3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Beta-blocker target dosing and tolerability in a dedicated Heart Failure Clinic Charlotte Maxeke Johannesburg Academic Hospital(2017) Bolon, Jonathan GrahamBACKGROUND: The benefit of Beta-blockers in chronic heart failure with left ventricular dysfunction is well established. However, actual use in “real world” heart failure patients has been relatively poor. Beta-blockers have generally been underused and under-dosed, largely due to perceptions about intolerability. Ivabradine, a pure heart rate lowering agent has recently been advocated for heart failure patients with elevated heart rates who could not tolerate target doses of beta-blockers. AIMS: The aim of this study was to document beta-blocker target dosing and tolerability in a dedicated heart failure clinic at Charlotte Maxeke Johannesburg Academic Hospital and assess the proportion of patients who may require Ivabradine therapy. METHODS: The records of all patients attending the heart failure clinic between 2000-2014 were reviewed. Demographic, clinical and outcome data was recorded for 500 patients. RESULTS: At their last clinic visit, 489 out of 500 (97.80%) patients were taking a beta-blocker. Patients were stratified into categories according to guideline target doses, with 59.8% (n=299) achieving ‘target dose’, 28.0% (n=140) a ‘moderate’ dose, 5.4% (n=50) receiving ‘low dose’ of beta-blocker and 11 patients (2.2%) no dose. Beta-blocker “intolerant” patients numbered 61(7.6%). Conventional reasons for beta-blocker caution (bronchospasm/breathlessness, syncope, cardiac decompensation, hypotension) were found to be rare. Bradycardia was the commonest cause of inadequate uptitration. Only 53 patients (10.6%) were deemed to be “Ivabradine suitable”. CONCLUSIONS: Beta-blockers are well tolerated with perceptions around intolerability and concerns about safety largely unsupported by our experience. As a consequence, the role for Ivabradine therapy in patients with chronic heart failure is limited. Key words: Beta-blockers, Heart Failure, IvabradineItem Renal dysfunction and heart failure - cardiorenal syndrome: a retrospective study at Charlotte Maxeke Johannesburg academic hospital(2017) Zachariah, DonINTRODUCTION The field of medicine has been challenged by the dual epidemic of heart failure and renal insufficiency. There is an increasing need to identify these patients at an early stage so as to delay progression to renal damage. Furthermore there is a lack of local data assessing the relationship between heart failure and renal dysfunction. AIMS • To identify the prevalence of renal dysfunction in patients attending the heart failure clinic at Charlotte Maxeke Johannesburg Academic hospital (Cardiorenal syndrome Type II) • To evaluate the relationship between severity of heart failure and severity of renal dysfunction • To compare heart failure with reduced ejection fraction (HFREF) variables between patients with and without renal dysfunction. METHODOLOGY This study is a single center retrospective study of patients attending Charlotte Maxeke Johannesburg Academic Hospital Heart Failure Clinic. Heart failure patients included in this study were those with an ejection fraction < 50% as this is an accepted definition for HFREF. Patients with HFREF were analyzed specifically for the following; presence of renal dysfunction, Ejection Fraction (EF), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Haemoglobin (HB), New York Heart Association (NYHA) functional class, furosemide dose , six minute walk test (6MWT) and Minnesota Living with Heart Failure Questionnaire (MLFQ) score . Presence of renal dysfunction was identified based on the glomerular filtration rate (eGFR) value of less than 60ml/min/1.73m2 as this is the threshold eGFR below which complications of renal impairment appear. The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) abbreviated formula: (186.3 X serum creatinine) -1.154 x (age) -0.203 x (0.742 if female) x (1.212 if African) The control group consisted of patients attending the clinic who did not have renal dysfunction. RESULTS A total 242 files were reviewed. Forty-two files were excluded from the study due to lack of adequate study data recorded in the file. Data was collected and entered into a database, which was analyzed using the Statistics/Data Analysis Program (STATA) Version 10.0. The mean age of the study group was 53.3 years (SD± 15.05) with the youngest subject being 21 years old and the oldest subject aged 85 years. The mean SBP was 119mmHg and the mean DBP was 75mmHg. The mean eGFR was 72.01 ml/min/1.73m2. The overall prevalence of low eGFR (<60ml/min/1.73m2) in the sample population was 34.5 %. The prevalence in female and male patients with a low eGFR was 35% and 33.6% respectively. Analysis of MLFQ, 6MWT, DBP and age yielded a positive correlation with eGFR, which was statically significant (p<0.05). An insignificant correlation was obtained comparing eGFR with SBP (p=0.07), EF (p=0.69) and HB (p=0.79). The Analysis of Variance Test (ANOVA), showed a significant correlation between eGFR values across the different NYHA functional classes (p 0.012). Thus it was found that the higher the NYHA class (clinically worse) was associated with worse renal function. The mean eGFR for NYHA I was 77.05 ml/min/1.73m2, for NYHA II was 70.61 ml/min/1.73m2, for NYHA III was 64.13 ml/min/1.73m2 and NYHA IV was 50.02 ml/min/1.73m2. DISCUSSION The overall prevalence of low eGFR (<60ml/min/1.73m2) in this study was 34.5%, a finding consistent with international trials. The majority of patients in this study were in NYHA functional class I or II, thereby highlighting the fact that renal dysfunction is common in heart failure patients and starts early. Statistically significant values were also obtained between eGFR and 6MWT, MLFQ, furosemide dose, age and DBP. The patients with higher 6MWT have better effort tolerance, thereby classifying their heart failure as milder. This in effect confirms that higher eGFR patients have higher effort tolerance. Higher MLFQ scores and higher furosemide doses are inversely correlated to eGFR. The more subjective symptoms you have, and the higher doses of furosemide you need, is a reflection of the severity of the heart failure. With regards to age, there is a normal physiological decline in eGFR with increasing age. In this study a statistically significant negative correlation between eGFR and NYHA was found. Thus a higher NYHA class is associated with worse renal function. This suggests that the clinically more advanced the patient, the poorer the renal function. Also, the prevalence of low eGFR (<60ml/min/1.73m2) within each NYHA class, as expected, increased with increasing NYHA class. It was 27% for NYHA I, 38% for NYHA II, 40% for III, while class IV had 80% of low eGFR prevalence CONCLUSION The findings of this study confirm that the cardio-renal syndrome is common in a local cohort of heart failure patients. The study also suggests that renal dysfunction starts in the early stages of heart failure (NYHA I/II) and becomes more prevalent in patients with more advanced stages of heart failure. These findings highlight the need to treat heart failure patients early after presentation and more appropriately if we are to decrease complications such as renal dysfunction, thereby improving morbidity and mortality.Item Left ventricular diastolic dysfunction in a community of African ancestry(2017) Peterson, Vernice RoxanneAlmost half of all cases of heart failure have a preserved ejection fraction. However, therapy targeting the mechanisms of this disorder has not improved outcomes. Left ventricular (LV) diastolic dysfunction is a characteristic feature of heart failure with a preserved ejection fraction. A more sound understanding of the mechanisms responsible for LV diastolic dysfunction produced by risk factors may lead to better approaches to preventing this syndrome. Although obesity is thought to be a major risk factor for LV diastolic dysfunction, this does not occur in all obese individuals. In the present thesis I have demonstrated in 737 randomly recruited participants from a community sample of African ancestry, that the relationship between insulin resistance (homeostasis model) and LV diastolic function, as assessed from trans-mitral velocity (E/A) and tissue Doppler imaging of the lateral and septal walls of the LV (e’ and E/e’), is markedly altered by the presence of a more concentrically remodelled LV (as indexed by LV relative wall thickness [RWT]). Importantly, insulin resistance was only associated with LV diastolic function or dysfunction in those with an RWT above a threshold value. In contrast no interactive effects on LV diastolic function between either blood pressure or age and RWT were noted. These data therefore suggest that obesity will only translate into LV diastolic dysfunction if it is associated with insulin resistance and a concentrically remodeled LV. Although hypertension is thought to play an important role in contributing to LV diastolic dysfunction, the pulsatile hemodynamic change primarily responsible for this effect is uncertain. In 524 randomly selected individuals from a community sample I have demonstrated that independent of confounders including left ventricular mass and RWT, aortic backward wave pressure effects (as determined using wave separation analysis), antedate the impact of aortic stiffness (indexed by aortic pulse wave velocity) or the factors determined by aortic stiffness (the time of backward wave return or forward wave pressures) on LV filling pressures (E/e’). These data therefore suggest that to adequately prevent LV diastolic dysfunction, targeting aortic backward wave pressures may be required. As conventional risk factors account for only a portion of the inter-individual variations in LV diastolic function, it is thought that the genetic factors may play a iv significant role. In 694 randomly recruited participants of African ancestry belonging to nuclear families, I demonstrated that independent of conventional risk factors, heritability accounts for approximately 50% of the variation in LV RWT, an important LV structural determinant of LV diastolic function. Moreover, in 442 randomly recruited individuals of African ancestry belonging to nuclear families, I also demonstrated that heritability accounts for approximately 50% of the variation in the index of LV filling pressures, E/e’, independent of LV mass or RWT remodeling and aortic function. These data provide strong evidence that genetic factors responsible for LV diastolic dysfunction and the structural determinants thereof should be sought. In conclusion, the results provided in the present thesis have advanced our knowledge of possible pathophysiological mechanisms that play a role in the development of LV diastolic dysfunction and hence possibly heart failure with a preserved ejection fraction.Item Myocardial deformation in African hypertensive patients with heart failure : an analysis using speckle tracking echocardiography(2014-09-08) Maharaj, NirvarthiHypertension and heart failure are intimately related with the incidence of heart failure among hypertensive subjects between 1% and 2% per year. Structural and functional myocardial abnormalities identified in hypertensive patients contribute to the progression of myocardial dysfunction. Systolic abnormalities in hypertension begin to develop in the early stages of the disease despite normal left ventricular (LV) ejection fraction (EF) and contribute to the progressive deterioration of LV systolic performance. However, these systolic abnormalities are initially not detectable by conventional echocardiographic methods. Speckle tracking echocardiography (STE) is a sensitive quantitative technique for assessing LV function. LV twist is an important contributing factor to the systolic function of the LV in health and disease and may be a better index of systolic function than ejection fraction (EF) in hypertensive patients (HTP). The remodelling process of the left ventricle in hypertension entails a complex interplay between myocyte hypertrophy and dysfunction, with qualitative changes in the extracellular matrix contributing to progressive dysfunction. Adverse LV remodeling in HTP is associated with an imbalance in collagen degradation and may contribute to the remodelling phenotype and systolic dysfunction in hypertension. Increased matrix metalloproteinase-1 (MMP1) levels contribute to development of LV dilatation and failure with higher levels of MMP1 in the myocardium of hypertensive patients with low EF than those with normal EF. Hypertension can cause systolic dysfunction as a consequence of adverse remodelling and LV hypertrophy, but given the multitude of factors involved in LV decompensation mediated by mechanical, neurohormonal and cytokine routes, the exact mechanisms that contribute to the adverse remodelling and EF deterioration are not fully elucidated. LV twist may be a contributing factor to systolic dysfunction independent of other factors, thus, a focus on abnormalities in the cardiac mechanics of twist in the left ventricle may be helpful in understanding the pathogenesis behind the transition from compensated to decompensated heart failure. Furthermore, the changes in the extracellular matrix may account for the varying morphology, EF and LV twist in HTP. The purpose of this thesis was to 1) determine LV twist in healthy adults of different age groups (n=127), 2) evaluate LV twist changes in African HTP with low (EF<50%) and preserved EF (EF ≥ 50%) (n=82) and 3) examine the relationship between LV twist and biomarkers of collagen degradation in HTP with preserved and low EF. Parasternal short-axis images of three consecutive end-expiratory cardiac cycles at LV basal and apical levels were obtained. Apical rotation (AR) and basal rotation (BR) during ejection and instantaneous LV peak systolic twist (net twist, defined as maximal value of instantaneous AR minus BR) were measured. 127 normal subjects were divided into four age groups: 20-29 (n=34); 30-39 (n=33); 40-49 (n=29); and 50-65 (n=31) years. LV twist and markers of collagen turnover (serum concentrations of matrix metalloproteinase -1 (MMP1), tissue inhibitor of MMP1 (TIMP1) and ratio of MMP1:TIMP1) were measured in 82 hypertensive patients, 41 with EF < 50% (HTLEF) and 41 with EF ≥ 50% (HTNEF). Rigid body rotation (RBR) was defined as AR and BR occurring in the same direction. Serum biomarkers were log transformed before analysis. LV twist increased with age in normal subjects. Multivariate linear regression analysis showed age as the main predictor of net LV twist (R2=0.82, P<0.0001) in normal subjects. Net LV twist was lower in HTLEF compared with HTNEF (3.34 + 1.10 vs. 11.70 + 0.67, p < 0.0001). Of 41 HTLEF patients, 28 (68%) had normal twist pattern while 13 (32%) exhibited RBR. The subgroup with RBR showed greater LV dysfunction (EF: 27.9±5.8% vs. 35±7.5%; p=0.005) and more spherical LV geometry (p=0.0009) compared with those who had normal pattern of twist. Log TIMP1, Log MMP1 and Log MMP1:TIMP1 ratio levels were higher in HTLEF compared with HTNEF (12.32 ± 0.25 vs. 11.81 ± 0.13, p<0.0001; 9.08 ± 0.32 vs. 8.00 ± 0.18, p<0.0001; -3.25 ± 0.30 vs. -3.81 ± 0.18, p<0.0001; respectively). There was an inverse correlation between Log MMP1:TIMP1 and net LV twist after adjusting for EF (r = -0.41, p <0.0001). This study established normative data and patterns for myocardial deformation (strain and LV twist) in a normal black-African adult population across different age groups and can be used as a baseline for future studies. Age was the major determinant of increased LV twist in a normal black population. LV twist may be a compensatory mechanism to preserve EF and maintain normal systolic function with advancing age and in hypertension. LV twist varies with the degree of remodeling and systolic function in hypertension. RBR represents a novel assessment of more severe LV remodeling and LV systolic dysfunction in hypertensive patients. Alterations in collagen turnover not only accompanies more adverse remodelling but also contributes to LV twist differences observed between HTLEF and HTNEF patients. The inverse relation between LV twist and loss of myocardial collagen scaffolding suggests that integrity of the extracellular matrix may play an important role in preservation of LV twist. These findings highlight the value of LV twist as a sensitive global parameter of LV systolic myocardial performance. Longitudinal studies assessing LV twist may provide significant value in clinical practice as an early marker for risk stratification in hypertensive patients who may benefit from aggressive medical therapy to prevent LV remodelling and heart failure.