Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload

Calcineurin is a Ca2+/calmodulin-dependent protein phosphatase that induces myocardial growth in response to several physiological and pathological stimuli. Calcineurin inhibition, induced either via cyclosporine or genetically, can decrease myocardial hypertrophy secondary to pressure overload without affecting left ventricular (LV) systolic function. Since hypertrophy can also affect LV diastolic function, the goal of this study was to examine the effects of chronic pressure overload (2 wk aortic banding) in transgenic (Tg) mice overexpressing Zaki-4β (TgZ), a specific endogenous inhibitor of calcineurin, on LV diastolic function. As expected, in the TgZ mice with calcineurin inhibitor overexpression, aortic banding reduced the degree of LV hypertrophy, as assessed by LV weight-to-body weight ratio (3.5 ± 0.1) compared with that in non-Tg mice (4.6 ± 0.2). LV systolic function remained compensated in both groups with pressure overload. However, the LV end-diastolic stress-to-LV end-diastolic dimension ratio, an index of diastolic stiffness and LV pressure half-time and isovolumic relaxation time, two indexes of isovolumic relaxation, increased significantly more in TgZ mice with aortic banding. Protein levels of phosphorylated phospholamban (PS16), sarco(endo)plasmic reticulum Ca2+-ATPase 2a, phosphorylated ryanodine receptor, and the Na+/Ca2+ exchanger were also reduced significantly ( P < 0.05) in the banded TgZ mice. As expected, genetic calcineurin inhibition inhibited the development of LV hypertrophy with chronic pressure overload but also induced LV diastolic dysfunction, as reflected by both impaired isovolumic relaxation and increased myocardial stiffness. Thus genetic calcineurin inhibition reveals a new mechanism regulating LV diastolic function.

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Peripartum Cardiomyopathy Presenting with Predominant Left Ventricular Diastolic Dysfunction: Efficacy of Bromocriptine

Case Reports in Medicine ◽

10.1155/2012/476903 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 10

Author(s):

Piercarlo Ballo ◽

Irene Betti ◽

Giuseppe Mangialavori ◽

Leandro Chiodi ◽

Gherardo Rapisardi ◽

...

Keyword(s):

Heart Failure ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Systolic Function ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Peripartum Cardiomyopathy ◽

Lv Function ◽

Lv Diastolic Dysfunction ◽

Lv Diastolic Function

Management of patients with peripartum cardiomyopathy (PPCM) is still a major clinical problem, as only half of them or slightly more show complete recovery of left ventricular (LV) function despite conventional evidence-based treatment for heart failure. Recent observations suggested that bromocriptine might favor recovery of LV systolic function in patients with PPCM. However, no evidence exists regarding its effect on LV diastolic dysfunction, which is commonly observed in these patients. Tissue Doppler (TD) is an echocardiographic technique that provides unique information on LV diastolic performance. We report the case of a 37-year-old white woman with heart failure (NYHA class II), moderate LV systolic dysfunction (ejection fraction 35%), and severe LV diastolic dysfunction secondary to PPCM, who showed no improvement after 2 weeks of treatment with ramipril, bisoprolol, and furosemide. At 6-week followup after addition of bromocriptine, despite persistence of LV systolic dysfunction, normalization of LV diastolic function was shown by TD, together with improvement in functional status (NYHA I). At 18-month followup, the improvement in LV diastolic function was maintained, and normalization of systolic function was observed. This paper might support the clinical utility of bromocriptine in patients with PPCM by suggesting a potential benefit on LV diastolic dysfunction.

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One-Year Change in the H2FPEF Score After Catheter Ablation of Atrial Fibrillation in Patients With a Normal Left Ventricular Systolic Function

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.699364 ◽

2021 ◽

Vol 8 ◽

Author(s):

Min Kim ◽

Hee Tae Yu ◽

Tae-Hoon Kim ◽

Jae-Sun Uhm ◽

Boyoung Joung ◽

...

Keyword(s):

Atrial Fibrillation ◽

Catheter Ablation ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Systolic Function ◽

Left Ventricular ◽

One Year ◽

Lv Diastolic Dysfunction ◽

Fat Volume ◽

Lv Diastolic Function

Background: It is unclear whether atrial fibrillation (AF) catheter ablation (AFCA) improves the left ventricular (LV) diastolic function. We evaluated the 1-year change in the H2FPEF score, which reflects the degree of LV diastolic function, after AFCA among patients with a normal LV systolic function.Methods and Results: We included 1,471 patients (30.7% female, median age 60 years, paroxysmal-type AF 68.6%) who had available H2FPEF scores at baseline and at 1-year after AFCA to evaluate the 1-year change in the H2FPEF score (ΔH2FPEF score[1−yr]) after AFCA. Baseline high H2FPEF scores (≥6) were independently associated with the female sex, left atrium (LA) diameter, LV mass index, pericardial fat volume, and a low estimated glomerular filtration rate. One year after AFCA, decreased ΔH2FPEF scores[1−yr] were associated with baseline H2FPEF scores of ≥6 [OR, 4.19 (95% CI, 2.88–6.11), p < 0.001], no diabetes [OR, 0.60 (95% CI, 0.37–0.98), p = 0.04], and lower pericardial fat volume [OR, 0.99 (95% CI, 0.99–1.00), p = 0.003]. Increased ΔH2FPEF scores[1−yr] were associated with a baseline H2FPEF score of <6 [OR, 3.54 (95% CI, 2.08–6.04), p < 0.001] and sustained AF after a recurrence within 1 year [SustainAF[1−yr]; OR, 1.89 (95% CI, 1.01–3.54), p = 0.048]. Throughout a 56-month median follow-up, an increased ΔH2FPEF score[1−yr] resulted in a poorer rhythm outcome of AFCA (at 1 year, log-rank p = 0.003; long-term, log-rank p = 0.010).Conclusions: AFCA appears to improve LV diastolic dysfunction. However, SustainAF[1−yr] may contribute to worsening LV diastolic dysfunction, and it was shown by increased ΔH2FPEF scores[1−yr], which was independently associated with higher risk of AF recurrence rate after AFCA.Clinical Trial Registration:ClinicalTrials.gov Identifier: NCT02138695.

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Neutrophil to Lymphocyte Ratio is Increased and Associated with Left Ventricular Diastolic Function in Newly Diagnosed Essential Hypertension Children.

10.21203/rs.3.rs-27242/v1 ◽

2020 ◽

Author(s):

Miao Hou ◽

Lei Cao ◽

Yueyue Ding ◽

Ye Chen ◽

Bo Wang ◽

...

Keyword(s):

Essential Hypertension ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Systolic Function ◽

Left Ventricular ◽

Neutrophil To Lymphocyte Ratio ◽

Healthy Children ◽

Newly Diagnosed ◽

Lymphocyte Ratio ◽

Lv Systolic Function

Abstract Aim Hypertension is associated with cardiac structural and functional changes, including left ventricular hypertrophy (LVH), LV systolic dysfunction, and diastolic dysfunction. Neutrophil to lymphocyte ratio (NLR) is a novel inflammatory biomarker associated with cardiovascular diseases. The current study aimed to evaluate NLR in children with newly diagnosed essential hypertension and its relationship between blood pressure and cardiac changes. Methods and subjects 44 children with newly diagnosed essential hypertension and 43 healthy children were included. Clinical characteristics, blood cell counts and biochemical parameters were collected. LVH was assessed by calculation of LV mass index (LVMI), and LV systolic function was evaluated by measuring LV ejection fraction and fractional shortening. LV diastolic function was primarily assessed with E/E’ ratio by doppler and echocardiography. Results The hypertension children had significantly higher LVMI and E/E’ ratio compared to the controls, whereas there was no difference in LV systolic function between two groups. The NLR was significantly higher in the hypertension group than the control group. Moreover, NLR and it was positively correlated with SBP and DBP levels in the hypertension group. Additionally, a significantly positive correlation between NLR and E/E’ ratio was found in the hypertension group. However, NLR was not related to LVH and LV systolic function indicators in hypertension children.Conclusion The higher NLR may be a potential indicator of increased risk for the development of hypertension in children. Moreover, NLR may help to assess the presence of LV diastolic dysfunction in hypertension children.

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Neutrophil to Lymphocyte Ratio Is Increased and Associated With Left Ventricular Diastolic Function in Newly Diagnosed Essential Hypertension Children

Frontiers in Pediatrics ◽

10.3389/fped.2021.576005 ◽

2021 ◽

Vol 9 ◽

Author(s):

Miao Hou ◽

Lei Cao ◽

Yueyue Ding ◽

Ye Chen ◽

Bo Wang ◽

...

Keyword(s):

Blood Pressure ◽

Essential Hypertension ◽

Diastolic Function ◽

Systolic Function ◽

Left Ventricular ◽

Neutrophil To Lymphocyte Ratio ◽

Newly Diagnosed ◽

Lymphocyte Ratio ◽

Lv Systolic Function ◽

Lv Diastolic Function

Aim: Hypertension is associated with cardiac structural and functional changes, including left ventricular hypertrophy (LVH) and LV systolic dysfunction diastolic dysfunction. Neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker associated with cardiovascular diseases. The current study aimed to evaluate NLR in children with newly diagnosed essential hypertension and its relationship between blood pressure and cardiac changes.Methods and Subjects: Sixty-five children with newly diagnosed essential hypertension and 54 healthy children were included. Clinical characteristics, blood cell counts, and biochemical parameters were collected. LVH was assessed by calculation of LV mass index (LVMI), and LV systolic function was evaluated by measuring LV ejection fraction and fractional shortening. LV diastolic function was primarily assessed with E/E′ ratio by Doppler and echocardiography.Results: The hypertension children had significantly higher LVMI and E/E′ ratio than the controls, whereas there was no difference in LV systolic function between the two groups. The NLR was significantly higher in the hypertension group than the control group. Moreover, NLR was positively correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels in the hypertension group. Additionally, a significantly positive correlation between NLR and E/E′ ratio was found in the hypertension group. However, NLR was not related to LVH and LV systolic function indicators in hypertension children.Conclusion: NLR is elevated in hypertension children, and it is associated positively with office blood pressure levels. Moreover, NLR may help assess LV diastolic function in hypertension children.

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Direct cardiac versus systemic effects of inorganic nitrite on human left ventricular function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00081.2021 ◽

2021 ◽

Author(s):

Kevin O'Gallagher ◽

Ana R Cabaco ◽

Matthew Ryan ◽

Ali Roomi ◽

Haotian Gu ◽

...

Keyword(s):

Diastolic Function ◽

Sodium Nitrite ◽

Diastolic Pressure ◽

Contractile Function ◽

Systolic Function ◽

Left Ventricular ◽

Lv Function ◽

Cardiac Contractile Function ◽

Lv Systolic Function ◽

Lv Diastolic Function

Background Inorganic nitrite generates nitric oxide (NO) in vivo and is considered a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. Methods and Results We studied 40 patients undergoing diagnostic cardiac catheterisation who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7-26 mmol/min, n=20) or an intravenous sodium nitrite infusion (50 mg/kg/min, n=20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP) while secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR) and the time to LV end-systole (LVEST) but had no significant effect on measures of LV systolic function or systemic haemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Conclusions These results indicate that inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. The systemic administration of nitrite has larger effects on LV diastolic function which are related to reduction in both preload and afterload. These effects of inorganic nitrite indicate a favourable profile for conditions characterized by LV diastolic dysfunction, e.g. heart failure with preserved ejection fraction.

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Left atrial systolic and diastolic function after cessation of pacing in tachycardia-induced heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.2.h921 ◽

1997 ◽

Vol 273 (2) ◽

pp. H921-H927 ◽

Cited By ~ 2

Author(s):

B. D. Hoit ◽

Y. Shao ◽

M. Gabel ◽

C. Pawloski-Dahm ◽

R. A. Walsh

Keyword(s):

Heart Failure ◽

Diastolic Dysfunction ◽

Diastolic Function ◽

Left Atrial ◽

Systolic Function ◽

Left Ventricular ◽

Rapid Pacing ◽

Lv Systolic Function ◽

Systolic And Diastolic Function ◽

Lv Diastolic Dysfunction

Studies in the rapid-pacing model of heart failure have shown that left ventricular (LV) systolic function normalizes on cessation of pacing and LV diastolic dysfunction persists, but there is no information regarding atrial function under these conditions. To determine the effects of cessation of pacing on left atrial (LA) systolic and diastolic function, ten dogs with rapid pacing-induced heart failure (250 beats/min for 3-4 wk), six dogs with regression of heart failure (4 wk after cessation of rapid pacing), and seven control dogs were instrumented with LA sonomicrometers and micromanometers. At matched LA pressure, LA ejection (10.2 +/- 3.0 vs. 17.4 +/- 5.5%), reservoir volume fractions (19 +/- 8 vs. 35 +/- 11%), and heart rate-corrected mean normalized systolic ejection rate (1.25 +/- 0.33 vs. 1.60 +/- 0.44 EF/s) were significantly less, and the volume-normalized diastolic stiffness constant (4.9 +/- 0.8 vs. 3.2 +/- 1.1) was significantly greater, in regression versus control dogs; these changes were associated with incomplete regression of LA hypertrophy and a persistent 77.4% increase in beta-myosin heavy chain (beta-MHC) in the LA body. LV systolic function and weight were not significantly different, whereas the time constant of LV relaxation was longer (52.5 +/- 4.4 vs. 40.8 +/- 7.6 ms; P < 0.05) and LV end-diastolic pressure was greater (12.2 +/- 1.8 vs. 7.1 +/- 2.0 mmHg; P < 0.05) in regression compared with control dogs. Thus, unlike the normalization of LV systolic function observed with cessation of rapid pacing, LA systolic function is persistently abnormal, owing in part to persistent LV diastolic dysfunction, residual LA hypertrophy, and MHC isoform switches.

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Tachycardia-induced myocardial ischemia and diastolic dysfunction potentiate secretion of ANP, not BNP, in hypertrophic cardiomyopathy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00110.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. H1064-H1070 ◽

Cited By ~ 2

Author(s):

Shinsuke Kido ◽

Naoyuki Hasebe ◽

Yoshinao Ishii ◽

Kenjiro Kikuchi

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Myocardial Ischemia ◽

Diastolic Dysfunction ◽

Diastolic Pressure ◽

Systolic Function ◽

Left Ventricular ◽

Atrial Pacing ◽

Catheter Tip ◽

Lv Systolic Function ◽

Lv Diastolic Dysfunction

The aim of this study was to investigate what factor determines tachycardia-induced secretion of atrial and brain natriuretic peptides (ANP and BNP, respectively) in patients with hypertrophic cardiomyopathy (HCM). HCM patients with normal left ventricular (LV) systolic function and intact coronary artery ( n = 22) underwent rapid atrial pacing test. The cardiac secretion of ANP and BNP and the lactate extraction ratio (LER) were evaluated by using blood samples from the coronary sinus and aorta. LV end-diastolic pressure (LVEDP) and the time constant of LV relaxation of tau were measured by a catheter-tip transducer. These parameters were compared with normal controls ( n = 8). HCM patients were divided into obstructive (HOCM) and nonobstructive (HNCM) groups. The cardiac secretion of ANP was significantly increased by rapid pacing in HOCM from 384 ± 101 to 1,268 ± 334 pg/ml ( P < 0.05); however, it was not significant in control and HNCM groups. In contrast, the cardiac secretion of BNP was fairly constant and rather significantly decreased in HCM ( P < 0.01). The cardiac ANP secretion was significantly correlated with changes in LER ( r = −0.57, P < 0.01) and tau ( r = 0.73, P < 0.001) in HCM patients. Tachycardia potentiates the cardiac secretion of ANP, not BNP, in patients with HCM, particularly when it induces myocardial ischemia and LV diastolic dysfunction.

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Echocardiographic Assessment of Left Ventricular Geometric Patterns in Hypertensive Patients in Nigeria

Clinical Medicine Insights Cardiology ◽

10.4137/cmc.s12727 ◽

2013 ◽

Vol 7 ◽

pp. CMC.S12727 ◽

Cited By ~ 1

Author(s):

Rasaaq A. Adebayo ◽

Olaniyi J. Bamikole ◽

Michael O. Balogun ◽

Anthony O. Akintomide ◽

Victor O. Adeyeye ◽

...

Keyword(s):

Diastolic Dysfunction ◽

Systolic Function ◽

Left Ventricular ◽

Geometric Pattern ◽

Color Flow ◽

Hypertensive Patients ◽

Geometric Patterns ◽

Concentric Hypertrophy ◽

Eccentric Hypertrophy ◽

Lv Systolic Function

Left ventricular (LV) hypertrophy is an important predictor of morbidity and mortality in hypertensive patients, and its geometric pattern is a useful determinant of severity and prognosis of heart disease. Studies on LV geometric pattern involving large number of Nigerian hypertensive patients are limited. We examined the LV geometric pattern in hypertensive patients seen in our echocardiographic laboratory. A two-dimensional, pulsed, continuous and color flow Doppler echocardiographic evaluation of 1020 consecutive hypertensive patients aged between 18 and 91 years was conducted over an 8-year period. LV geometric patterns were determined using the relationship between the relative wall thickness and LV mass index. Four patterns of LV geometry were found: 237 (23.2%) patients had concentric hypertrophy, 109 (10.7%) had eccentric hypertrophy, 488 (47.8%) had concentric remodeling, and 186 (18.2%) had normal geometry. Patients with concentric hypertrophy were significantly older in age, and had significantly higher systolic blood pressure (BP), diastolic BP, and pulse pressure than those with normal geometry. Systolic function index in patients with eccentric hypertrophy was significantly lower than in other geometric patterns. Doppler echocardiographic parameters showed some diastolic dysfunction in hypertensive patients with abnormal LV geometry. Concentric remodeling was the most common LV geometric pattern observed in our hypertensive patients, followed by concentric hypertrophy and eccentric hypertrophy. Patients with concentric hypertrophy were older than those with other geometric patterns. LV systolic function was significantly lower in patients with eccentric hypertrophy and some degree of diastolic dysfunction were present in patients with abnormal LV geometry.

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Abstract 13910: Importance of Non-invasive Estimates of Left Ventricular Filling Pressures in Critically Ill Patients

Circulation ◽

10.1161/circ.142.suppl_3.13910 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Abdelrahman M Ahmed ◽

Brandon Wiley ◽

Jacob C Jentzer ◽

Nandan S Anavekar ◽

Allan S Jaffe

Keyword(s):

Diastolic Dysfunction ◽

Diastolic Function ◽

Critically Ill ◽

Critically Ill Patients ◽

Troponin T ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Adverse Outcomes ◽

Icu Mortality ◽

Lv Diastolic Function

Introduction: The presence of cardiac dysfunction predicts adverse outcomes in the intensive care unit (ICU). We explored the relationship of cardiac injury and left ventricular (LV) systolic and diastolic dysfunction (LVDD) to outcomes in critically ill patients. Methods: This is a retrospective analysis of adult medical ICU admissions from May, 2018 through October 2019. Patients with elevated high-sensitivity troponin T (hs-cTnT) and an echocardiogram performed within 72 hours of admission were included. Patients were classified as having normal LV diastolic function, isolated LVDD, concomitant LV diastolic and systolic dysfunction (LVDDSD) or indeterminate LV diastolic function based on American Society of Echocardiography 2016 guidelines. LV systolic dysfunction was defined as an ejection fraction (EF) < 50%. Results: Overall, 222 patients were included. LVDD was seen in 123 patients (55.4%). Thirty patients (13.5%) were classified with indeterminate diastolic function and 56 normal diastolic function (25.2%). Of those with LVDD , 59.3% had LVDDSD while isolated LVDD was seen in 40.7%.Patients with LVDDSD had a higher median hs-cTnT at baseline compared to patients with isolated LVDD [102ng/L IQR (50-257) vs. 77 ng/L (33.5-166); p=0.047]. Medial e’ velocity and tricuspid valve systolic regurgitant velocity were often associated with LV systolic dysfunction (p=0.0172 and 0.0013, respectively). LVDDSD was associated with a longer length of stay than patients with isolated LVDD [2.9 (1.6-4.0) vs.1.8 (1.1-3.3); p-value 0.03].Twenty-nine patients died during their ICU stay (13%). Patients with LVDDSD had 9.6-fold higher odds of dying in the ICU than patients with isolated LVDD (p=0.0048). Reduced medial e’ velocity (OR 0.63, CI 0.4-1.0, p=0.0285) and increased E/e’ (OR 1.08, CI 1.01-1.15, p=0.0192) were associated with ICU mortality. The association between LVEF<50% and ICU mortality was less pronounced (OR 0.95, CI 0.01-0.98; p=0.0023). Conclusions: Concomitant LV systolic and diastolic dysfunction and measures of increased cardiac filling pressures are strong predictors of mortality.

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P901 Left ventricular diastolic and systolic functions are compromised in patients with hypothyroidism

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jez319.539 ◽

2020 ◽

Vol 21 (Supplement_1) ◽

Author(s):

R Tafarshiku ◽

M Y Henein ◽

V Berisha-Muharremi ◽

I Bytyci ◽

P Ibrahimi ◽

...

Keyword(s):

Diastolic Function ◽

Systolic Function ◽

White Blood Cells ◽

Left Ventricular ◽

Blood Analysis ◽

Lv Function ◽

Anthropometric Parameters ◽

Age And Gender ◽

And Gender ◽

Lv Diastolic Function

Abstract Background and Aim Long standing hypothyroidism may impair myocardial relaxation, but its effect on systolic myocardial function is still controversial. The aim of this study was to investigate left ventricular (LV) systolic and diastolic function in patients with hypothyroidism. Methods This study included 81 (age 42 ± 13 years, 92% female) patients with hypothyroidism, and 22 age and gender matched controls. All subjects underwent a detailed clinical examination followed by a complete biochemical blood analysis including thyroid function assessment and anthropometric parameters measurements. LV function was assessed by 2 dimensional, M-mode and Tissue-Doppler Doppler echocardiographic examination performed in the same day. Results Patients had lower waist/hip ratio (p < 0.001), higher urea level (p = 0.002) and lower white blood cells (p = 0.011), compared to controls. All other clinical, biochemical and anthropometric data did not differ between the two groups. Patients had impaired LV diastolic function (lower E wave [p < 0.001], higher A wave [p = 0.028], lower E/A ratio [p < 0.001], longer E wave deceleration time [p = 0.01], and higher E/e’ ratio [p < 0.001]), compared with controls. Although LV global systolic function did not differ between groups, LV longitudinal systolic function was compromised in patients (lateral mitral annular plane systolic excursion - MAPSE [p = 0.005], as were lateral and septal TDI s’ [p < 0.001 for both]). Conclusion In patients with hypothyroidism, in addition to compromised LV diastolic function, LV longitudinal systolic function is also impaired compared to healthy subjects of the same age and gender. These findings suggest significant subendocardial function impairment, reflecting potentially micro-circulation disease, that requires optimum management.

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