The integration of patient–reported outcome measures (PROMS) into health care delivery systems is being increasingly recognized as an important component of quality, person-centered care, especially for chronic illnesses like congestive heart failure (CHF). However, while PROMS are increasingly being used to follow up CHF patients in high income countries, their use in sub-Saharan Africa is still limited. We adapted the Kansas City Cardiomyopathy Questionnaire (KCCQ-23), an internationally validated, CHF-specific PROM and tested its use in measuring outcomes in an outpatient CHF clinic at a cardiac referral hospital in Tanzania.Adaptation of the KCCQ-23 included translation into Swahili by linguistic experts, in-depth cognitive debriefing in native Swahili–speaking CHF patients, and input from Tanzanian Cardiologists, PROMS experts, and the tool developer. Using a cross-sectional design, we tested the usability and observed the results of the translated KCCQ-23 in a convenience sample of 60 CHF patients attending outpatient clinic at the Jakaya Kikwete Cardiac Institute (JKCI) in Dar es Salaam.r = 0.95; p < 0.0001).The survey was successfully completed by 59 (98.3%) of 60 enrolled participants. The mean (SD) age of participants was 54.9 (14.8) years (range 22–83), 30.5% were women and 72.2% had class 3 or 4 New York Heart Association (NYHA) symptoms at enrollment. The overall KCCQ-23 score was low, with a mean (SD) score of 21.7 (20.4) indicating generally very poor to poor patient reported outcomes in this population. The mean (SD) scores for the specific KCCQ-23 domains were 15.25 (24.2) for social limitation, 23.8 (27.4) for physical limitation, 27.1 (24.1) for quality of life and 40.7 (17.0) for self-efficacy. No socio-demographic or clinical characteristics were associated with their overall KCCQ-23 scores. Comparing the short version (KCCQ-12) with the full KCCQ-23 revealed excellent correlation between the two (We successfully translated a validated tool, the Swahili KCCQ, for use in improving the care of patients with CHF in Tanzania and a broader population of Swahili–speaking patients. Both the Swahili KCCQ-12 and KCCQ-23 can be used, with similar outcomes. Work to expand the use of the tool in the clinic and other settings is planned.The online version contains supplementary material available at 10.1186/s12872-023-03265-0. The global burden of congestive heart failure (CHF) is expected to increase as a result of several factors such as an aging population, improved outcomes of acute cardiovascular events, and a rise in cardiovascular risk factors globally , 2. MostTraditionally, measures of patients’ progress in CHF have been based on providers’ assessment of clinical status and laboratory or other diagnostic tests. While these are essential to help achieve some of the goals of quality, person-centered care among CHF patients, there is also a growing recognition of the importance of assessing patients’ clinical status through patient-reported outcome measures (PROMS) , 5. PROMThe Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered PROM developed to independently measure a patient’s perception of their health status, which includes CHF symptoms, impact on physical and social function, and how CHF impacts their quality of life within a 2-week recall period . The tooThe use of PROMS in African countries is steadily growing in HIV care , 19, butIn this study we report on the process we undertook to translate and adapt the KCCQ-23 into Swahili and the results of a pilot study using this Swahili KCCQ-23 to assess PROs in CHF patients in an outpatient cardiology clinic in Tanzania. The results contribute to work to increase patient–centered outcome research, inform planning of clinical interventions to improve patient outcomes including in symptoms, functioning and quality of life, and empower CHF patients in Tanzania and the Eastern, Central, and Southern African regions where Swahili is widely spoken [We conducted a cross–sectional study in the outpatient clinic of the Jakaya Kikwete Cardiac Institute (JKCI) in Dar es Salaam to understand the usability of the tool and to report on PROs resulting from the KCCQ-23. The study was part of a larger effort to explore feasibility, adoption and appropriateness of measuring PROMS and patient-reported experiences among CHF patients in a referral clinic in Tanzania. JKCI is the major referral cardiac hospital in Tanzania, receiving patients from all over the country. The outpatient clinic is run from Monday to Friday and attends to an average 200 patients per day, of whom 30% have CHF . On averWe reviewed both disease-specific (CHF-specific symptoms) and general PROMs  which had been used in Swahili, and those previously used in SSA. Following discussions with experts in the field of PROMS, as well as with cardiologists at JKCI and at Northwestern University (United States), the KCCQ-23 was selected as the most appropriate tool to be used based on length, use in other countries in the region, and validation in clinical care. We chose to start with the KCCQ-23 tool, with a secondary goal of comparing KCCQ-23 and the shorter KCCQ-12. The KCCQ-23 and KCCQ–12 scores range from 0 to 100 and are classified as very poor to poor (0 to 24), poor to fair (25 to 49), fair to good (50 to 74) and good to excellent (75–100).The translation, cognitive debriefing and adaptation of the KCCQ-23 followed established procedures already validated and widely used by the developer of the tool . The proUsing a cross-sectional study design, the translated and adapted KCCQ-23 was administered to a convenience sample of 60 adult CHF patients being seen in the clinic for a previously scheduled appointment. The survey also captured additional socio-demographic and clinical data including age, sex, education, residence, type of visit, presence of comorbidities, and common symptoms of HF. Patients were eligible if they were aged ≥ 18 years and known to have a diagnosis of CHF (from any cause) of at least six months duration based on physician diagnosis. Briefly, in the morning of each cardiac outpatient clinic day, a trained research assistant would identify possible participants and determine their eligibility. Once eligible, the patient and/or their caregiver would be approached for consent. Once consented, the patient and/or caregiver was given the paper questionnaire to fill in their responses. The research assistant then collected the questionnaires which were later entered into a REDCap (Research Electronic Data Capture) database created for this study.Descriptive statistics were used to describe the range of scores, including measures of central tendency , spread  and response category frequencies. Because the results were not normally distributed, we used the Mann-Whitney U test to explore differences in the KCCQ-23 score and selected dichotomous variables  and linear regression for continuous variables (age). We also calculated correlation between the KCCQ-23 and KCCQ-12 summary scores using Pearson Correlation Coefficient to explore the potential for using the shorter version in clinical practice. All analyses were done using STATA 17.0 .Overall, 59 (98.3%) of the 60 enrolled individuals were able to complete and return the KCCQ-23 tool. One patient did not return their questionnaire to the research assistant and was therefore excluded in the analysis. One–third (30.5%) of the 59 respondents were female, with 67.5% of respondents aged ≥ 50 years, and 32.2% having completed secondary school or higher  and median of 17.5   , reflectStudies from HICs have highlighted the challenges of integrating PROMS into clinical care, including within cardiology. For example, Wohlfarht found that cardiology providers from the United States identified three such barriers as: the burden of data collection, ambiguity in interpreting and presenting scores, and defining the tools’ utility and value . There iOur study had a number of limitations. Our sample was small, and limited our power to identify patient factors that were associated with the level of symptoms. To address this limitation, work to expand the use in the clinic and other settings is planned. Since the current study was conducted in a referral hospital which is likely to have individuals with more advanced disease, it limited the generalizability of the results. Therefore, the tool needs to also be tested in other settings where CHF patients receive care including primary care clinics. Finally, we did not measure acceptability or feasibility of integrating survey administration and result interpretation into routine care, work which is planned in the future.We have successfully translated a validated tool for measuring PROMS among people with CHF in patients with CHF in Tanzania. The translated tool was able to be self-administered, with high rates of self-reported heart failure-related morbidity. This work provides opportunities for expanded PROM use in other countries through the availability of the Swahili KCCQ. Important planned next steps include expanding the population with PROs measured to better understand variability based on socio-demographics, and identifying the strategies needed for integration into clinical care and use for broader quality improvement initiatives in order to improve outcomes among Swahili-speaking patients with CHF.Below is the link to the electronic supplementary material.Additional File 1: Bivariate Analysis of the KCCQ-23 total scores and Patient? CharacteristicsAdditional File 2: Dodoso la Ugonjwa wa Misuli ya moyo la Kansas City (KCCQ)


ADPKD) develop hypertension similarly to patients with ARPKD. Conversely, a significantly lower percentage of patients with classic forms of ADPKD develops hypertension during childhood, although probably more than originally thought. Data published in the past decades show that about 20%–30% of ADPKD children are hypertensive. Development of hypertension before 35 years of age is a known risk factor for more severe disease in adulthood. The consequences of hypertension on cardiac geometry and function are not well documented in ARPKD due to the rarity of the disease, the difficulties in collecting homogeneous data, and differences in the type of parameters evaluated in different studies. Overall, left ventricular hypertrophy (LVH) has been reported in 20%–30% of patients and does not always correlate with hypertension. Conversely, cardiac geometry and cardiac function are preserved in the vast majority of hypertensive ADPKD children, even in patients with faster decline of kidney function. This is probably related to delayed onset of hypertension in ADPKD, compared to ARPKD. Systematic screening of hypertension and monitoring secondary cardiovascular damage during childhood allows initiating and adapting antihypertensive treatment early in the course of the disease, and may limit disease burden later in adulthood.Autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney disease are the most widely known cystic kidney diseases. They are significantly different from each other in terms of genetics and clinical manifestations. Hypertension is one of the main symptoms in both diseases, but the age of onset and secondary cardiovascular complications are significantly different. Most ARPKD children are hypertensive in the first year of life and need high doses of hypertensive drugs. ADPKD patients with a very early onset of the disease (VEO Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are the most well-known cystic kidney diseases. They belong to the group of ciliopathies, but are significantly different from each other in terms of genetics and clinical manifestations. In a not too distant past, they were named “adult” and “infantile” polycystic kidney diseases, respectively. Nowadays, these terms have been abandoned because they do not describe accurately the natural history of the diseases. Most ARPKD children are hypertensive in the first year of life and need very early high doses of antihypertensive drugs. A significantly lower percentage of ADPKD patients develop hypertension during childhood, but this percentage is probably underestimated. The PROPKD score, which has been validated based on outcome measures, indicates that early onset hypertension (before the age of 35 years) is a risk factor for fast progression of chronic kidney disease (CKD). The purpose of this review is not to compare ARPKD with ADPKD, but to review of the available pediatric studies  and expePKD1 gene, located on chromosome 16p13.3 and in the PKD2 gene, located on chromosome 4q21, encoding for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PKD1 is responsible for the more severe phenotype and is involved in approximately 85% of cases. Most cases managed by pediatrician are secondary to PKD1 variants or to rare digenic conditions, since these manifest earlier in life compared to PKD2 variants. Cyst formation requires mutations of both alleles in either PKD1 or PKD2 genes. Since every cell carries one germ line mutation (first hit), a second somatic mutation in the normal allele (second hit) is needed to lead to the formation of cysts from previously normal epithelial cells of renal tubules and biliary ducts. The phenotypic expression of the disease is variable. Several factors explain this variability. In particular, the phenotypic expression depends on the type of variant, ranging from hypomorphic to variants that cause complete loss of function, which impacts on the amount of residual functioning polycistin proteins. The lower the levels, the faster the cyst formation and growth , usually around 50–60 years of age, depending on the underlying genetic defect. The disease is caused by pathogenic variants in the d growth .ADPKD is a systemic disorder with many clinical manifestations, including hypertension, left ventricular hypertrophy (LVH), heart valve disease, hepatic cysts, urinary tract infections, proteinuria, hematuria, kidney stones, intracranial and extracranial aneurisms . CardiovIn the past two decades, considerable progresses have taken place in our knowledge of the pathogenesis and clinical manifestation of ADPKD in children. As pediatricians, we now know that ADPKD is not only an adult disease and that some renal and extra-renal manifestations may appear during childhood, albeit sometimes they remain underdiagnosed .ADPKD), suffer from a severe form of the disease that manifest with significant symptoms between 1.5 and 15 years of age. These patients have early hypertension and rapid progression of CKD (ADPKD), develop oligohydramnios and hyperechoic enlarged kidney in utero , the sympathetic nervous system, and endothelial dysfunction .The activation of the RAAS system plays a fundamental role. Progressive increase in the size of cysts causes compression of renal arterioles, leading to localized ischemia and hypoxia, which, in turn, activates the RAAS system . RAAS acPKD1 and PKD2 gene expression have been associated with reduced nitric oxide synthesis, which results in impaired vascular response to stress and activation of the RAAS system  and 12 adolescents and adults (age 15.2–24.9 years), and 24 controls matched for age, sex and body surface area. All patients had normal kidney function. The authors studied left ventricular mass (LVM) by real-time directed M-mode echocardiography and observed a significantly higher LVMi across all ages without overt LVH. Blood pressure, measured by ABPM, was normal in children but was significantly higher in young adults, compared to controls. Left ventricular systolic function was normal in the two groups .p = 0.07). When the LVMi was compared with systolic and diastolic blood pressure values in affected and unaffected children, a significant positive relationship between systolic blood pressure and LVMi  was observed in ADPKD children. Hypertensive patients had significantly higher LVMi compared to normotensive patients. The latter group has LVMi values similar to normotensive controls  was found in affected patients compared to unaffected controls (12% vs. 3%). Patients with MPV were older and had more severe renal disease (>10 cysts). In addition, a significantly higher prevalence of hypertension was observed in affected children. In respect to LVMi, the authors observed a non-statistically significant trend towards higher values in ADPKD children , borderline hypertension , normotensive patents . The authors compared LVMi, TKV, microalbuminuria, and kidney function in these three groups. No significant differences were observed in kidney function and microalbuminuria. Compared to patients with normal blood pressure, both hypertensive and borderline hypertensive patients had higher LVMi. Of note, overt LVH was not present in any subgroup, but a statistically significant increase in LVMi was detected in patients with borderline pressure with still normal TKV .Data from the same cohort were subsequently published after 5 years of follow-up, during which patients received treatment with ACE-i. The RAAS blockade appeared to stabilize LVMi and prevent deterioration of kidney function in normotensive or borderline hypertensive ADPKD children, but not in patients that were hypertensive. The authors hypothesized that once hypertension was established, treatment with ACE-i alone may no longer be sufficient to prevent cardiovascular disease .p = 0.01], but no overt LVH , stiffening of the large elastic arteries, such as the aorta and carotid arteries, and increased carotid intima-media thickness (cIMT) are important independent predictors of cardiovascular events. In adult subjects with ADPKD, these parameters are abnormal, independently from the progression of kidney disease and before the onset of hypertension .Some studies have demonstrated that vascular dysfunction begins very early in the course of the disease, including during childhood. In 2017, Nowak et al., studied vascular dysfunction in 15 ADPKD children and young adults (age range 6–22 years) with normal kidney function, and in 15 controls. All subjects had normal blood pressure (<140/90 mmHg if adults or <95th percentile), but 8/15 (46%) patients with ADPKD were treated with ACE-is. The authors observed a significant decrease in the EDD in ADPKD subjects, as measured by brachial artery flow mediated dilation. The carotid-femoral pulse wave velocity (PWVcf), a measurement of arterial stiffness, was on average 14% higher in ADPKD children and young adults. The carotid augmentation index (cAIx) and carotid systolic blood pressure were also higher compared to the control group, while cIMT was similar . In 2018Studies in young adults with ADPKD have also shown early vascular dysfunction independently from blood pressure values. Borresen et al. reported in 2007 that the reflection of the pulse wave was amplified in young normotensive ADPKD patients, demonstrating early arterial damage . In 2009Marlais et al. compared in 2019 a large population of ADPKD children under the age of 18 with age-matched healthy controls. No significant differences in PWVcf were observed. This data differs from previous reports and differences are probably related to the younger age of patients in their cohort, suggesting that vascular changes develop only during late childhood and early adulthood. On average, children with ADPKD had higher blood pressure and LVMi, although overt LVH was not observed; 35% of patients lack nocturnal dipping .More recently, Seeman et al. studied the vascular function in ADPKD children and observed higher pulse pressure amplification in ADPKD subjects compared to controls, but no significant differences in the PWVcf .Taken together, current data indicate that the prevalence of hypertension in ADPKD children ranges 6%–47%. When considering only studies that have used ABPM to assess blood pressure, hypertension was observed in approximately one-third of patients. The main mechanism driving hypertension is the activation of the RAAS system, but other factors contribute to the elevation of blood pressure, including over-expression of endothelin receptors, increased synthesis of endothelin 1, sodium retention, and reduced synthesis of nitric oxide in the vascular endothelium. Most hypertensive children with ADPKD do not develop overt LVH, although their LVMi is on average higher compared to normotensive patients and to control subjects. Data on vascular dysfunction are scanty and findings are not uniform. They raise however, intriguing hypotheses on the pathogenesis of vascular damage in ADPKD that deserve further studies. Of note, children may be the ideal subjects to perform these studies because they may show early signs of vascular dysfunction independently from the development of hypertension.Several limitations apply when analyzing the literature on ADPKD in children in respect to the prevalence of arterial hypertension. The majority of studies are retrospective. The size and age of cohorts are often very different. Most studies were carried out in third-level centers that tend to recruit more severe patients and more motivated families. This may cause overestimating the prevalence of hypertension and cardiovascular consequences. In addition, the methodologies used to assess blood pressure and cardiovascular damage vary in different studies.Nevertheless, the available data support regular measurement of blood pressure once a year in children with ADPKD or at risk of ADPKD, as suggested by expert opinion publications . MeasuriPKHD1 gene that encodes for the nephrocystin protein. In the kidneys, nephrocystin localizes to the sensory cilium in the cortical and medullary collecting ducts and thick ascending limbs of the loop of Henle. In addition, nephrocystin is expressed in the biliary and pancreatic tracts. Compared to ADPKD, recessive inheritance causes early onset and more severe symptoms, although significant phenotypic variability is observed. Severe perinatal disease has been associated with biallelic null variants, but biallelic missense variants do not exclude very early onset of a severe disease. A recent genotype-phenotype correlation study including 304 children with ARPKD has shown that the location of variants in different domains of the PKHD1 gene plays an important role in determining the phenotype  needed antihypertensive treatment during the observation period, and 50% were hypertensive at diagnosis. Overall, that study showed a very high prevalence of early-onset hypertension; 64% of patients had started anti-hypertensive therapy within the first year of life. At the last observation, one-third of patients had not achieved satisfactory blood pressure control .In 1997, Roy et al. reported somewhat lower rates of early-onset hypertension in another cohort followed from the first month of life. In their cohort, the percentage of patients requiring antihypertensive therapy increased from 39% at 1 year of age to 60% at the age of 15 years . A higheIn 2003, Guay-Woodford et al. published data from the North American ARPKD Clinical Database. The study included 209 patients stratified by year of birth; 21% and 79% of patients were born before and after 1990, respectively. The prevalence of hypertension and the risk of developing hypertension were higher in patients born before 1990 (80% vs. 65%). The interpretation of this finding is unclear and may be altered by biases. The median age at diagnosis was significantly lower in more recent patients, most likely reflecting improvements in the diagnosis and care of sick newborns and infants over the years. The age of onset of hypertension and of CKD was significantly lower in infants requiring mechanical ventilation, reflecting more severe disease. In patients born after 1990 that survived the first month of life, the age of onset of hypertension and of CKD were positively correlated, although this finding does not necessarily imply a direct cause-and-effect relationship between these two variables. In addition, 96% of patients with early-onset hypertension had hyponatremia, supporting the hypothesis that hypertension in ARPKD may be the result of a dysregulation in the sodium reabsorption mechanism in the ectatic collecting ducts, but they also recognize that this mechanism has not been demonstrated by other studies .In a 6-year follow-up study published by Bergmann et al., in 2015 to assess genotype-phenotype correlations, the prevalence of hypertension was 43% at the beginning of observation period and 73% at the end of follow-up. Anti-hypertensive treatment was started at an average age of 3 years; half of patients were receiving treatment at the age of 6 months  Bergman.As for ADPKD, most studies in ARPKD children have assessed hypertension with office blood pressure measurements. More recently, ABPM has also been used in children with ARPKD. Seeman et al. have published a retrospective study on 36 children with ARPKD, of whom 29 had performed at least two ABPM recordings. The median age at the first ABPM was 4.4 years and the average interval between the first and the last recording was 5 years. Confirming previous reports , the iniThe pathophysiology of hypertension in ARPKD is still incompletely understood. Volume overload secondary to CKD may represent the main factor driving blood pressure increase . In 2005Despite several studies have reported low circulating renin levels in children with ARPKD, RAAS inhibitors are the most frequently medications used to treat hypertension and are efficient in most patients.Studies on cardiac involvement in ARPKD children are very limited and data are not homogeneous due to differences in the techniques that have been used to assess cardiac geometry and function.In 2007 Phillips et al. have studied cardiac geometry in an ARPKD mouse model (Lewis polycystic kidney) in which kidney cysts develop from the age of 3 weeks, hypertension at 6 weeks of age, and LVH at 24 weeks of age, indicating a clear temporal sequence between progression of kidney disease, hypertension, and cardiac damage .Dell et al. have studied the cardiac geometry as a secondary outcome measure in pediatric patients with ARPKD and children with mild-to-moderate CKD secondary to renal dysplasia and urinary tract obstruction. No significant differences in the prevalence of LVH and hypertension (defined with ABPM) were observed. However, a significantly greater percentage of ARPKD children received blood pressure medications compared to children with other renal diseases .Seeman et al. have also evaluated cardiac geometry in ARPKD children using two-dimensional echocardiography. They observed LVH in 30% of patients, including some patients that had good blood pressure control .We have studied 27 ARPKD children at an initial age of 3.8 years. Of these, 92% were treated with antihypertensive drugs, which had been started before 6 months of life in 48% of patients. Compared to age- and sex-matched healthy children, patients with ARPKD had on average significantly higher LVMi and showed a significantly higher prevalence of LVH, mainly of the concentric type . MultivaSome illustrative images of advanced echocardiography are shown in Altogether and despite the small number of patients included in the few available studies, current data indicate that children with ARPKD have significantly higher LVMi and develop concentric LVH in a significant proportion of cases. In addition, many have evidence of subclinical cardiac dysfunction, similarly to children with CKD secondary to other causes , but difCompared to ADPKD, ARPKD is a much rarer disease. Therefore, fewer data are available on cardiovascular consequences. Furthermore, younger age and more severe disease of patients at diagnosis renders more difficult assessing blood pressure using ABPM and performing sophisticated cardiac investigations. Overall, severe, early-onset hypertension is more frequent in ARPKD children. The prevalence of hypertension ranges 55%–100% in different studies. The pathogenesis of hypertension is not fully elucidated and may not be entirely due to the activation of the RAAS. However, ACE-i and ARBs remain the mainstay of treatment, together with calcium channel blockers. Frequently, more than one drug is needed to treat hypertension, although blood pressure control tends to improve spontaneously over time. Approximately one-third of patients surviving the neonatal period have abnormal cardiac geometry. More studies are needed to establish the role of genotype in the severity of cardiovascular changes.ARPKD and ADPKD are severe ciliopathies that are characterized by marked cardiovascular involvement. In both diseases, early detection of hypertension and of cardiac anomalies allows limiting cardiovascular damage and long-term complications. To which extent very early treatment of cardiovascular symptoms impact on the evolution of kidney diseases remains uncertain but deserves more attention in the future. In the meantime, pediatricians can play a crucial role in balancing prevention and excessive medicalization, in particular in children with ADPKD.


The impact of blood pressure (BP) control and its timing on left ventricular (LV) structure and function remains unclear. The present study was to evaluate whether BP control correlated with conventional LV geometry and function indexes or global longitudinal strain (GLS) progression, and when echocardiographic changes would occur in essential hypertension.n = 33) had higher LV mass index (P = 0.02), higher left atrial volume index (P = 0.01), worse GLS (P = 0.005) and GLS changes (P = 0.003) compared with controlled BP (n = 29) at the 6-month follow-up examination. Patients with uncontrolled BP (n = 25) had higher LV mass index (P = 0.001), higher LV mass index changes (P = 0.01), higher relative wall thickness (P = 0.01), higher E/e′ (P = 0.046), worse GLS (P = 0.02) and GLS changes (P = 0.02) compared to BP controlled group (n = 24) at the 18-month follow-up examination. GLS changes were associated with BP control  in stepwise multivariate regression analysis. LV mass index changes was corelated with systolic BP  at the 18-month follow-up examination in stepwise multivariate regression analysis. Neither was GLS changes nor LV mass index changes were related to antihypertensive medication class, including combination therapy in 6- or 18-month follow up examination.A total of 62 participants  with uncontrolled hypertension were enrolled in the longitudinal study. Patients were followed up at the 6-month and 18-month, when echocardiographic measurements were performed and BP control was evaluated during the follow up period. At the 6- and 18-month examination, we divided the hypertensive patients into two groups as BP controlled and uncontrolled group. Patients with BP uncontrolled (Our findings offer new clinical evidence on the association of BP control with echocardiographic changes in hypertensive patients, and, in particular, support the view that GLS progression was earlier and subtler than conventional LV geometry and function parameters. GLS changes were significant between BP controlled and uncontrolled patients even in 6-month follow-up period. Hypertension is both a most prevalent cardiovascular disease and a most significant cause of cardiovascular mortality. In China, hypertension affects about 30 percent of adults, but blood pressure control rate is only 16.8% according to the 2018 revised Chinese guidelines for the management of hypertension  can identify subtle adaptive changes in asymptomatic hypertensive patients , 5. ManyBetween September 2013 and December 2015, 80 uncontrolled hypertensive patients were recruited from the department of hypertension and outpatient clinic of Ruijin Hospital, Shanghai, China. All the participants provided prior written informed consent for participation in this study. This study was approved by the Ethics Committee of Ruijin Hospital. Exclusion criteria included recent acute coronary syndrome (within 6 months), active myocarditis, significant valvular heart disease, uncontrolled arrhythmia, acute heart failure, secondary hypertension, peripheral artery disease and white coat hypertension.Of the 80 participants, 62 participants  were followed up from the initial medical visit to the 6-month examination, 12 patients declined to further participate in the study and 6 patients were diagnosed as white coat hypertension by ambulatory blood pressure monitoring (ABPM). All the 62 participants were willing to be reexamined for the 6-month follow-up echocardiographic examination and clinical data recollection. Among them, 56 subjects accepted the 18- month follow up examination, from April 2015 to December 2016, for a total time interval of 12.8 ± 1.5 months from the second medical visit, of which 49 had a valuable echocardiographic examination.All participants provided their medical history and standardized questionnaires were used to determine medication use, and cardiovascular risk assessment at baseline, at the 6-month, and at the 18-month follow-up medical visit. Clinical examination, including echocardiography were performed at the three times of medical visits. The hypertensive patients were defined as systolic blood pressure >130 mmHg and/or diastolic blood pressure >80 mmHg by ABPM or use of antihypertensive agents for controlling BP at the initial medical visit. Blood pressure (BP) control was defined as blood pressure less than 140/90 mmHg at office and/or less than 135/85 mmHg at home during the follow up period.Validated oscillometric SpaceLabs 90,217 monitors  were used for ABPM measurement in the follow-up study. They were programmed to obtain BP readings at 20 min intervals in daytime (from 06:00 to 22:00) and at 30 min intervals at night (from 22:00 to 06:00). Omron HEM-7051 monitors  were used for clinic and home BP measurements in the study. Three consecutive BP readings were obtained according to the recommendation of the Chinese guidelines for the management of hypertension after the participants had rested in the sitting position for more than 5–10 min. The three readings were averaged for analysis afterwards.2 was indexed from LV mass to body surface area. LA volume index (LAVI) in g/m2 was indexed from left atrial volume to body surface area. The peak early (E) and late (A) transmitral flow velocities, the ratio of early to late peak velocities (E/A) were measured from apical 4-chamber view, by placing a pulsed-wave (PW) Doppler sample volume between mitral leaflet tips during diastole. The deceleration time of E velocity and isovolumic relaxation time (IVRT) were measured from apical 5-chamber view by placing a continues wave Doppler sample volume between the LV out flow and inflow tract. The IVRT measurement was estimated from the cessation of the aortic flow and the onset of transmitral inflow. The relative wall thickness (RWT) was calculated as the ratio of two times posterior wall thickness to LV diastolic diameter.Echocardiographic data were collected with a commercially available instrument  according to standard procedures. LV diameters, septal and posterior wall thickness were measured according to the guidelines of the American Society of Echocardiography from 2-dimensionally guided M-mode tracings, with a recording speed at 50–100 cm/s . LV masse′) from the TDI recordings. The ratio of peak early (E) to tissue Doppler early peak diastolic (e′) was calculated. The average values of septal and lateral ratios were calculated for the assessment of global LV diastolic function (Tissue Doppler imaging (TDI) was assessed by means of mitral annulus in four-chamber view. Tissue Doppler sample volume was placed at the septal and lateral sides of the mitral annulus to determine the early diastolic annular . Three endocardial markers were placed in an end-diastolic frame at apical 4-chamber, 2-chamber and 3-chamber views for 2D longitudinal speckle tracking analysis. The longitudinal strain was obtained by the myocardial motion of each segment at each cardiac cycle in the region of interest tracked frame by frame, and the corresponding curve was measured by the software automatically as well. Adequate tracking could be verified in real time, which was corrected by adjusting the region of interest or correcting the contour to ensure optimal tracking by manually. Finally, the left ventricular GLS was calculated based on the average value derived from all segments' longitudinal strain.To calculate the intra-observer and inter-observer left ventricular GLS variability, the speckle tracking parameters were remeasured in the first 13 patients by the same observer 4 weeks after the initial evaluation and two different observers without reviewing the patients' previous reports. The intra-observer and inter-observer variation coefficients of left ventricular GLS were 1.5% and 3.8%, respectively.The respective differences (Δ) in all the measured echocardiographic parameters, including left ventricular GLS between the baseline and at the 6-month, as well as 18- month follow-up examination was calculated.α, power and effect size, the total sample size is 56. Data were stored and analyzed using the SPSS 23.0 statistical package . Continuous data were presented as mean ± SD and the frequencies of subjects in each category were presented as categorical variables. Comparison between different studied groups were performed by independent t-tests or paired t-tests. Comparisons of categorical variables among groups were performed using χ2 test. Associations among continuous and categorical variables were assessed using linear regression analysis and Pearson correlation analysis. Association with the GLS changes and LVMI changes were determined by multivariate linear regression analysis with forward selection followed by backward elimination of covariates, which only resulted with significantly increased predictability of the dependent variable. Age, sex, body mass index (BMI), BP control, diabetes mellitus, hyperlipoidemia, systolic and diastolic blood pressure were selected as independent variables, the GLS changes during 6-month or 18-month follow-up period was the dependent variable. Age, sex, BMI, BP control, diabetes mellitus, hyperlipoidemia, systolic and diastolic blood pressure, usage of ACE-I or ARB were selected as independent variables, the LVMI changes during 18-month follow-up period was the dependent variable. The GLS changes and LVMI changes were entered as continuous values in the model. A 2- tailed P value of <0.05 was defined as statistically significant, and a P value of <0.01 as highly significant.We use G*Power 3.1.9.7 to estimate the sample size, given n = 29, 46.8%) and uncontrolled group . Among the 49 patients who had echocardiographic examination at the third medical visit, 21 patients had consistently uncontrolled BP at the 18-month and 6-month visits, 18 patients had consistently controlled BP at the 18-month and 6-month visits, 6 patients had controlled BP at the 18-month visit and uncontrolled BP at the 6-month visit and 4 patients had uncontrolled BP at the 18-month visit but had controlled BP at the 6-month visit. Among the 13 patients who did not receive echocardiographic measurement at the 18-month visit, 6 patients were uncontrolled and 7 were controlled patients at the 6-month visit.The present analysis included 62 essential hypertensive patients  with complete data and measurable echocardiographic variables of interest at baseline and at the 6-month follow-up analysis. The patients were classified into two groups based on their BP control during the 6-month follow up period as controlled group  and longer IVRT  than controlled group, but there was no difference in E/A ratio, deceleration time, e′ or average E/e′ between groups at baseline  and lower e′ . Whereas the changes in LVMI  had no difference between groups during the 6-month follow-up period. LVMI changes were not related to antihypertensive medicine, including combination therapy in 6-month follow up examination (data not shown).P = 0.005) (P = 0.003) at the 6-month follow-up examination , BP control , whereas they were inversely related to age , sex  and systolic BP  in univariate analysis. While in multivariate analysis, changes in GLS only had correlation with BP control . Changes in GLS were unrelated to diabetes mellitus, hyperlipoidemia or diastolic BP during the 6 months follow up period  . The chamination . Changesp period .n = 24, 49.0%) and uncontrolled group . Uncontrolled group had higher interventricular septum  and posterior wall thickness , higher LVM , LVMI  and average E/e′ . There was no difference in heart rate, LAVI, E/A ratio, deceleration time, IVRT, e′ or right heart function between groups at the 18-month follow-up visit. Changes in LVMI were significantly higher in BP uncontrolled group than in controlled group at the 18-month follow-up visit . In univariate analysis, changes in LVMI were directly related to systolic BP , diastolic BP  and the usage of ACEI or ARB , whereas they were inversely related to BP control  at the 18 months follow-up examination .As shown in mination . As in mP = 0.02) (P = 0.02) at the 18-month visit, as shown in r = 0.324, P = 0.01), although it was not related to age, sex, BMI, diabetes mellitus, hyperlipoidemia, or diastolic BP in univariate analysis during the 18 months follow up period. While in multivariate analysis, changes in GLS only had correlation with BP control   . The cha = 0.02) . NeitherThis study demonstrated that BP control was associated with echocardiographic progression during 18-month follow-up period in essential hypertensive patients. GLS improvement was significant between BP controlled and uncontrolled patients even in 6-month follow-up period. Our findings especially support the view that GLS was an earlier and subtler marker than conventional LV geometry and function parameters.Several studies have previously provided independent and incremental prognostic information of GLS for cardiovascular morbidity and mortality –22. The The role of antihypertensive medications on LV remodeling is always a debated issue. Many studies reported that improvement in GLS was associated with the use of antihypertensive medications, while some studies found that even the antihypertensive classes have different impacts on LV geometry and function –16, 24. In many studies, GLS improvement was associated with LVMI reduction , 13, 26,Studies in experimental animals reported that longitudinal strain impairment was significantly related to the level of subendocardial layer fibrosis after adjustment for the corresponding layer wall stress . Both coSeveral important limitations must be acknowledged. First of all, it was a single-center study with a very small population sample from the department of hypertension and outpatient clinic in Ruijin Hospital, Shanghai. We are unable to extrapolate these findings in a multi-centered Chinese population study. Additionally, parasternal short-axis views, which were used to assess circumferential strain, were not included in this study. Moreover, the antihypertensive medicine for the present study was not controlled, and the target of BP control in the present study was 140/90, as many researchers found that LV geometric and functional parameters can be ameliorated in the setting of a lower BP target or targeted antihypertensive treatment , 16 MoreIn conclusion, our study revealed that BP control was associated with the echocardiographic progression in essential hypertensive patients, even after adjustment for some conventional CVD risk factors, including age, sex, diabetes mellitus, hyperlipidemia, BMI, and blood pressure. GLS improvement was significant between BP controlled and uncontrolled patients even in 6-month follow-up period, however, LVMI reduction was not significant until 18-month follow-up examination between groups. Our findings suggest blood pressure control was more important to GLS and LVMI improvement than the usage of antihypertensive medication class in the treatment of hypertension.


This study aimed at summarizing the available literature on fall risk associated with diuretic and SGLT2i use in older heart failure patients, including the underlying pathophysiology, and to assist clinicians in safe (de)prescribing of these drug classes.Both heart failure and diuretic or SGLT2 inhibitor use increase fall risk in older adults. Diuretics and SGLT2 inhibitors not only have various fall-related adverse effects, which partly overlap (e.g. tendency to cause hypotension), but also differ: compared to SGLT2is, diuretics display more fall risk factors . The tendency to cause fall-related adverse effects may differ according to diuretic sub-class or even within sub-classes.Decisions to continue or deprescribe diuretics or SGLT2is in fall-prone older HF patients are generally highly complex, but detailed insight into fall-related side effect profiles of these drug classes, and practical clinical decision tools and resources, assist prescribers in rational and personalized (de)prescribing. Both heart failure and its treatment with diuretics or SGLT2 inhibitors increase fall risk in older adults. Therefore, decisions to continue or deprescribe diuretics or SGLT2 inhibitors in older heart failure patients who have fallen are generally highly complex and challenging for clinicians. However, a comprehensive overview of information required for rationale and safe decision-making is lacking. The aim of this clinical review was to assist clinicians in safe (de)prescribing of these drug classes in older heart failure patients.We comprehensively searched and summarized published literature and international guidelines on the efficacy, fall-related safety issues, and deprescribing of the commonly prescribed diuretics and SGLT2 inhibitors in older adults.Both diuretics and SGLT2 inhibitors potentially cause various fall-related adverse effects. Their fall-related side effect profiles partly overlap , but there are also important differences; based on the currently available evidence of this relatively new drug class, SGLT2 inhibitors seem to have a favorable fall-related adverse effect profile compared to diuretics . In addition, SGLT2 inhibitors have potential beneficial effects , whereas diuretic effects are merely symptomatic.(De)prescribing diuretics and SGLT2 inhibitors in older heart failure patients who have fallen is often highly challenging, but this clinical review paper assists clinicians in individualized and patient-centered rational clinical decision-making: we provide a summary of available literature on efficacy and (subclass-specific) safety profiles of diuretics and SGLT2 inhibitors, and practical guidance on safe (de)prescribing of these drugs . She has orthostatic complaints and initial orthostatic hypotension. Laboratory testing: serum creatinine 118 µmol/L, BUN 15 mEg/L, eGFR 32 mL/min/1.73 m2, sodium 132 mEq/L, potassium 4.2 mEq/L, HbA1c 70 mmol/mol (8.6%)).A 83-year-old woman visits the falls clinic for analysis of recurrent falls. Multifactorial falls risk assessment (including comprehensive geriatric assessment ) revealsEvery year in the European Union, at least 3.8 million older adults visit emergency departments for fall-related injuries, of which 1.4 million require hospital admission . BesidesIn patients with a history of HF, however, deprescribing diuretics may not be an effective fall preventive intervention as it may cause congestive HF, in itself an independent fall risk factor . On the In this clinical review, we aim to provide the reader with a summary of the evidence base for diuretics in older HF patients, a summary of the literature on deprescribing these drug classes, and an overview of their potential fall-related side effects. In addition, we will also discuss the relatively new SGLT2i drug class: like diuretics, SGLT2is have diuretic effects and are recommended in HF treatment. Over the past years, the use of SGLT2is has increased rapidly in all age groups, including the oldest adults . Given tThis narrative review summarizes the currently available evidence on both benefits and fall-related harms of chronic use and deprescribing diuretic and SGLT2i formulations in older HF patients. The review was informed by a literature search conducted in November 2022 in Medline and Google Scholar with keywords “falls”, “diuretic”, “SGLT2 inhibitor”, “deprescribing” and “older adults”. Personal reference libraries and diuretic/SGLT2i SmPCs (summary of product characteristics) were also utilized. We included the most commonly prescribed diuretics and SGLT2is. Advanced, non-pharmacological HF therapies (e.g. cardiac resynchronization devices) were beyond the scope of this review. We screened titles and abstracts of potentially relevant articles in English language and included based on relevance to the aim of the project. We performed citation and reference checking of the included papers. Based on availability, we selected the most recently published and/or highest quality evidence. Consistent with the narrative review methodology, we did not appraise methodological quality or risk of bias of the included articles.Diuretics are the cornerstone of congestion treatment in HF   alongsidn = 16,687) in older patients, the prevalence of inappropriate loop diuretic prescriptions (for example for venous insufficiency) was 11% [Whereas diuretics are effective cornerstones for symptom control in patients with systolic HF and congestion, they lack disease-modifying effects. Chronic, long-term diuretic therapy to prevent congestion is not supported by high-quality evidence, and safety in outpatient settings is controversial . Inappro was 11% . Frequen was 11% . Often o was 11% . Not onlSGLT2is augment the diuresis effect caused by diuretics . This maDiuretics are heterogeneous in their pharmacological properties . As an ePharmacokinetic and pharmacodynamic profiles of the SGLT2is as a group are comparable, and favorable for older individuals as follows: oral bioavailability is generally good, elimination half-life relatively long , renal excretion limited and tendency to cause drug–drug interactions low . Of noteDiuretic use is associated with dose-dependent, severe, potentially life-threatening adverse effects. In fact, up-titrating diuretics is associated with worsening renal function, increased hospital admission rates and mortality . Fall riAfter successfully treating congestion, guidelines recommend down-titration of loop diuretics in chronic HF when patients have no signs of volume overload . It is eIn contrast to diuretics, SGLT2is do not require identification of individualized optimal dose (they are fixed-dose) and appear to be devoid of a tendency to cause acute kidney injury (AKI)  or kidne2. When GFR falls below 30 mL/min, thiazide diuretics are unable to achieve sufficient concentrations to exert their action in the distal tubule [Chronic kidney disease is a common comorbidity in HF patients, especially in HFrEF . When prl tubule . Althoug2, evidence is rapidly emerging that SGLT2is are safe and efficacious in chronic kidney disease patients with lower eGFR (empagliflozin has been studied in patients with eGFR ≥ 20 mL/min per 1.73 m2) [In contrast to diuretics, SGLT2is maintain natriuresis in patients with reduced eGFR . Althoug1.73 m2) , 50, 51.1.73 m2) . It shou1.73 m2) .Table 1PBoth diuretics and SGLT2is exhibit effects with a direct or indirect link to falls (e.g. related to electrolyte disorders  or OH), In this paragraph, we provide a narrative summary of the available evidence regarding fall-related adverse effects of diuretics and SGLT2is.Low blood pressure is linked to falls  through Orthostatic syncope is common, especially in older adults. In older patients living with dementia, orthostatic syncope is the leading cause of syncope . A systeSGLT2is cause both natriuresis and osmotic diuresis , but theMost loop and thiazide diuretics are associated with insulin resistance and a dose-related increase in incident diabetes risk . HyperglEven though SGLT2is cause glycosuria, the risk of developing hypoglycemia with these drugs appears to be low and not age-dependent , even inHyperuricemia and gout attacks are among the most prevalent adverse effects of diuretic therapy , especiap < 0.001).Whereas diuretics increase the risk of developing hyperuricemia and gout flares , SGLT2isHyponatremia related to secondary ADH secretion is present in ~ 5% of all patients suffering from HF on diuretics. The risk of hyponatremia is especially high for thiazide diuretic users, and within this subclass higher for chlorthalidone than for hydrochlorothiazide . Thiazid2. Concomitant use of spironolactone with ACEis/ARBs, amiloride, triamterene and potassium supplements increase the risk of developing hyperkalemia, especially in case of dehydration and chronic kidney disease. Literature suggests that SGLT2i use is not associated with incident hyperkalemia, not even in high-risk patients with type 2 diabetes mellitus and chronic kidney disease [Hyperkalemia is present in up to 40% of chronic HF patients  and resu disease , 82.Hypokalemia in chronic HF patients has been linked to increased mortality and risk of sudden death, syncope and falls , even whAn important effect of diuretics and SGLT2is to consider in geriatric patients with a history of falls is the potential to cause weight loss . After iChronic use of high doses of loop diuretics (except torasemide ) are assPatients with hepatic impairment, cirrhosis and ascites are at increased risk for dehydration-associated hepatic encephalopathy , which mHigh intravenous and oral doses of loop diuretics  are associated with impaired hearing, tinnitus and vertigo  and, thep < 0.01). Hip bone mineral density (BMD) was lower in chronic long-term loop diuretic users compared to nonusers (p = 0.03) [Several studies have demonstrated an association between fragility fractures and the use of diuretics in individuals ≥ 65 years old. Fracture risk was highest in the first weeks after initiating diuretic therapy , 93, 94. = 0.03) . Also in = 0.03) .The risk of bone fractures associated with SGLT2i use is controversial . In the https://kik.amc.nl/falls/decision-tree/). In the next subparagraphs, the evidence of deprescribing these drug classes is summarized, and recommendations for successful deprescribing outlined.In patients who have fallen, deprescribing diuretics and/or SGLT2is should always be considered and discussed with the patient, especially when fall-related adverse drug effects have been identified. The first step in diuretic users is to check whether dose-reduction can be attempted, for instance in individuals with poor dietary intake or signs/symptoms of dehydration. For diuretics, a step-by-step deprescribing approach for clinical use has been developed recently . Recurrence of HF (present in approximately one in four patients) was the most common reason for failed withdrawal attempts , 102 in Failure of deprescribing attempts will generally be evident within the first weeks to months. After that time-frame, the risk of re-initiating diuretic therapy is low . FactorsBased on (scarce) published data, blood pressure may increase after diuretic withdrawal, but that this generally is of mild to moderate severity, and temporary in nature. In a recent Norwegian study , the effTo the best of our knowledge, there is no published data on deprescribing SGLT2is in older patients.A recent study in older HFpEF patients  showed tDiuretic deprescribing attempts require careful monitoring for re-occurrence of congestion. Like in ambulatory HF care, patients should be encouraged to measure their body weight daily, and to alarm when their body weight increases and/or signs or symptoms of HF arise , 80. Earhttps://kik.amc.nl/falls/decision-tree/).Given the high baseline prevalence of (orthostatic) hypotension in older HF patients , and theOlder HF patients are a highly complex and vulnerable population. If they experience unexplained, recurrent falls, referral to a dedicated falls and syncope expert center should be considered to assess likeliness of cardiac (pre)syncope, and identify potentially modifiable fall risk factors such as FRID use: older HF patients are not only at risk for cardiac syncope, but also at very high fall risk due to both high prevalence of fall risk increasing conditions and multimorbidities . The use of diuretics and/or SGLT2is, drug classes with various potential fall-related adverse effects add to the increased fall risk in this population. Because falling is an important risk factor for functional decline, loss of quality of life and mortality, falls prevention is of great importance to older HF patients. To be effective, an individualized, patient-centered multifactorial treatment should be adopted, in which all factors contributing to fall risk in a patient should be adequately addressed.Given the potential to cause or aggravate fall risk, diuretics and/or SGLT2is should be prescribed with caution and in the lowest dose necessary to maintain euvolemia in older fall prone HF patients. During regular follow-up visits, volume status, blood pressure and orthostatic response should be assessed. Also, regular evaluation of electrolytes is indicated, particularly in frail patients with poor dietary intake and/or risk of dehydration.In carefully selected fall-prone older HF patients, diuretic withdrawal may be attempted in an effort to reduce fall risk. Careful monitoring of impending congestive HF and hypertension, however, is mandatory. Switching to SGLT2i therapy may be an attractive treatment option in some patients : SGLT2isDecisions to (de)prescribe diuretics and SGLT2is in older HF patients are highly complex and challenging to clinicians. This paper is aimed to support clinicians in decision making regarding continuation/deprescribing diuretics and SGLT2is: we summarized the best available evidence from the literature to safely prescribe and deprescribe these drug classes and provide the clinician with guidance and practical tools to be used in everyday clinical care for older HF patients who have fallen. It should be emphasized that falls are usually multifactorial in nature. To effectively reduce fall risk, a multifactorial and comprehensive approach should be adopted, in which all fall risk factors—including risk medication— present in a patient are addressed , 112. Fohttps://kik.amc.nl/falls/decision-tree/). For this patient, SGLT2i therapy may be a safer alternative to diuretic use; compared to diuretics, tendency to cause electrolyte abnormalities of SGLT2is is low, and effect on blood pressure and diuresis is relatively weak. Also, whereas diuretics are only effective in treating/preventing congestion, SGLT2is have disease-modifying effects, linked to reductions in heart failure hospitalization and MACE outcomes. Last, introducing SGLT2i therapy will allow insulin dose reduction or even insulin cessation and, therefore, hypoglycemia risk. A safe approach to switch the patient from diuretic to SGLT2i therapy would be to cross-titrate , while carefully monitoring for signs/symptoms of congestion and increases in blood pressure. If serum creatinine increases upon initiating SGLT2i therapy, the clinician can use the recently published practical recommendations for dealing with (pseudo)worsening of kidney function after starting SGLT2is in heart failure patients [An important goal of care for this 83-year-old lady is to prevent future fall incidents and to prevent hospital admission. To this end, all identified (modifiable) fall risk factors should be addressed and discussed with her. Deprescribing furosemide and hydrochlorothiazide should be considered because these drugs may have caused nocturia, (orthostatic) hypotension, dehydration, azotemia, and hyponatremia. For practical guidance, the clinician can follow the STOPPFall clinical decision tree on deprescribing diuretics (Fig. patients . To furt


However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage . Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD.The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m Diabetic kidney disease (DKD) is a common microvascular complication that develops in approximately 40% of patients with diabetes. It is the main cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) and is a major cause of mortality and morbidity in diabetics not only due to ESRD but also because of the resulting cardiovascular risk .The clinical relevance of DKD compared with other complications of type 2 diabetes needs to be highlighted; indeed, while other complications associated with diabetes have seen a decline in recent years, the same has not occurred for DKD: possible explanations for this phenomenon are increased ESRD survival with the improvement of cardiovascular prognosis or the still unmet need for better treatment  analysis of data from both trials (FIDELIO-DKD and FIGARO-DKD)  concludeIn a recent network meta-analysis , a totalIntensive glycemic control has been shown in large randomized clinical trials to delay the onset and progression of DKD in diabetic patients . The choSeveral glucose-lowering agents, such as metformin, DiPeptidyl Peptidase 4 (DPP-4) inhibitors , GLP1-RAMetformin is the first-choice antidiabetic medication for most cases. Christiansen et al. showed that patients who started metformin reported a lower risk of experiencing a severe decline in eGFR . There aDe Bhailís et al.  in a revFour cardiovascular outcome trials (CVOTs) evaluated the CV and renal safety of DPP-4 inhibitors in a total of 43,522 patients. In the SAVOR-TIMI 53 trial , type 2 Many studies showed the potential renoprotective effects of GLP1-RAs. In a secondary analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial , LiragluSimilar positive findings were reported with another two GLP1-RAs; semaglutide  and exenData are available in the literature about the important renal protection effect exerted by SGLT2 inhibitors on DKD, which act with different mechanisms of action, as shown in SGLT2i exerts indirect nephroprotective effects through the improvement of HBA1c, reduction of body weight, reduction of glucotoxicity, improvement of insulin resistance, and of pancreatic beta-cell function. They also stimulate osmotic diuresis and natriuresis, with a reduction of plasma volume, anti-edema effects, and, therefore, reduction of blood pressure . MoreoveDirect nephroprotective effects of SGLT2i have also been proposed: the first and most important is the action on the hemodynamic pathway, through afferent arteriolar vasoconstriction, thereby suppressing intraglomerular pressure and therefore reducing glomerular hyperfiltration ; downregThe systematic review and meta-analysis of trials on SGLT2i by Neuen et al.  confirmeThree large multinational, randomized trials that were primarily designed to evaluate the cardiovascular outcomes of dapagliflozin , canagliflozin , and empagliflozin  reported the renal endpoints as secondary outcomes. The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE) trial, instead, was primarily designed to assess the renal safety of canagliflozin in diabetic patients with pre-existing renal disease.n = 17,160), provided the strongest evidence. Participants on dapagliflozin had a lower risk of renal mortality or ESRD as well as a reduced risk of a sustained decline in eGFR. This positive nephroprotective effect was shown in a similar population for canagliflozin from the CANVAS Program study  [n = 1517) [n = 4401) also reported reductions in the proportions of participants using canagliflozin and developing ESRD, dialysis, or renal death [The DECLARE-TIMI 58 study , which s 10,142)  and empa = 1517) . The CREal death .2 per year between the study groups.Additionally, in the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial , the ratCurrently, there are no specific therapies for non-albuminuric DKD. It is generally assumed that management of several risk factors such as high glucose levels, high blood pressure, hypercholesterolemia, and other factors, can protect renal function and delay the progression to chronic renal failure; however, whether this approach may be effective in patients with non-albuminuric DKD remains to be shown.Whether RAS blockers can be used for non-albuminuric DKD treatment is currently unclear. According to Dwyer et al., RAS inhibitors may slow the progression of non-albuminuric DKD by reducing proteinuria, but more studies are required to confirm this hypothesis since there are still subjects whose proteinuria goes down but nonetheless have a progression of their underlying renal status .The American Diabetes Association and the European Association for the Study of Diabetes (ADA/EASD) published an updated Consensus Report for the management of hyperglycemia in diabetics in 2022  recommenThese classes of drugs have extensively demonstrated their protective effect on kidney disease in diabetic patients, as previously reported. However, data concerning therapy in the non-albuminuric phenotype are still inadequate and no studies have been carried out investigating this subgroup of patients with DKD. Nonetheless, some data come from sub-analyses of important studies on SGLT2i.The Empagliflozin in Patients with Chronic Kidney Disease (EMPA-KIDNEY) trial  was desi2 and a UACR of 200 mg/g to 5000 mg/g were randomly assigned to receive dapagliflozin or a placebo. Among patients with CKD, regardless of the presence or absence of diabetes, the risk of a composite of a decline in the eGFR of at least 50%, ESRD, or renal or CV death was significantly lower with dapagliflozin than with a placebo.In the Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD) study , adults The CANVAS-Renal trial  demonstrHowever, none of these studies specifically analyzes the distinction of the effect of SGLT2i on the various phenotypes of DKD. Unfortunately, subgroup analysis evaluated patients only on the basis of preserved/reduced eGFR and presence/absence of albuminuria, without considering both factors simultaneously for defining the phenotypes, albuminuric and non-albuminuric, as we know them now. This prevented them from drawing any conclusion on the possible therapeutic effect of these drugs in non-albuminuric DKD.For this reason, there are still no specific guidelines on the use of these drugs in one phenotype rather than the other, generically referring to diabetic patients with CKD. In the future, further studies investigating the CV and renal risk in diabetic patients with renal disease will have to be conducted on the various classes of drugs, especially investigating the difference between the classic form of DKD with albuminuria and the new non-albuminuric form with reduction of glomerular filtrate.


Metabolic abnormalities such as dyslipidemia, glucose and high blood pressure are common in diabetic patients. Visit-to-visit variabilities in these measures have been reported as potential residual cardiovascular risk factors. However, the relationship between these variabilities and their effects on cardiovascular prognosis have not been studied.A total of 22,310 diabetic patients with ≥ 3 measurements of systolic blood pressure (SBP), blood glucose, total cholesterol (TC), and triglyceride (TG) levels during a minimum of three years at three tertiary general hospitals were selected. They were divided into high/low variability groups for each variable based on the coefficient of variation (CV) values. The primary outcome was the incidence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke.All high CV groups had a higher incidence of MACE than those with low CV . In multivariable Cox regression analysis,, high SBP-CV , high TC-CV , high TG-CV  and high glucose-CV  were independent predictors of MACE.Variability of SBP, TC, TG and glucose are important residual risk factors for cardiovascular events in diabetic patients.The online version contains supplementary material available at 10.1186/s12933-023-01848-x. Diabetes mellitus (DM) is often accompanied by other metabolic disorders such as dyslipidemia and hypertension; dyslipidemia affects up to 90% of type 2 diabetes patients and hypertension is found concomitantly in up to 70% of diabetic patients , 2. WhilIndividual parameters such as systolic blood pressure (SBP), lipid profile and glucose levels are often prone to visit-to-visit variability. Recent evidence suggests that variabilities of aforementioned parameters increase adverse cardiovascular outcomes including all-cause mortality, stroke and heart failure –8. ExtenPreviously, the authors of the present study have shown that variability of triglyceride levels may be harmful in diabetic patients . The prehttps://github.com/OHDSI/CommonDataModel]. In Korea, the ICD-10 coding system is used to classify diseases, and OMOP-CDM gives concept IDs uniquely matched to this code. Subsequently, the data were evaluated utilizing the OMOP-CDM concept ID, which was transferred to the ICD-10 code  Common Data Model (CDM) database of three tertiary institutions in Korea . The Observational Health Data Sciences and Informatics cooperation offers the OMOP CDM schema, which is used to standardize hospital electronic health records in the OMOP CDM database [For the study population, 24,694 people who were 40 years old or older and whose SBP, serum TC, TG and glucose levels were measured at least three times, and the first measurement taken between January 2017 and June 2019 were chosen. The date of the first measurement was recorded as the index date for each patient. Variability was calculated based on these three-year values (the modeling phase). Patients who were not diabetic were excluded, as were those who had a known malignancy, myocardial infarction (MI), or stroke at baseline. Outcome events occurring only after the collection of at least three measurements of target parameters were recorded. Patients whose outcome event occurred before the measurement of target parameters  for three times or more, as specified above, were excluded. Patients with missing values, including serum creatinine, high density lipoprotein cholesterol (HDL-C), or urine albumin, were also excluded. Finally, a total of 22,310 patients were included. The Institutional Review Board of each participating center approved this study. Due to the retrospective study design and use of anonymized data, written informed permission was waived.Blood samples for routine laboratory tests were drawn during the day after an overnight fast. Using a uniform enzymatic colorimetric technique, serum lipid profile levels were determined. Blood pressure (BP) measurements were taken in an outpatient setting after 5 min of rest, and patients were advised not to drink caffeine or smoke cigarettes before BP measurements for at least 30 min. In order to determine the coefficient of variation (CV), we analyzed the measurements of SBP, TC, TG and glucose levels. The CV, as the variability index, was calculated as 100 × σ/µ, where σ is the standard deviation and µ is the mean of the measurements. The median CV for each measurement served as the dividing line between the high CV and low CV groups.2. Patients on antihypertensive drugs, statins, TG-lowering drugs such as fenofibrates and omega-3 fatty acids, antiplatelets, and anticoagulants were defined as those who were prescribed the medications with a proportion of days covered (PDC) of 50% during the modeling phase. Information on alcohol consumption and smoking status were obtained from patient-reported medical records. Smoking status was classified as current smoker or never/previous smoker. SCORE2 risk prediction algorithm was used to estimate cardiovascular risk for each patient, and the results were classified into low-moderate, high- and very high-risk groups [Hypertension was defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, anti-hypertensive drug use, or OMOP-CDM concept ID for hypertension. Diabetes mellitus was defined as a fasting plasma glucose level ≥ 126 mg/dL, a HbA1c level ≥ 6.5%, anti-diabetic drug use, or OMOP-CDM concept ID for diabetes mellitus. Dyslipidemia was defined as serum TC ≥ 240 mg/dL, LDL-C ≥ 160 mg/dL, TG ≥ 200 mg/dL, or HDL-C < 40 mg/dL, taking lipid lowering drugs, or OMOP-CDM concept ID for dyslipidemia. Based on the Modification of Diet in Renal Disease equation, chronic kidney disease was defined as a glomerular filtration rate of less than 60 mL/min/1.73 mk groups .The primary outcome was the occurrence of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, new-onset MI and stroke. The dates and causes of death were extracted from death certificates in medical records. MI was determined by the presence of a serum creatinine kinase myocardial band (CK-MB) level over the upper limit of normal with a rising and/or falling pattern during hospitalization via the emergency department. Stroke was defined as having the matching OMOP-CDM concept ID or having a brain MRI that showed an acute, subacute, or recent cerebral infarction. The entire follow-up duration was used to analyze the time-to-event outcomes, and patients were censored at the time of death or the last available follow-up.Categorical variables are reported as numeric values (percentages) and continuous variables are reported as mean ± standard deviation. The study compared categorical variables by using either the χ2 test or Fisher’s exact test, and continuous variables by using either Student’s t-test or Mann-Whitney U-test, as appropriate. Pearson’s correlation coefficient was used to assess the correlation between each metabolic parameter’s CV and mean values. The cumulative incidences were calculated using Kaplan-Meier censoring estimates. Multivariable Cox proportional hazard regression analysis was used to compute the hazard ratios (HRs) and 95% confidence intervals (CI). To determine the independent predictors of MACE, Cox proportional hazards analysis was performed to identify significant variables, which were subsequently included in backward stepwise multivariable analysis. The final multivariable model included age, sex, serum creatinine, dyslipidemia, prior history of MI, prior history of stroke, anti-hypertensive drugs, statins and insulin. A p-value of < 0.05 was considered statistically significant. All analyses were performed using SAS  and R Statistical Software .Supplemental Table S2.The baseline characteristics of the high-CV and low-CV groups for each variable are shown in Table Supplemental table S3). Overall, 89.4% of the total patients had at least one high-CV parameter; 24.8% showed high variability in one parameter, and 30.1%, 23.1% and 11.4% in two, three and four parameters, respectiely , with the second highest being SBP and glucose (r = 0.25) and lowest for SBP and TG (r = 0.02). The between-variable correlation for mean values of each variable was highest for TC and TG (ρ = 0.31) and lowest for glucose and TC (ρ = 0.01) .The strength of correlation between each variable’s CV and other variables’ CV were investigated, as shown in The clinical outcomes occurring from +28 days post the index date were recorded, for a median duration of 1095 days. The cumulative incidences of the clinical outcomes are summarised in Table In multivariable analysis by the Cox regression model, high SBP-CV , high TC-CV  high TG-CV  and high glucose-CV  were independent predictors of MACE  high variability in one metabolic variable is associated with high variability in other metabolic variables; (2) variabiltiy appears to be more effective in predicting MACE compared to mean values; and (3) high variability groups tended to consist of more alcohol consumers and smokers compared with low CV groups.Variability as a risk factor for adverse cardiovascular outcomes is increasingly being recognised. However, the interaction between variability of different metabolic variables on the effect of cardiovascular outcomes is not clear. A nationwide cohort study based on the National Health Insurance System in Korea compared the variabilities of blood pressure, glucose and cholesterol concentrations and body mass index, but while each variable was associated with the occurrence of adverse events, the correlation between the variables were not strong  . There iThe evaluation of risk of MACE occurrence in our study showed that high variability of SBP, TC, TG and glucose all had an advantage over the respective mean values in prediction of MACE occurrence. High SBP variability, in particular, exhibited a near twofold increae in MACE risk, while high mean SBP did not show significance in univariable analysis. Previous studies on have shown that visit-to-vist SBP variability is a strong predictor of adverse coronary events and stroke, independent of mean SBP levels –17. A reIn our study, high TC variability was also associated with a 54% increase in MACE risk. TC variability was first recognised as a cardiovascular risk factor in the Framingham study . High TCRegarding TG, high TG variability was recently shown to be an independent risk predictor for adverse cardiovascular outcomes including all-cause death and MI, as compared with cumulative exposure to high levels of TG . While KPrevious analyses also showed that variations in fasting plasma glucose (FPG) was an independent predictor of cardiovascular death and mortality in general population and also in diabetic population , 27, 28.Notably, baseline demographics from our study show that smoking and alcohol drinking were positively associated with high CV across the all four variables in interest. This is in contrast to other variables such as age or sex, which showed varied proportions for low and high CV groups. Cigarette smoking is known to be associated with BP variability both during the day and between visits, likely contributing to the detrimental cardiovascular effects of smoking , 30. TheSupplemental table S3, the number of measurements and the interval betweeen measurements were similar for TC, TG and glucose. Considering the laborous task of coming into the hospital and providing a blood sample, it is likely that many of the TC, TG and glucose measurements would have been taken at the same time. The number of SBP measurements is naturally larger than the others due to its less-invasive quality. Third, adherence to treatment was not checked. However, the fact that multiple measurements over more than three years were needed for eligibility indirectly suggests at least moderate compliance of the enrolled patients.Our study has several limitations. First, being a retrospective cohort study, precautions should be taken for the interpretation of the results as the possibility of selection bias cannot be ignored. The relationships found in our study between metabolic variabilities and clinical outcomes, for example, should be understood as associations rather than cause-and-effect. This warrants future trials based on randomisation of the patients in order to further consolidate our findings. Second, the measurements of the four variables of interest, namely SBP, TC, TG and glucose, were not all taken simultaneously. However, as shown in In conclusion, in diabetic patients, metabolic variability parameters such as SBP-CV, TC-CV, TG-CV and glucose-CV are important risk factors for cardiovascular events, independent of the respective mean values. The exact mechanisms by which variability of different parameters affect each other are yet to be elucidated in future studies.Below is the link to the electronic supplementary material.Supplementary Material 1


However, no significant reduction of cvMTT was observed . Mean arterial pressure was significantly increased between follow-up and first CTP . The combined multimodal rescue therapy was effective in addressing the general microvascular perfusion impairment but did not affect the mechanisms underlying microvascular perfusion heterogeneity. This highlights the need for research into new therapeutic approaches that also target these pathophysiological mechanisms of DCI.General microvascular perfusion and its heterogeneity are pathophysiological features of delayed cerebral ischemia (DCI) that are gaining increasing attention. Recently, CT perfusion (CTP) imaging has made it possible to evaluate them radiologically using mean transit time (MTT) and its heterogeneity (measured by cvMTT). This study evaluates the effect of multimodal rescue therapy  on MTT and cvMTT during DCI in aneurysmal subarachnoid haemorrhage (aSAH) patients. A total of seventy-nine aSAH patients who underwent multimodal rescue therapy between May 2012 and December 2019 were retrospectively included in this study. CTP-based perfusion impairment (MTT and cvMTT) on the day of DCI diagnosis was compared with follow-up CTP after initiation of combined multimodal therapy. The mean MTT was significantly reduced in the follow-up CTP compared to the first CTP (3.7 ± 0.7 s vs. 3.3 ± 0.6 s;  Not only the initial bleeding event in aneurysmal subarachnoid haemorrhage (aSAH) but also the subsequent pathophysiological processes lead to the high mortality and morbidity associated with this disease ,2,3. PatSimilar to the pathophysiological concepts behind DCI, therapeutic concepts have also changed. For a long time, the so-called “triple H” therapy consisting of hypertension, hypervolemia, and haemodilution was the treatment of choice for cerebral vasospasm and DCI ,25,26,27However, the therapeutical effects of this rescue therapy on microvascular perfusion heterogeneity in patients suffering from DCI are currently unclear. In the present study, we therefore investigated the effects of multimodal rescue therapy, including blood pressure elevation and intra-arterial nimodipine administration in the DCI phase, on microvascular perfusion heterogeneity, as measured by the cvMTT of CT perfusion imaging, in aSAH patients.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki Declaration and its later amendments. This study was approved by the local ethics committee (study ID: 5760R) and the need for written informed consent was waived. Data will be made available upon reasonable request. We prepared the manuscript according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines  and the We retrospectively included all patients with SAH admitted to our tertiary-care hospital between May 2012 and December 2019 who met the following inclusion criteria: (1) patient treated for SAH, (2) the treatment was performed in our specialized neurosurgical intensive care unit, (3) the patient received CTP imaging on two consecutive days due to MTT increase in the first imaging, and (4) the patient received an intra-arterial administration of nimodipine (spasmolysis) during her or his stay in the intensive care unit. Patients were excluded from the study on the basis of the following criteria: (1) there was no CTP before the spasmolysis (on the same day) or (2) no CTP on the day following the spasmolysis was available; if (3) the image quality of a CTP imaging was insufficient for the evaluation; or (4) if there was a definite cause for subarachnoid haemorrhage other than a ruptured aneurysm .We managed patients according to an in-house standardised protocol for general care  based onAfter aneurysm repair, CTP imaging followed our local DCI diagnosis and treatment guidelines . We perfBased on CTP imaging, especially MTT prolongation, and clinical symptoms, further therapy was decided upon in an interdisciplinary consultation. If there was a clinical correlate, i.e., a neurological deterioration without any other reason or MTT prolongation in accordance with the DCI criteria , a totalhttp://www.eccet.de/, accessed on 1 June 2023) for standardised parameter value extraction from the different cortical brain regions. Angiotux automatically delineated a 10 mm wide band along the cortex, excluding outer CSF spaces, the rostral falx cerebri, and the superior sagittal sinus. We reviewed the automated definition of the region of interest and corrected any potential deviations. A running average spanning 10° of the ROI was computed in 2° steps for each perfusion parameter, yielding 180 measurements per parameter per CTP scan.We acquired CTP data using a multislice CT scanner  as previously described . ContrasWe defined heterogeneity of microvascular perfusion as heterogeneity of cerebral perfusion among the measured ROIs, assessed by the coefficient of variation (cv or relative SD) of the MTT (cvMTT) for each individual scan. The cv is a measure of the dispersion of a probability distribution independent of the mean of the examined variable :cvMTT=stThe analysis of this study included the CTP demonstrating the initial prolongation of the MTT and the control CTP on the following day after the induction of multimodal rescue therapy within the DCI period. If a patient received multiple endovascular rescue therapies in one stay, only the CTP pair of the first rescue therapy was considered in this study.Demographic data including age at diagnosis and sex were collected retrospectively from patients’ charts. For further correlation with cvMTT, we selected the mean arterial blood pressure, the intracranial pressure (ICP), and the cerebral perfusion pressure (CPP), recorded as previously described in detail . In briet-test, and correlations between two numerical variables were compared using linear regression analysis. Significance was defined as p-value < 0.05. All calculations were performed in Python 3.9.16, using numpy, scipy, and statsmodels libraries.Continuous variables are presented as mean ± standard deviation, ordinal values are presented as median values and minimum–maximum ranges. For categorical data, frequencies and percentages are presented. For each patient, mean arterial pressure (MAP) and CPP were measured and average MTT was calculated from the CTP imaging, both before and after therapy. In addition, the coefficient of variation (cv) of the MTT values was calculated for each patient. Numerical values between two discrete groups were compared using the Seventy-nine of the initial five hundred and thirty-five patients with aSAH developed severe DCI requiring multimodal rescue therapy with intra-arterial nimodipine application during the observation period and were included in the analysis . The meap < 0.0001), as depicted in p < 0.05)  B.p = 0.44, Contrary to the mean MTT, there was no significant change in the cvMTT .The mean MTT of the initial CTP imaging was 3.67 ± 0.74 s and decreased significantly to 3.31 ± 0.60 s in the follow-up CTP imaging after the initiation of the multimodal rescue therapy, as depicted in p = 0.96, R2 = −0.014; p = 0.02, R2 = 0.054; p = 0.95, R2 = −0.026; post-multimodal rescue therapy; Correlations of the MAP and CPP with the cerebral perfusion (mean MTT and cvMTT) were analysed using linear regression analysis. The mean MTT showed no significant correlation with the MAP before multimodal rescue therapy  or the CPP  at any time.For the cvMTT, there was no significant correlation with either the MAP   E.This retrospective study in patients with DCI after aSAH had the following main findings: (1) Multimodal rescue therapy in DCI consisting of intra-arterial nimodipine injection (spasmolysis) and blood pressure elevation improved general microvascular perfusion in the medium term as the mean MTT significantly decreased even 24 h after the induction of the therapy, but (2) multimodal rescue therapy in DCI had no effect on the microvascular perfusion heterogeneity, measured by cvMTT of CT perfusion imaging.Effective therapy of severe DCI after a SAH is still challenging and a matter of current debate. One established therapeutic concept for severe DCI with neurological deterioration and impairment of cerebral perfusion is the elevation of blood pressure and local intra-arterial nimodipine application (spasmolysis) as rescue therapy ,11,12,13Unexpectedly, we neither observed an influence of the MAP on the MTT or cvMTT nor a correlation between the MAP change during multimodal therapy and the mean MTT/cvMTT. We cannot exclude that a larger cohort and a prospective design would have resulted in statistical significance. In fact, higher blood pressure is associated with a lower MTT in the phase of early brain injury (EBI) before aneurysm repair . Apart fv1.2 and Cav1.3 L-type calcium channels have their significance in major cerebral vessels, such as the basilar artery [Besides cerebral vasospasm, DCI is a multifactorial event with various pathophysiological responses. In this context, the concept of CTH is becoming increasingly important ,19. CTH r artery . In contr artery ,38. Morer artery ,41,42,43r artery . In lighr artery ,41,42,43We acknowledge several limitations.The retrospective study design results in lower data quality than in a prospective study, which might influence the results. Thanks to our internal hospital documentation system with up-to-the-second recording of all vital parameters and electronic progress documentation, we believe that we nevertheless achieved good data quality in the present study.As described in detail before , due to Again, our CTP setup is likely neither able to measure capillary perfusion nor capillary transit times heterogeneity as described by Østergaard et al. The MTT is most likely a correlate of the microvascular tissue perfusion and the cvMTT of its microvascular perfusion heterogeneity. Standard values of the cvMTT for normal brain tissue have not been established. Furthermore, possible influencing factors such as intracranial pressure or other variables are unclear. Since patients without ICP measurement are awake according to our treatment guideline, we assume a comparable intracranial pressure, which means that ICP should not have a strong influence on the results of this study.In the present study, the focus was on the changes due to the multimodal therapy, and we did not analyse for a possible correlation with the outcome of the patients. A correlation of cvMTT and MTT with outcome has already been reported on in previous studies.Due to the variety of different CTP protocols and post-processing, CTP imaging data are more difficult to compare and may not be transferable one-to-one to other sites. It is also not clear to what extent different medications or pre-existing conditions affecting the microvasculature  influence CTP imaging.In summary, our study suggests limitations of the currently employed multimodal rescue therapy in DCI. While the therapy aims to address general microvascular perfusion restrictions, it does not impact microvascular perfusion heterogeneity. Increasing general microvascular perfusion by elevating blood pressure or treating macro-vasospasm alone arguably does not seem to be a sufficient approach to address all of the damaging pathomechanisms associated with DCI. Our findings emphasize the need for future therapeutic approaches targeting the heterogeneity of microvascular perfusion to potentially improve patient outcomes.