to age-related structural changes, such as nephron loss. On the contrary, patients with NA-DKD might have different basal conditions, such as interstitial nephritis or nephrosclerosis, leading to eGFR decline.21 In patients with T1DM with normal albuminuria, an investigation found that 10% (N=286) experienced a progressive decline in eGFR (≥3.3%/year) before the onset of microalbuminuria.22In normal ageing, the annual rate of eGFR decline is estimated to be <1 mL/min/1.73 m6 Currently, renal biopsy is not routinely indicated in these patients; however, it is still the gold standard for diagnosing diabetic nephropathy (DN), and recent evidence favours determining the histology of renal disease in patients with diabetes.24 Therefore, very few studies have analysed renal histological alterations in the early stages of diabetes.25Renal biopsy in patients with diabetes is usually performed in those with significant renal manifestations such as severe proteinuria, microscopic haematuria, rapid and unexplained worsening of kidney function, or a decrease of more than 30% in eGFR after starting RAAS inhibitors.26 These findings suggest early renal involvement in patients with NA-DKD.A recent study from necropsies found that a significant percentage of patients with diabetes without early clinical signs of DKD such as microalbuminuria already show moderate to severe histological involvement related to DN; however, comorbidities and renal progression factors did not significantly differ from patients with albuminuria.27 The classical pathological interstitial changes in DN include tubular basement membrane thickening, interstitial fibrosis, tubular atrophy and arteriosclerosis.28 A study found that interstitial expansion was independently associated with reduced kidney function in T1DM.29 Another investigation in patients with DN showed that interstitial fibrosis contributes to further kidney function decline compared with glomerular injury, and this decline was independent of albuminuria.30 This suggests that eGFR decline is partly related to interstitial injury in T2DM. Ekinci et al. found that three of eight (37.5%) patients with NA-DKD had interstitial and vascular lesions by renal biopsy, and only 1 in 23 (4.3%) patients with albuminuric DKD had interstitial and vascular lesions.31The tubulointerstitium is composed of tubular epithelium, vascular structures and interstitium, and accounts for 90% of renal tissue.32 In accordance, investigations reported that eGFR decline without albuminuria was associated with age-dependent arterial stiffness in patients with and without diabetes.34 This may explain why other renal conditions such as hypertensive nephropathy or age-related nephrosclerosis have similar phenotypes.Beyond the histological evidence, the prevailing underlying pathology of NA-DKD might be macroangiopathy instead of microangiopathy. Moreover, some findings suggest that renal impairment in NA-DKD is not mainly caused by hyperglycaemia or microangiopathy, and that genetic susceptibility, ageing and arteriosclerosis might contribute more to this specific phenotype.35 Therefore, many tubular biomarkers have been suggested.35Conventional approaches to evaluating and monitoring the early stages of DKD have focused on changes in the glomerulus. However, the current standard screening tools, albuminuria, and eGFR are especially insufficient in detecting early tubular and other kidney damage.36As albuminuria is a marker for glomerular damage, biomarkers that reflect other pathological mechanisms of DKD, such as tubular injury, would be acceptable complementary DKD markers to albuminuria. Tubular injury markers such as α1-microglobulin (A1M), liver-type fatty acid-binding protein (L-FABP), N-acetyl-β-D-glycosaminidase (NAG), urinary immunoglobulin G and M, and kidney injury molecule-1 (KIM-1) are associated with DKD.37 Proteomics is a large-scale experimental analysis of proteins through protein purification and mass spectrometry. Proteomic studies have revealed collagen fragments as a potential biomarker of DKD, even 3–5 years before the onset of microalbuminuria in patients with diabetes.38More recently, proteomic and metabonomic analyses have shown promise in evaluating the NA-DKD phenotype. Metabonomic assessment is a relatively new biological approach that provides global metabolic information in biological samples. Hippurate and allantoin are associated with reduced eGFR and are potential markers of nephrotoxicity and tubular dysfunction.Figure 1).39Optimal management of NA-DKD is complex and not entirely known. Nonetheless, multifactorial intervention is needed to target kidney disease progression and cardiovascular disease risk factors. Initial therapy consists of lifestyle modification, including dietary counselling, physical activity and smoking cessation support. Furthermore, controlling hypertension, dyslipidaemia and hyperglycaemia is essential, as in patients with albuminuric DKD (40 Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) are widely recommended in patients with DKD and albuminuria. However, less evidence exists for patients with NA-DKD. Some studies have found that lisinopril, enalapril and losartan are effective at reducing progression of kidney disease and controlling blood pressure in patients with NA-DKD.42Recently, first-line drug therapy proposed by the Kidney Disease Improving Global Outcomes (KDIGO) 2020 clinical practice guideline for diabetes management in CKD includes RAAS blockade, metformin, SGLT2 inhibitors and statins.46 In addition to reducing blood pressure and improving metabolic parameters such as glycated haemoglobin (HbA1c) and weight, SGLT2 inhibitors provide renal protection by correcting glomerular hyperfiltration, reducing albuminuria, improving kidney hypoxia and reducing proinflammatory and profibrotic pathways.47 Although there is no subgroup analysis of albuminuria in the pivotal studies of the different SGLT2 inhibitors, the EMPA-REG OUTCOME,46 CANVAS44 and DECLARE-TIMI 5843 studies analysed empagliflozin, canagliflozin and dapagliflozin, respectively, and included both non-albuminuric and albuminuric patients. Of note, DECLARE-TIMI 58 demonstrated the effect of dapagliflozin in earlier stages of kidney disease, as 65% of the patients showed no expression of any renal markers  and 59% of patients had no previous cardiovascular disease.43 Interestingly, dapagliflozin seems to prevent and reduce DKD progression compared with placebo in T2DM patients with or without established atherosclerotic cardiovascular disease, most of whom had preserved renal function.44 Although the possible mechanisms of benefit were multiple and incompletely understood, in most cases this benefit, seen in all SGLT2 inhibitors, has been independently associated with glycaemic control.48 On the contrary, one exploratory analysis of the EMPA-REG OUTCOME study found no significant between-group difference in the rate of albuminuria.49 New clinical trials explicitly testing the effect of SGLT2 inhibition in patients with NA-DKD are needed.SGLT2 inhibitors have several cardiovascular and renal benefits in patients with diabetes.52 However, in pivotal studies for GLP1-RAs, baseline albuminuria levels were not specified, although a trial testing semaglutide did not exclude normoalbuminuric patients.53 GLP1-RAs in patients with T2DM and CKD are safe and well tolerated, and significantly improve cardiovascular and renal variables.50 On the other hand, in NS-MRA studies, there were no patients with NA-DKD;49 thus, current recommendations are unavailable for these patients.The next step of the therapy proposed by the KDIGO guidelines is GLP1-RAs and non-steroidal mineralocorticoid receptor antagonists (NS-MRAs).55 Because patients with NA-DKD have elevated levels of tumour necrosis factor-α and other cytokines, they could respond to pentoxifylline. Further studies investigating this and other anti-inflammatory drugs in patients with NA-DKD are needed.Finally, given the inflammatory activities associated with diabetes, some anti-inflammatory drugs, such as the tumour necrosis factor-α inhibitor pentoxifylline, decrease or stabilize the progression of DN with additional renoprotective effects.Diagnosing and managing the NA-DKD phenotype represents a real challenge for the nephrology community, as more accurate diagnosis methods are needed alongside albuminuria. Detecting biomarkers early may help to avoid DKD progression. The rapid rise of new agents such as SGLT2 inhibitors, GLP1-RAs, NS-MRAs and their combinations may contribute to improving the outcomes of patients with NA-DKD, though further study is needed.


Elevated blood pressure and hyperglycaemia frequently coexist and are both components of metabolic syndrome. Enhanced cardiovascular risk is strongly associated with diabetes and the occurrence of hypertension. Both hypertension and type 2 diabetes, if treated inappropriately, lead to serious complications, increasing the mortality of patients and generating much higher costs of health systems. This is why it is of great importance to find the missing link between hypertension and diabetes development and to simultaneously search for drugs influencing these two disorders or even drugs aimed at their pathological bases. Standard antihypertensive therapy mainly focuses on blood pressure reduction, while novel drugs also possess a wide range of pleiotropic modes of actions, such as cardio- and nephroprotective properties or body weight reduction. These properties are especially desirable in a situation when type 2 diabetes coexists with hypertension. This review describes the connections between diabetes and hypertension development and briefly summarises the current knowledge regarding attempts to define targets for the treatment of high blood pressure in diabetic patients. It also describes the standard hypotensive drugs preferred in patients with type 2 diabetes, as well as novel drugs, such as finerenone, esaxerenone, sodium–glucose co-transporter-2 inhibitors, glucagon-like peptide-1 analogues and sacubitril/valsartan. The prevalence of hypertension and type 2 diabetes (T2D) is still increasing worldwide. The International Diabetes Federation reported that the number of cases of diabetes was estimated to be 463 million in 2019 and would increase to 700 million by 2045 [Hypertension influences diabetes, and so diabetes affects hypertension. It has been shown that patients without controlled blood pressure despite hypotensive treatment have an increased risk of diabetes development . SystoliHypertension and diabetes are components of metabolic syndrome; they coexist and affect each other’s courses. Constantly elevated blood pressure occurs in 50–80% of patients suffering from T2D and in 30% of individuals with type 1 diabetes ,8. The cThis review briefly describes the pathophysiology of hypertension, especially under the condition of T2D, and outlines attempts over the years to define targets for the treatment of high blood pressure in patients living with diabetes. It mentions the standard hypotensive treatment and focuses on novel drugs that have pleiotropic properties, such as finerenone, esaxerenone, sodium–glucose co-transporter-2 inhibitors, glucagon-like peptide-1 analogues and sacubitril/valsartan.Hypertension may be divided into secondary hypertension, which has a precise known cause, for instance, renal artery stenosis, aortic coartaction, hyperthyroidism, or sleep apnea, and essential hypertension. Essential hypertension is defined as elevated BP without any known causes (after the exclusion of secondary reasons), usually clustering with aging, obesity, insulin resistance, diabetes and hyperlipidaemia—factors which are known to be cardiovascular risk factors . InapproThe main phenomena controlling blood pressure are peripheral vascular resistance and circulatory fluid volume. Peripheral vascular resistance results from vascular tension, which is affected by the rennin–angiotensin–aldosterone system (RAAS), other vasoconstrictors and vasodilators, the activity of the sympathetic nervous system, and vascular remodelling . The oveT2D results from the functional failure of β-cells, which is triggered by insulin resistance . It is cAmylin is a peptide that is cosecreted with insulin by β-cells and participates in carbohydrate metabolism, inhibiting the incorporation of glucose into muscular glycogen and decreasing the secretion of insulin ,43. UndeHyperglycaemia, hyperinsulinemia, inflammation and oxidative stress development, alongside the dyslipidaemia associated with T2D, contribute to vascular remodelling. This in turn causes arterial stiffness and an increase in peripheral vascular resistance, leading to the loss of blood pressure autoregulation . Under pInsulin resistance is the main phenomenon underlying the pathophysiology of diabetes. Hyperglycemia and hyperinsulinemia, as well as other accompanying states, for instance inflammation, oxidative stress, dyslipidaemia or increased atherogenesis, affect the homeostatic system that regulates blood pressure. They activate the sympathetic nervous system and RAAS, trigger the remodelling of the vasculature leading to a larger peripheral vascular resistance and increases in CO and circulatory fluid volume. As a result, T2D participates in hypertension development.Both hypertension and diabetes are risk factors for cardiovascular disease, leading to an increase in mortality due to coronary artery disease, heart failure or stroke ,57. TherThe first trial that focused on this issue was the UK Prospective Diabetes Study (UKPDS). In the study, tight blood pressure control (<150/85 mmHg) was associated with a 24% reduction in end points related to diabetes, a 32% reduction in deaths associated with diabetes, a 44% reduction in strokes, and a 37% reduction in microvascular end points, mainly due to a decreased risk of retinal photocoagulation, in comparison to the less tight control of BP (<180/105 mmHg) . In the The target threshold of antihypertensive treatment has been changed multiple times over the past decade in response to various guidelines. Currently, guidelines state that antihypertensive treatment should be implemented in patients with diabetes if their BP is ≥140/90 mmHg and should be sufficiently intensive to reduce it to lower than 130/80 (<140/90 in elderly patients) .Commonly used antihypertensive drug classes include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), thiazide-like diuretics, mineralocorticoid receptor antagonists (MRAs), and β-blockers. Less commonly used antihypertensive treatments include α-blockers, renin inhibitors, loop diuretics, substances affecting the central nervous system such as methyldopa or clonidine, and drugs that directly lower the tension of vascular smooth muscle, for instance dihydralazine. The exact choice of hypotensive drugs depends on various factors, such as comorbidities, estimated glomerular filtration rate, side effects and ethnicity.ACEIs and ARBs consistently and significantly reduce the incidence of T2D when used in patients suffering from hypertension or congestive heart failure, likely because of an improvement of insulin secretion and insulin sensitivity . They arMRAs, spironolactone and eplerenon, are other drugs which affect RAAS. The addition of spironolactone to standard hypotensive treatment was found to reduce the level of albuminuria in patients with diabetes complicated by diabetic nephropathy . MoreoveCCBs are recommended as first-line treatment in diabetic patients, especially in elderly individuals with isolated systolic hypertension . PreviouTherefore, ACEIs, ARBs, CCBs and thiazide-type diuretics are all acceptable options for diabetic patients as an initial hypotensive treatment. It is crucial to also consider the adverse effects of antihypertensive drugs, especially those associated with cardiometabolic consequences. Treatment with thiazide-type diuretics such as chlorthalidone may result in hyperglycaemia because of their properties that influence insulin resistance ,82,83. MAside from standard hypotensive drugs, there are many new therapeutic possibilities that show additional beneficial properties, which may be especially advantageous in patients with T2D.Finerenone is a novel non-steroidal mineralocorticoid receptor agonist with a more selective activity than spironolactone and eplerenone. It prevents the activation of mineralocorticoid receptor by aldosterone, and thus helps to reduce remodelling, fibrosis and inflammation processes, especially in the heart, kidney and peripheral vasculature. Finerenone is mainly used in heart failure treatment, and it can cause a decrease in N-terminal pro-B-type natriuretic peptides (NT-proBNP) levels. Aside from this, it is possible to use finerenone to treat refractory hypertension and diabetic nephropathy due to its ability to reduce albuminuria. Because the activity of finerenone is more selective, it does not cause a significant increase in serum potassium level . SeveralEsaxerenone, another novel non-steroidal mineralocorticoid receptor agonist, has been already approved in Japan for the treatment of hypertension and diabetic nephropathy . Due to Sodium–glucose co-transporter-2 inhibitors (SGLT-2is or flozins) and glucagon-like peptide-1 analogues  are novel classes of antidiabetic drugs. Aside from the ability to reduce glycaemia, they possess a wide range of pleiotropic modes of action, such as cardio- and nephroprotective properties or body weight and blood pressure reduction. SGLT-2is act mainly by blocking glucose and sodium reabsorption in the proximal renal tubule, resulting in glycosuria. Increased osmotic diuresis and natriuresis leads to plasma volume depletion and, as a consequence, to blood pressure reduction. Drugs such as canagliflozin, dapagliflozin, empagliflozin or ertugliflozin belong to the group of SGLT-2is. SGLT-2is influence the mechanisms responsible for the pathogenesis of hypertension in diabetic patients. They improve arterial stiffness and endothelial dysfunction, reduce oxidative stress and preserve the circadian BP pattern .The sodium hydrogen exchanger-3 (NHE-3) plays a role in the regulation of extracellular volume and blood pressure through the reabsorption of sodium in the kidney. In patients with T2D, increased levels of insulin and glucose stimulate the activity of NHE-3. Enhanced sodium influx causes a rise in peripheral vascular resistance, which increases cardiac output . Due to GLP-1 analogues act mainly by an incretin effect, stimulating insulin release, suppressing glucagon secretion, delaying gastric emptying and promoting satiety . They caAnother new drug used mainly for the treatment of heart failure is a combination of valsartan, an angiotensin receptor blocker, and sacubitril, a neprilysin inhibitor. Due to the inhibition of neprilysin activity, the variety of endogenous vasoactive peptides increases, which results in enhanced natriuresis, diuresis and vasodilatation, and a reduction in cardiac fibrosis and hypertrophy . A meta-Patients with diabetes and hypertension belong to a group with very high cardiovascular risk. Both diabetes and hypertension influence each other and often coexist with other components of metabolic syndrome. Thus, it is of great importance to administer treatment to these patients as early as possible that not only allows the alleviation of hypertension or hyperglycaemia, but also poses a wide range of additional beneficial modes of action. Novel non-steroidal mineralocorticoid receptor agonists, such as finerenone and esaxerenone, in addition to BP regulation, may cause a reduction in microalbuminuria and reduce the risk of cardiovascular events. SGLT-2 inhibitors and GLP-1 analogues are antidiabetic drugs with cardio- and nephroprotective properties and the ability to reduce blood pressure and body weight. Sacubitril/valsartan is a combination used in heart failure treatment that also has the ability to reduce blood pressure and improve glucose tolerance. Further studies are needed to explain the exact mechanisms of the multifarious actions of these medications, but their application should be considered from the very beginning of treatment in order to better protect patients from the consequences of their diseases.


Primary aldosteronism (PA) is the most common cause of secondary hypertension. The diagnosis of PA currently requires multiple complicated measures. The aims of this study were to identify easy-to-obtain clinical and biochemical predictors, and to create predictive model to facilitate the identification of a patient at high risk of having PA.This 2-year retrospective cohort study was conducted at a tertiary care medical center. A total of 305 patients who had been tested for plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were identified. Patients with incomplete results of PAC and PRA and those who had an established diagnosis of Cushing’s syndrome or pheochromocytoma were excluded. Logistic regression analysis was used to identify significant predictors and to create predictive model of PA.2 . Predictive model was created with a total score ranged from 0 to 42. A score above 7.5 indicated a higher probability of having PA with a sensitivity of 72% and a specificity of 70%. The diagnostic performance of the predictive model based on area under the curve was 71%.PA was diagnosed in 128 of the patients (41.96%). Significant predictive factors for PA were age >60 years , female , smoking , coronary artery disease , obstructive sleep apnea , systolic blood pressure >160 mmHg , serum potassium <3 mEq/L , fasting blood glucose >126 mg/dL  and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73mThe clinical and biochemical predictive factors including predictive model identified in this study can be employed as an additional tool to help identify patients at risk of having PA and could help reduce the number of screening and confirmation tests required for PA. The most common cause of secondary hypertension is primary aldosteronism (PA) which accounts for 5 to 10% of hypertensive patients and 20% of resistant hypertensive patients . If leftRecent screening guidelines for PA identified various indications which indicate an increased likelihood of of PA , 6. The If easy-to-obtain clinical and biochemical predictive factors for PA could be identified, it could facilitate the diagnosis of PA and also reduce the number of tests for PA screening. To the best of our knowledge, only one study has reported predictive factors and constructed predictive scores for diagnosing PA . ReporteThis study aimed to identify clinical and biochemical predictive factors and to create the predictive model which could facilitate the prediction of PA.A 2-year retrospective cohort study was conducted using data acquired from electronic medical records at Maharaj Nakorn Chiang Mai Hospital, a tertiary care hospital in northern Thailand, during December 2017 to December 2019. The inclusion criteria were patient age over 18 years who had been identified for PA screening according to the 2016 Endocrine Society Clinical Practice Guideline, by using plasma aldosterone concentration (PAC) and plasma renin activity (PRA), to calculate the aldosterone-renin ratio (ARR) [Our institution adopted diagnostic criterion of primary aldosteronism from the 2016 Endocrine Society Clinical Practice Guideline. In brief, PAC and PRA are measured with appropriate patient preparation. Positive screening results for PA include the following: (1) ARR >20 (ng/dL)/(ng/mL/hr), (2) PAC levels of >15 ng/dL and (c) PRA <1.0 ng/mL/hr. Those who meet all the screening criteria proceed to confirmation tests unless the patients has either: (1) spontaneous hypokalemia, undetectable PRA and PAC >20 ng/dL, or (2) ARR >100 (ng/dL)/(ng/mL/hr) , 9. Thos®, Nivelles, Belgium) [Standard procedures for ARR measurement are as follows. Before PAC and PRA are collected, the patient should have a liberal sodium intake and be in a normokalemic state. Antihypertensive medications which interfere with the interpretation of ARR should be discontinued 2–4 weeks before blood is drawn. To maintain optimal blood pressure, antihypertensive medications with less effect on ARR are begun including extended-release verapamil, hydralazine and doxazosin. Blood collection is conducted midmorning after the patients have been upright for at least 2 hours and then seated for 5–15 minutes. The blood is collected in EDTA tubes. PAC and PRA are performed using the enzyme-linked immunoassay method (ELISA) (DIASource ImmunoassaysBelgium) . The intThe saline infusion test (SIT) is the confirmation measure employed in our institution. Four liters of 0.9% normal saline are infused intravenously over 4 hours and PAC is collected before and after the infusion. If post-infusion PAC is >10 ng/dL, PA is confirmed. If post-infusion PAC is <5 ng/mL, PA can be ruled out. Repeated SIT are conducted in patients with an equivocal post-infusion PAC number between 5–10 ng/dL. Computerized tomography and adrenal venous sampling are performed to differentiate PA subtypes and to make a distinction between unilateral and bilateral adrenal diseases.In this study, moderate to severe hypertension was defined as sustained elevated blood pressure >160/100 mmHg. Resistant hypertension was defined as blood pressure >140/90 mmHg while on three antihypertensive medications including one diuretic. Hypertension with spontaneous or diuretic-induced hypokalemia was defined as documented serum potassium <3.5 mEq/L regardless of the diuretics used. Hypertension with adrenal incidentaloma was defined as an adrenal tumor discovered in hypertensive patients on imaging performed for any reason unrelated to adrenal diseases. Hypertension in the young population was defined as hypertensive patients whose onset of hypertension occurred before 40 years of age. Hypertension with OSA was diagnosed and confirmed by polysomnography. A history of smoking was defined as smoking regularly during the past 6 months. Clinical presentations of PA documented in the medical records included headache and proximal muscle weakness. The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI method.Statistical analysis was performed using the STATA program. The statistical significance was specified as a p-value <0.05 for two-tailed tests. Data are shown as count and percentage or mean and standard deviation (SD) for categorical and continuous data, respectively. Fisher’s exact test and either the t-test or the Mann-Whitney U test were performed for inferential statistics with categorical and continuous data, respectively. Univariable and multivariable analyses of predictive factors for PA were performed using logistic regression analysis clustered by confirmation test and reported as odds ratios (ORs) with a 95% confidence interval. The predictive factors analyzed in the multivariate analysis model were selected based on p-values <0.1 in univariable analysis or on having clinically significant relationship to PA. Stepwise selection with backward elimination by removing variables with p-value >0.2 was conducted to create the final prediction model. Continuous variables were transformed to categorical variables in the final predictive model based on median values. Item scores were calculated by the transformation of the regression coefficient. The coefficient of each level for each factor was divided by the smallest coefficient of the model and rounded to the nearest 0.5. Item scores were then added together to calculate a total score. The total scores were then divided into 2 groups: groups at a low risk and at a high risk of having PA. The cut-off point for the risk levels was retrieved from the level that yielded the highest sensitivity, specificity. To evaluate the performance of the predictive model, the area under the receiver operating characteristics curve (AuROC) was used. Variables with missing data >5% were subjected to multiple imputation regression analysis.Table 1.Of the 305 patients who were screened for PA, 41.96% (128/305) were diagnosed with PA. Of these, 36.7% (47/128) had an aldosterone-producing adenoma and 63.3% (81/128) had idiopathic bilateral adrenal gland hyperplasia. Males had a non-significantly higher prevalence of PA than females. The overall mean age was 43.14±0.90 years, with the mean age significantly higher in the PA group (47.07±15.79) than in the essential hypertension group (40.30±15.14). A history of smoking was more commonly found in the PA than in the essential hypertension group. Among all patients, the most common indications for PA screening were hypertension in the young  followed by patients with moderate to severe hypertension . Among the indications for PA screening, hypertension with hypokalemia and OSA were more commonly documented in PA patients than in the essential hypertension group. In those with PA, proximal muscle weakness was more frequently reported than in the essential hypertension group. Duration of hypertension was longer in the PA than in the essential hypertension group. Other clinical characteristics, including BMI, co-morbidities, blood pressure level, number of antihypertensive agents and type of anti-hypertensive agents revealed no statistically significant difference between the two groups. Baseline laboratory investigations found a statistically significant lower serum potassium level in the PA than in the essential hypertension group. Other laboratory values showed no statistically significant differences between the groups. Baseline characteristics are shown in 2 . Data are shown in Table 2.The predictive factors analyzed in the multivariate analysis model were selected based on p-values <0.1 in univariable analysis or on having clinically significant relationship to PA. Hypertension in the young as an indication for screening and proximal muscle weakness were not incorporated in the final multivariate model due to redundancy with age and serum potassium level, respectively. Continuous predictive variables were transformed into categorical variables for ease of interpretation. After stepwise backward elimination of predictive factors for PA, nine clinical and laboratory predictors were identified in the final predictive model. Those factors consisted of age > 60 years , female , smoking , coronary artery disease , OSA , systolic blood pressure > 160 mmHg , serum potassium < 3 mEq/L , fasting blood glucose > 126 mg/dL  and eGFR < 60 mL/min/1.73mTable 3. The total scores were classified into two groups: a low-risk group (scores 0–7.5) and a high-risk group (scores above 7.5). This cut-off had a sensitivity and a specificity of 72% and 70%, respectively. The predictive ability of the final model represented by AuROC was 0.71 (95% CI: 0.64–0.77) .Predictive score was created to predict the probability of patients having PA. The transformed scores ranged from 1.0 to 9.5 with a total score of 42. The scoring system is shown in The key finding in this study is that nine easy-to-obtain clinical and biochemical factors can facilitate the prediction of PA. The predictive performance of the final predictive model which integrated these factors had acceptable predictive performance based on AuROC.Our study reported a higher prevalence of PA (41.96%) compared to other studies which reported a prevalence of PA ranging from 5–22% , 11. ThePrevious studies have reported that PA is generally recognized in middle-aged adults in the third to fifth decades of life. This agrees with the finding from our study that the mean age of patients with PA was approximately 47 years old. Nevertheless, recent evidence suggests that PA is becoming more common in the elderly (age over 65 years) , 13. LikRegarding the association of gender and PA, the present study showed that being female tended to increase PA risk by 1.65 times compared to males. This finding is similar to other studies which have reported that the prevalence of PA tends to be higher in females than in males. However, in those studies after adjusting for confounders, being female represented no statistically significant increased risk of PA compared to males , 17. AnoThe present study demonstrated that hypokalemia (<3 mEq/L) and moderate to severe hypertension (systolic blood pressure >160 mmHg) are significant predictors for PA, a finding supported by multiple studies. Approximately 30% of patients with PA have hypokalemia . As to tCoronary artery disease, OSA and chronic kidney disease (low eGFR) are linked to the pathophysiology of PA by various mechanisms. Increased aldosterone levels in PA patients can activate proinflammatory and oxidative stress and can have profibrotic effects on the vessels contributing to cardiovascular disease . Higher Our study revealed that current smokers had a higher risk of having PA. Cigarette smoking could be linked with PA indirectly. Patients with PA who are current smokers may have a higher risk of cardiovascular events caused by increased oxidative stress resulting in endothelial injury . HoweverIn a prospective study by German cohort, diabetes and metabolic syndrome were found to be significantly more prevalent in PA than in a matched control population. For that reason, at first we hypothesized that diabetes could be one of the positive predictors of PA. Interestingly, in our cohort fasting study, blood glucose >126 mg/dL had a negative predictive effect on PA (OR 0.48). This unexpected result is similar to that reported by Kietsiriroje et al. . The hypThe present study demonstrated that there is a statistically significant association among easily accessible clinical and biochemical factors and the risk of having PA. The final predictive model combining these factors provided acceptable diagnostic performance. The results help suggest when a clinician should refer a patient for PA screening, especially in institutions where investigative resources are not available. In the future, creation of a predictive risk scoring system would make the system more practical.The associations between the predictors and PA identified in this study could be explained by underlying physiology and the evidence already presented. To reduce the occurrence of bias, possible confounding factors have been adjusted for in the multivariable model and the criteria for definitive diagnosis of PA as well as other key aspects have been defined. Additionally, cluster analysis was performed to reduce variation in the confirmation tests. A strict criterion for PA diagnosis, i.e., PAC levels >15 ng/dL, was employed to reduce the incidence of false positive diagnoses of PA based on a very low PRA. The relatively large sample size in this study provided sufficient power of analysis.There are some limitations in this study. First, this is a retrospective and single-center study, a potential source of selection bias which could limit the applicability of the results to other institutions. Second, hypertension in the young population was included as one of the indications for PA screening in our cohort even though this has not been established elsewhere in the standard guidelines. This issue could have had the effect of reducing the incidence of PA identified in our cohort as most of the young (<40 years) patients were diagnosed with essential hypertension. Third, the sample size was not calculated prior to the analysis. However, backward calculation for the power of analysis showed a power of > 0.80 which indicated an adequate sample size to interpret the results. Lastly, some predictors, e.g. young age at onset of hypertension and multiple anti-hypertensive medications used, were not significantly related to PA in our proposed model. These predictors had been reported in multiple studies with the strong associations with PA , 33. TheNumerous clinical and laboratory investigations can facilitate the prediction of PA. This predictive model can be used as an additional tool to allow the physicians in institutions where resources for investigating PA are not readily accessible to decide which patients needed to be referred. Using these predictors could result in time- and cost-savings as the number of PAC, PRA and confirmation tests can be reduced. External validation in future research should be accomplished to confirm the predictive ability of this model.


Hypertension is associated with high morbidity and mortality and this has been linked to poor treatment and control rates. To optimize drug treatment, patient-centered strategies such as coping, resilience, and adherence to medication may improve control rates and decrease the morbidity and mortality associated with hypertension. This study, therefore, assessed coping skills and resilience among patients with hypertension in Ghana.p-value of ≤ 0.05.A cross-sectional study was conducted at Korle Bu Teaching Hospital. 224 consented patients with a diagnosis of hypertension were consecutively selected from the outpatient clinic. Questionnaires comprising socio-demographic characteristics, clinical parameters, Adult Resilience Measure, and the Africultural Coping Systems Inventory were administered. Data were analyzed using Stata version 16.1 and significance level was set at The mean age of participants was 62.03 ± 11.40 years and the majority were female (63%). The overall coping strategy mean score was 43.13 ± 13.57. For resilience, median relational and personal resilience (PR) scores were 32 (IQR-7) and 39 (IQR-9), respectively. Increased systolic BP significantly increases the overall coping strategy score. Collective coping strategy and systolic BP significantly increased coping scores (95%CI = 0.05–3.69 vs. 95%CI = 0.58–5.31). Overall coping strategy significantly increased personal and relational resilience (RR) domain scores by 0.004 (95%CI = 0.002–0.01) and 0.005 (95%CI = 0.003–0.006) units, respectively. This study demonstrated that Cognitive and emotional debriefing coping strategy was mostly used by patients with hypertension.Coping strategies had a positive and significant correlation with personal and RR, specifically collective and cognitive debriefing had a significant positive association with resilience among study participants. There is a need to actively put in measures that can improve the coping strategies and resilience among patients with hypertension to adjust to the long-term nature of the illness and treatment as this will promote better treatment outcomes. Hypertension is a major public health problem with significantly associated morbidity and mortality. Globally, an estimated 1.28 billion adults aged between 30 and 79 years are living with hypertension and two-thirds live in low- and middle-income countries (LMIC) . AfricanHypertension has been associated with 7.5 million deaths worldwide representing 12.8% of all total deaths. This accounts for 57 million disability-adjusted life years (DALYs) . High blChronic disease and their treatments have been shown to cause psychological problems such as depression, anxiety, and cognitive dysfunction . The preTo our knowledge, there is limited research on the impact of resilience and coping in patients with hypertension in Ghana . ExaminiThis was a cross-sectional study involving 224 consecutively selected patients with hypertension, 18 years and older who attend two outpatient clinics at the Korle-Bu Teaching Hospital. Consent was obtained from the patients after they were given appropriate information about the study. Inclusion criteria comprised; patients diagnosed with hypertension who have been on medication for at least 6 months, while those with dementia, neuropsychiatric illness and a history of trauma based on information in their medical records, were excluded.The investigators and trained research assistants collected the data. A structured questionnaire was administered to consented participants to obtain data on the socio-demographics and clinical parameters. The socio-demographic characteristics included age, gender, religion, educational status, employment status, monthly income, marital status, and socio-economic status. The clinical parameters were blood pressure readings, height, weight, and waist circumference. The standardized instruments the Resilience Scale for Adults and the Africultural Coping Systems Inventory were used to measure resilience and coping strategy of participants, respectively.A digital blood pressure monitor (OMRON HEM-907) was used to measure blood pressure. Blood pressure was measured 3 times at least 5 min apart. The mean of the last two measures was recorded.2) was calculated from the weight and height. Waist circumference was measured using a tape measure and recorded to the nearest centimeter.Anthropometric parameters such as height (m), and weight (kg) were measured and recorded. Height was measured using a stadiometer with patients wearing no shoes and recorded to the nearest centimeter. Weight was measured using a SECA Digital weighing scale to the nearest 0.5 kg. Body mass index (BMI) (30 kg/mThe revised Adult Resilience Measure (ARM-R) is a self-report measure of social and ecological resilience and is used by researchers and practitioners worldwide. It consists of 17-items and is scored 5- point Likert scale and responses include “Not at all,” “A little,” “Somewhat,” “Quite a bit,” and “A lot.” The items in the measures are all positively worded and therefore scoring involves summing of the responses obtained. In addition to overall score, scores can be obtained for two subscales [personal and relational resilience (RR)]. RR refers to characteristics associated with relationships shared with either partner or family while PR relates to intrapersonal and interpersonal items. Cronbach’s alpha is 0.82 for personal and RR subscales, and 0.87 for overall resilience subscale .did not use, 1 = used a little, 2 = used a lot, 3 = used a great deal) to denote strategies they used to cope. For each subscale, items were summed, and higher scores indicated more use of that coping strategy. Cronbach’s alpha for the total scale was 0.90  was used to measure four dimensions of culture-specific coping: (a) Cognitive and Emotional Debriefing (11 items); (b) Collective Coping (8 items); (c) Spiritual-Centered Coping (8 items); and (d) Ritual-Centered Coping (3 items) . As partwas 0.90 .t-test and ANOVA was used depending on the levels of the categorical variable. To assess factors associated with the exposure variable, authors adopted Ordinary Least Square (OLS) regression methods to assess the strength of the association by considering adjusted variables. Before OLS analysis, multicollinearity assumption was tested using the variance inflation factor where the “help from family” was highly correlated with help from friends, therefore the variable was modeled during the adjusted OLS regression analysis.The data were analyzed using Stata version 16.1. Two independent analytical processes were conducted to achieve the objective of the study; these involved descriptive and inferential analysis. For descriptive analysis, sociodemographic characteristics were summarized in tables by reporting the proportion and means of the variables involved in the study. For inferential analysis, two approaches were adopted: mean differences and regression analysis. The mean difference of the study outcomes by the explanatory variables was adopted and one sample Kolmogorov–Smirnov test was performed to assess normality. All variables did not violate the normality assumptions and were therefore confirmed using the Shapiro-Wilk test of normality. The p-value < 0.05.To assess the relationship between the exposure and the outcome variable, OLS was performed and adjusted with significant factors associated with the domain of the exposure variable. Analysis was performed using Stata 16.1 and the significance level was set at The study involved 224 persons living with hypertension aged between 27 and 92 years with mean ± Standard deviation of 62.03 ± 11.40 years and the corresponding median (interquartile range) was 63 (15.5) years. The proportion of female and male participants were 63 and 37%, respectively. The majority of the participants were obesed (48.9%) .The overall coping mean (95%CI) ± SD score was 43.13 ± 13.57 and the scores for the individual domains involving; Spiritual, Collective, Ritual centered, and Cognitive/Emotional were 14.36 ± 5.14, 10.09 ± 5.18, 0.28 ± 0.96, and 18.40 ± 6.32, respectively . For ResOrdinary Least Square regression analysis showed that the overall coping strategy was significantly influenced by systolic and diastolic pressure. Interestingly, having an increased systolic BP significantly increases the overall coping score compared with systolic BP < 120. Diastolic BP ranging from 90 or more significantly decreased overall coping by 6.05-unit score (95%CI = −11.94 to −0.17).In the individual coping strategies domains, diastolic BP between 80 and 89 increased the unit score of spiritual coping by approximately 2.4 units (95%CI = 4.52 to −0.20) compared with diastolic BP < 80. With Collective coping strategy, having 3 or more friends significantly increase coping strategy by approximately 1.9 units significant (95%CI = 0.05–3.69) compared with patients with no friends. In addition, having a systolic BP ranges from 120 to 139 increased the Collective Coping by 2.9 unit score (95%CI = 0.58–5.31) compared with patients with < 120 systolic BP. Interestingly, no variable was associated with Ritual Coping strategy. For cognitive coping strategy, being aged 60–69 years significantly increased the strategy by 3.4 (95%CI = 0.00–6.79) compared with aged group < 39 years. Having 3 friends or more and increasing systolic BP significantly increase the log count of cognitive coping whiles diastolic BP of 90 and above significantly decrease the log count by 6.05 (95%CI = −11.94 to −0.17) .p-value < 0.05). In addition, spiritual coping strategy, had a positive and significant correlation with relational resileince (RR). The regression analysis showed that, overall coping strategy significantly influenced PR and RR domains by 0.004 (95%CI = 0.002–0.01) and 0.005 (95%CI = 0.003–0.006) unit, respectively. Meanwhile, specific coping strategies showed that Collective and Cognitive debriefing significantly increase the unit of Resilience domains by approximately 0.01 , there was positive and significant correlation with Collective, Cognitive, and overall coping strategies  in stressful situations where blood pressure is high. In contrast, while Emotion Oriented coping is supposed to reduce stress, it is not always successful and can actually induce stress and thus, indirectly raise blood pressure . As a rePrevious studies showed a significant and positive correlation between Emotion-oriented coping styles and blood pressure, while problem-oriented coping styles had a negative correlation with blood pressure . ConversIn addition, increasing age and having three friends or more increased the cognitive coping strategy. Social support and coping strategies are protective factors that serve as a buffer in stressful situations. In our study higher levels of social support (having 3 or more friends) improved patients’ use of cognitive coping strategies thereby improving their blood pressure management. In a study by This study found that decreased overall coping scores increased diastolic blood pressure. In a study that examined the effects of subjective stress and coping resources on blood pressure reactivity, there was a significant association between coping strategies and diastolic blood pressure and that the interactive effects of subjective stress and coping resources predicted diastolic blood pressure reactivity but not systolic blood pressure reactivity . These eFurthermore, our study found that increased diastolic pressure was associated with increased Spiritual coping. Our study also showed high scores in the Spiritual coping domain among patients with controlled hypertension. Religiosity and spirituality have long been associated with hypertension. Again, our study showed that an increased systolic BP was associated with increased use of collective coping and that having 3 or more friends also significantly increased collective coping strategy compared to patients with no friends. This implies that patients in our study sought more social support to cope with high systolic pressure. This contradicts the study by In terms of Resilience, the study observed a significant correlation between overall coping and three components of coping: collective coping, cognitive and emotional debriefing, and spiritual coping. The regression analysis showed that, PR positively correlated with collective, cognitive, and emotional debriefing, and overall coping strategies. Similarly, RR positively correlated with the spiritual coping domain. Again, in the regression analysis, overall coping had a positive and significant correlation with personal and RR, specifically collective and cognitive debriefing strategies significantly improved resilience among hypertensive patients in this study. The findings of this current study are novel as previous studies, to the best of our knowledge have not explored the relationship between resilience and coping particularly among patients with hypertension. However, it is not surprising as other studies have found that the positive contribution of higher levels of resilience and an adaptive coping strategy improves the level of health of patients with chronic diseases .This study focused on one chronic disease (hypertension), thus the findings cannot be generalized to other chronic diseases such as asthma, sickle cell disease, cancer, and diabetes. Future studies should fill this gap by involving other chronic illnesses to understand the effect of coping and resilience in people with chronic diseases more holistically. In view of the cross-sectional nature of this study, the associations cannot be used to demonstrate causality and the results of the coping strategies should be viewed in that context.This study demonstrated that cognitive and emotional debriefing coping strategy was mostly used by patients and high systolic blood pressure was significantly associated with overall coping score and cognitive/emotional debriefing domain scores. In addition, increasing age and having social support increased cognitive coping strategy. Coping had a positive and significant correlation with personal and RR, specifically collective and cognitive debriefing strategies significantly improved resilience among study participants. This is an important finding as it demonstrates the need to introduce measures to improve the coping mechanisms and resilience of patients to help with effective management of hypertension.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The protocol was approved by the University of Ghana College of Health Sciences Ethical and Protocol Review Committee and the protocol identification number was CHS-Et/M.4-P4.1/2020-2021. The patients/participants provided their written informed consent to participate in this study.VB, EY, and VG contributed to the concept, design, conduct, and manuscript writing. AG-M and GE-F involved in the design, conduct, and drafting of the manuscript while IK and CM-K helped with writing of manuscript and the final editing. All authors contributed to the article and approved the submitted version.


Research efforts have been focused on limiting secondary injury after traumatic spinal cord injury by performing spinal decompression and early optimization of spinal cord perfusion. The Winnipeg Intraspinal Pressure Monitoring Study (WISP) was designed to validate the technique of intraspinal pressure monitoring at the site of injury using a fiberoptic pressure monitor placed at the site of injury.To describe the design of the WISP study.Descriptive.We explain the current limitations in the available scientific literature around the topic of blood pressure management for acute traumatic spinal cord injury and rational for the WISP study. Then, we describe the design of WISP including the patient selection criteria, study interventions, follow up schedules and outcome measurements. A multitude of future research avenues are also discussed.The WISP study is a single center pilot study designed to validate the technique of intraspinal pressure monitoring following acute traumatic spinal cord injury. The study involves the measurement of intraspinal pressure from within the subarachnoid space at the site of injury to derive a number of physiological parameters including spinal cord perfusion pressure, spinal cord blood volume, measures of spinal cord compliance and vascular reactivity indices. Twenty eligible patients will be recruited and followed for a period of 12 months with visits scheduled for the first 5 days and 1, 3, 6, and 12 months following surgical intervention.The WISP study will provide the first attempt in North America at validation of intraspinal pressure monitoring with a fiberoptic pressure monitor at the site of injury. Successful validation will lead to future studies to define optimal spinal cord perfusion pressure, relationships of neural injury biomarkers and outcomes as well as epigenetic studies.NCT04550117).This study has been registered at clinicaltrials.gov (registration#  In North America, the incidence of traumatic spinal cord injury (tSCI) is estimated to be 40 per million people . To dateOptimizing blood flow to the spinal cord has been an ongoing area of research for decades . The objSimilarly, data in humans regarding manipulation of blood pressure in the management of tSCI has limitations. A prior systematic review performed at our institution  identifiRecently, researchers have described the use of an intraspinal pressure monitor to better define spinal cord perfusion pressure(SCPP) . In theiDespite the elegance and significance of this work, the methodology has not been validated in any other institution to date. The Winnipeg Intraspinal Pressure Monitoring Study (WISP) aims to be the first North American study to validate the methodology of intraspinal pressure monitoring at the site of injury.This study has been reviewed and approved by the University of Manitoba Biomedical Research Ethics Board (Ethics# HS23117(B2019:075).The primary objective of the WISP study is to validate the methodology of invasive intraspinal pressure monitoring to derive parameters for optimal SCPP, spinal cord reserve capacity and spinal reactivity index following tSCI. The following specific aims will be achieved through the primary objective:The temporal profile of intra-spinal pressure (ISP) and arterial blood pressure (ABP) over the course of the patient’s SICU stay will be characterized, assessing the time series behaviors of ISP and ABP, and by determining SCPP as: ABP–ISP.Feasibility of intra-compartmental compensatory reserve will be characterized by evaluating the relationship between slow-wave vasogenic fluctuations in the Fast Fourier Transformed pulse amplitude of ISP  and ISP over time.Spinal cord vascular reactivity will be characterized continuously using the relationship between slow-wave vasogenic fluctuations in ISP or sAMP, and either mean arterial pressure (MAP) or SCPP.Secondary objectives of the WISP study will be to a) evaluate the safety of invasive ISP monitoring, b) prospectively evaluate the relationship between SCPP and functional outcomes in patients with tSCI and c) evaluate the relationship between SCPP, motor evoked potentials and functional outcomes after tSCI.The WISP study will be a single center pilot study involving patients with acute traumatic tSCI with American Spinal Injury Association Score of A, B or C  admitted to the surgical intensive care unit at Health Sciences Centre in Winnipeg, Manitoba, Canada. Approximately 20 patients with acute traumatic spinal cord injury present to the institution on an annual basis. Given that this is a feasibility and validation study, we will select a convenience sample of 20 for enrollment in this study. Patients are eligible for the WISP study if they meet all of the following criteria:Inclusion Criteria:patients with tSCI patients requiring surgical intervention for spinal instabilityage between 18–70yrsExclusion Criteria:patients with central cord syndromepatients presenting to HSC >48hrs from time of tSCIpatients undergoing surgical decompression and fixation for tSCI >48hrs from time of spinal cord injury.patients unable to communicate in English languagepre-existing cognitive impairmentpenetrating tSCIpre-existing neurodegenerative disorder involving brain or spinal cordpatients with concomitant injuries requiring emergent surgical interventionAppendix A in the supplementary materials lists the time frame for enrollment, intervention and assessments. Research assistants will be employed to continually scan patient lists in the intensive care unit to identify potential candidates for enrollment into the study. A standardized recruitment script will be used to inform patients about the rationale for the study, risks of participation and potential benefits. Informed consent will be obtained based on institutional ethics guidelines. Long term retention of patients in the study will be supported via dedicated clinic follow ups with patients. Patients will not be compensated for participation in this study.Study patients may withdraw voluntarily from the study or the investigator may terminate the patient’s participation if the subject meets an exclusion criterion (either newly developed or previously not recognized) or a medical condition occurs that precludes furthur study participation. In situations where a patient is withdrawn from the study, complete adverse events data will be captured and stored in case of future need. We will then aim to extend the duration of the study until study enrollment is complete.Initial demographic information, medical history, physical examination and imaging findings will be recorded using standardized data collection forms for all patients. Patients will then be taken for surgical intervention within 24hrs of admission. A fiberoptic pressure monitor  will be placed into the subarachnoid space at the site of injury . The preDuring the care period in the SICU, intraspinal pressure and physiological parameters incuding heart rate, respiratory rate, blood pressure and mean arterial pressure will be captured at the bedside using a secure laptop for a maximum of 5 days following admission to the SICU.http://www.neurosurg.cam.ac.uk/icmplus) connected to our SICU monitors. Signals from all of the monitoring devices described below are subsequently recorded in time series using this software over the course of the recording periods described above. All physiologic signals from monitoring devices within the SICU for neurologically ill patients are currently recorded and archived as part of a separate prospective signal database study that will be ongoing at HSC.Both ABP and ISP will be obtained through either radial or femoral arterial lines connected to pressure transducers , with all signals recorded in high frequency time series, sampled at 100 Hz or higher through and analogue to digital signal converters , using ICM+ software  will be determined by calculating the maximum ABP over a 1.5 second window, updated every second. Similarly, diastolic ABP (ABPd) will be determined by calculating the minimum ABP over a 1.5 second window, updated every second. Pulse amplitude of ISP (sAMP) will be determined by calculating the fundamental Fourier amplitude of the ISP pulse waveforms over a 10 second window, updated every 10 seconds.Ten second moving averages (updated every 10 seconds to avoid data overlap) will be calculated for all recorded signals: ISP, ABP (which produced MAP), ABPs and ABPd. Ten second moving averages will be calculated in order to focus on slow-waves of parent signals, decimating the frequency to the range associated with vascular autoregulation.Spinal vascular reactivity indices(sPRx) will be derived as follows: a moving Pearson correlation coefficient will be calculated between ISP and MAP using 30 consecutive 10 second windows (ie. five minutes of data), updated every minute. Similarly, other vascular reactivity metrics will be derived using the correlations between slow-waves of sAMP and MAP , and sAMP and SCPP . Finally, spinal compensatory reserve will be assessed by deriving the spinal RAP index (sRAP), using the moving Pearson correlation between sAMP and ISP. Data for further analysis will be provided in the form of a minute by minute time trends, output into comma separated values (CSV) datasets.Patients with incomplete tSCI (ASIA grade C) will undergo evaluation for motor evoked potential monitoring. Motor evoked potentials (MEP) will be acquired using single pulse transcranial magnetic stimulation (TMS) via a figure of 8 induction coil (Medtronic MagstimPro). Bilateral surface recordings from the thenar eminence will be attempted with targeted stimulation of the motor cortex hand area. The ground lead will be placed on the dorsal surface of the hand unilaterally. The MEP recordings will be amplified as required and bandpassed filtered (30 – 3000Hz). The stimulus location is typically 8 cm lateral to midline at a point 2 cm posterior to the coronal suture. 100% of coil output will be applied unless robust MEP are detected whereby the stimulus intensity can be titrated downwards. MEP peak-to-peak amplitude (μV) and onset latency (ms) will be registered. The MEP data will be captured and stored using a Cadwell Elite neuromonitoring workstation. Between 5–10 trials will be averaged if MEP responses are small (< 50 μV). Any changes in these MEP characteristics will be noted as arterial pressure optimization is achieved. We will capture transcranial magnetic motor evoked potentials through the first 5 days after surgery and during follow up assessments at 1, 3, 6, 9 and 12 months.Post-operative adverse events will be collected for the first 30 days following surgical intervention. Thereafter, each patient will undergo standardized functional assessments at 1, 3, 6, 9 and 12 months in a dedicated multidisciplinary clinic involving spine surgeons, physiatrists, physical therapists and occupational therapists.The outcome measures for our primary objective will focus on various signal processing techniques to derive ISP, MAP, SCPP, sAMP, sRAP and various spinal cord vascular reactivity metrics during the post-acquisition processing phase.Safety of intraspinal pressure monitoring will be measured based on accuracy of placement of the probe from post-operative computed tomography (CT) scan imaging, as well as collection of adverse events including infection rates, rates of pseudomeningoceles, neurological injury, probe dislodgement, meningitis, and/or subdural hematoma at site of probe placement.Functional outcomes will be determined by examining changes to the total score on the ASIA impairment scale, Spinal Cord Independence Measure (SCIM III) and Quality of Life Index for Spinal Cord Injury (QLI-SCI) at the planned follow up intervals.Changes in motor evoked potentials will be measured for patients with incomplete spinal cord injury with some preservation of motor function (ASIA C). Alterations in the MEP signals will be evaluated in relation to spinal cord perfusion parameters.The investigators will be responsible for study oversight to ensure that the study is conducted according to protocol and ensuring data integrity. Investigators will review the data for safety concerns at regular intervals, and will promptly report any unanticipated problems, protocol deviations, or any other significant event that arises during the conduct of the study to the research ethics board. A data safety monitoring committee will be convened as to ensure patient safety during this feasibility study.All medical and surgical adverse events will be recorded on dedicated forms at the prescribed follow up intervals. A list of the adverse events that will be captured are included in Appendix B in the Supplementary Information. The severity of the adverse event will be categorized based on the need for minor or complex treatment, need for surgical intervention or ICU stay, anticipated duration or impact of the adverse event and threat to life. All serious adverse events will be reported to the research ethics board within 1 week of the investigator becoming aware of the event. Serious adverse events are defined as those that i) result in death, ii) are life threatening, iii) result in prolongation of existing hospitalization, or iv) result in persistent or significant disability. A safety monitoring committee will be convened to review all adverse events during the study. The safety monitoring committee will consist of the primary investigators, critical care physicians and neurosurgeons. The committee will review all adverse events for every cohort of 5 patients enrolled into the study. To ensure timely review of adverse events, the data safety monitoring committee will review adverse events within the first 30 days of the surgical and study interventions.https://www.R-project.org/). Alpha for statistical significance will be set at 0.05, with normality for all continuous variables tested via Shapiro-Wilks test. Basic descriptive statistics will be performed, with comparison between groups and variables conducted via t-test, Mann-Whitney-U, chi-square, analysis of variance (ANOVA), Kruskal-Wallis, Friedman and Joncheere-Terpstra testing, where appropriate. General correlations will be described using Pearson/Spearman coefficients, where applicable.Statistical analysis will be performed utilizing R statistical software (R Core Team (2018). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL Descriptive statistical analysis of the relationships between physiologic variables will be facilitated through various error bar plots, linear models, quadratic models  and locally weighted scatterplot smoothing (LOESS) techniques, depending on the physiologic relationship being assessed.All indices of cerebrovascular reactivity will be output in minute-by-minute time series format. Correlation between ISP and MAP slow-waves will be further evaluated in time series using cross correlation techniques, cross-correlation function (CCF) plots, vector autoregressive integrative moving average (VARIMA) models, impulse response function (IRF) plots and Granger causality testing. Further, using Box-Jenkins time series modelling, the autoregressive integrative moving average (ARIMA) structure of each time series will be assessed and compared. ARIMA model accuracy for each index will be confirmed using autocorrelation function (ACF), partial autocorrelation function (PACF) plot, augmented Dickey-Fuller (ADF) and Kwiatkowski–Phillips–Schmidt–Shin (KPSS) testing, and the presence of random normally distributed residuals. VARIMA and ARIMA model superiority will be confirmed via ANOVA testing and comparing Akaike information criterion (AIC), Bayesian information criterion (BIC) and log-likelihood (LL).ISP, MAP, SCPP, sAMP, sRAP and the spinal vascular reactivity indices will be evaluated in relationship to motor evoked potential recordings, and functional outcome measures at the defined time periods of assessment. Such analysis will involve linear and logistic regression modelling techniques, evaluating the relationship between the physiologic parameters with: ASIA, SCIMIII and QLI-SCI functional outcome metrics.Blood pressure management after tSCI has been an area of interest for many decades. Researchers have attempted to define mechanisms of spinal cord autoregulation and perfusion that serve to protect the spinal cord penumbra around the site of injury.The WISP study aims to validate the technique of intraspinal pressure monitoring at the site of injury. Other researchers , 13 haveTo our knowledge, no other group has attempted to validate this technique since it was originally conceptualized. Through the WISP study, we expect to demonstrate the feasibility and safety of introducing a fiberoptic pressure monitoring probe in the subarachnoid space at the site of injury. We will be able to derive important relationships to assess spinal cord blood volume, measures of spinal cord compliance and vascular reactivity indices.The WISP study may have significant implications for patients with tSCI. To date, broad based guidelines have recommended maintenance of the mean arterial pressure greater than 85mmHg. However, this overlooks the various metabolic factors that could alter spinal cord autoregulation. Continuous monitoring of intraspinal pressure at the site of injury holds the potential for individualized physiological targets and the possibility of preserving more functional spinal cord tissue around the site of injury.Following successful completion of the WISP study, we anticipate several future avenues for research. First, there will be a need for future large multicenter network of patients being monitored for SCPP, aimed at providing multi-center validation of the technique and results. This will be facilitated through collaborative networks within Canada, US and Europe. As the understanding around optimal SCPP is still very much in its infancy, we expect numerous local and multi-center studies evaluating: feasibility of derivation, determinants of yield in calculation, baseline patient demographic associates, and the link to long-term functional outcome after tSCI. Finally, aside from exploring novel personalized physiologic targeting in tSCI, there is also the need to link this high-fidelity intra-spinal pressure data with other omics data. We envision such omics data to encompass genomic, epigenomic and proteomic information, integrated with high-frequency physiome from intraspinal monitoring and derived metrics. Future work at our lab is planned to evaluate the association between cerebrospinal fluid and serum proteome and small molecule profile for markers of neural injury, pro-inflammatory cytokines and vascular mediators. As in the traumatic brain injury literature, it is expected that individual genetic variation, in the form of single nucleotide polymorphisms, may dictate the host response to injury, both systemically and within the central nervous system.S1 Checklist(DOC)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOC)Click here for additional data file.