Effect Of Neuroendocrine Antagonist On Left Ventricular Diastolic Dysfunction In Patients With Coronary Heart Disease

Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. With the improvement of life enviroment and increase of the life-span in human being, chronic heart failure (CHF) is becoming an important and growing clinical problem, especially in the elderly. CHF is the most common inpatient diagnosis. The annual hospital cost of treating these patients is more than the cost of treating patients with myocardial infarction. Increasingly, many evidences indicate that diastolic dysfunction is a major contributor to the pathophysiology of CHF, which traditionally has been identified with systolic dysfunction. Interestingly, because of the lack of evidence-based data, many guidelines for treatment of CHF either do not address diastolic heart failure or do not give definitive therapeutic recommendations. Diastolic dysfunction refers to abnormalities in ventricular relaxation and filling (right ventricle, left ventricle, or both) with prolonged or incomplete return to presystolic length and force. In the progression of most cardiac diseases, diastolic dysfunction typically precedes systolic impairment. One of the earliest signs of diastolic dysfunction is exercise intolerance due to exertional dyspnea. Because of increased chamber stiffness, the end-diastolic volume in patients with diastolic dysfunction cannot increase during exercise. Usually as a result of myocardial hypertrophy, fibrosis, or ischemia, left ventricular filling is slowed or incomplete, causing pulmonary venous congestion.The presence of asymptomatic left ventricular diastolic dysfunction is related to the symptomatic heart failure in the patients with coronary heart disease. Diastolic dysfunction is difficult to differentiate from systolic dysfunction on the basis of history, physical examination, electrocardiographic and chest radiographic findings. Objective diagnostic testing is required. Cardiac catheterization was the first method used to diagnose diastolic dysfunction. However, the catheterization is invasive and impractical for long-term follow-up. A few reports investigated the severity of impaired LV diastolic function in patients with coronary artery disease and its relationship to the number and coronary score in coronary artery lesions visualized at coronary angiography. It is necessary to evaluate the effect of the severity of coronary stenosis on the left ventricular diastolic function by catheterization and echocardiographic strain rate imaging method in order to carry out the intensive treatment for the patients with diastolic dysfunction and improve the patients'prognosis. Strain rate imaging is an accepted, reliable, and practical method for diagnosing diastolic dysfunction.The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of both systolic dysfunction as well as diastolic dysfunction. The beneficial role of angiotensin-converting enzyme (ACE) inhibitors as well as aldosterone antagonists in systolic dysfunction has been well established. Because of its unique role of the RAAS in establishing fibrosis at a molecular level, RAAS blockade provides an opportunity to expand the therapeutic options for diastolic dysfunction. Thus far, in patients with primary diastolic dysfunction only the angiotensin receptor type 1 antagonist has been reported to decrease morbidity. Other kinds of neuroendocrine blockers are currently underway to establish the role in patients with diastolic dysfunction.Our current research included three parts. In the part 1, we aimed to investigate the severity of impaired left ventricular diastolic function in patients with coronary heart disease and its relationship to the number and coronary score of coronary artery lesions visualized at coronary angiography and echocardiography. The part 2 was designed to assess the effects of spironolactone on left ventricular diastolic dysfunction on the basis of ACE inhibitor andβblocker in patients with coronary heart disease by echocardiographic strain rate imaging. In the part 3, we established rat model of left ventricular injury. The effect of ACE inhibitor,βblocker and spironolactone on hemodynamics and remodeling of injury left ventricles in rats were analyzed.Part 1 Relationship between severity of coronary lesions and left ventricular diastolic function in patients with coronary heart disease by cardiac catheterization and echocardiographic imagingObjective:We aimed to investigate the severity of impaired LV diastolic function in patients with coronary heart disease(CHD) and its relationship to the number and coronary score in coronary artery lesions visualized at coronary angiography and echocardiography.Methods:Seventy-five consecutive patients with CHD confirmed by coronary angiography were divided into 4 groups according to extent of coronary lesions(the degree of stenosis≥50% and≤75% defined as mild stenosis, stenosis in one vessel>75% as single branch lesion, in two vessels >75% as double branch lesion and in three vessels>75% as triple branch lesion ) and the diseased coronary artery Gensini score was evaluated. The systolic pressure and diastolic pressure in aorta, heart rate, left ventricular end-diastolic pressure (LVEDP), maximum and minimum value of the first derivative of left ventricular pressure (dp/dtmax, dp/dtmin), ejection fraction in left ventricles(EF) were measured and then, the time constant of isovolumic pressure decay in early period of left ventricular relaxation(T) was calculated. The left atrial dimension(LAD), left ventricular end-diastolic volume(EDV), left ventricular end-systolic volume(ESV), stroke volume(SV), the early 1/ 3 filling volume (1/3V) and filling fraction (1/ 3 FF) of left ventricle were measured by left ventriculography and echocardiography. Peak systolic strain rate (SRs), peak early diastolic strain rate (SRe) and peak late diastolic strain rate( SRa) in each segment of left ventricles were measured. The correlation of the peak strain rates and other diastolic parameters was analyzed.Results:The significant difference in echocardiographic study was only the diameter of LAD which in triple branch lesion group(38.74±4.57mm)was more than in mild stenosis group(33.87±3.80mm) and in single branch lesion group(33.77±3.94mm). There was no significant difference in LVEDP, dp/dtmax, dp/dtmin among those groups. The time constant(T) was better in mild stenosis group(30.31±6.50 ms) than in single vessel lesion(40.92±11.79), double vessel lesion(43.02±15.83ms) and triple-vessel lesion group(50.32±23.57ms, P<0.05). The increase in time constant in obvious stenosis showed the impaired diastolic function of left ventricle, especially for the isovolumic diastole. The early filling 1/3V (55.69±24.87,31.44±21.17,24.29±14.79,19.15±13.01ml in mild stenosis group, single, double and triple branch lesion group, respectively ) and 1/3FF%(45.95±19.90,33.29±20.49,25.52±15.06,24.22±15.29 in mild stenosis group, single, double and triple branch lesion group, respectively) was more in mild stenosis group than in obvious stenosis groups. The level of EF and SV in mild stenosis group was more than in triple branch lesion group. The comparison of LAD, EF, early 1/3V and 1/3FF of different coronary Gensini score was significant difference in score"<15"and"15~","30~"group. The parameters of"<15"group was better than in"15~"and"30~"group. There was no significant difference of the time constant (T) and LVEDP among the groups by coronary Gensini score. The catheterization and strain rate image of echocardiography were carried out in sixteen patients. A strong correlation between the EF by echocardiogram and by invasive catheter(r=0.89, P<0.01) was existed. Invasive EF was significantly related to SRs( r=-0.74, P<0.01). SRe was also correlated to the time constant of left ventricular pressure decay (r=-0.66, P<0.01) and early 1/3FF(0.61, P=0.01), whereas a lack of significant correlation was found between the time constant and the peak of mitral early diastolic velocity(E), and SRe and E.Conclusions: The different severity of coronary lesion affected ventricular diastolic function at a certain extent. Whether by the lesion numbers or the coronary Gensini score, the more the severity of coronary lesion was, the more serious ventricular diastolic dysfunction was. The grouping by the lesion numbers was more sensitive than the grouping by Gensini score in predicting diastolic dysfunction. Strain rate imaging in echocardiogram is reasonable accuracy for evaluating diastolic dysfunction in patients with CAD. Part 2 Effect of angiotensin-converting enzyme inhibitor,βblocker and spironolactone on left ventricular diastolic function in patients with coronary heart diseaseObjective: This study was designed to assess the effects of angiotensin-converting enzyme inhibitor (ACEI),βblocker and spironolactone on left ventricular diastolic dysfunction in patients with coronary heart disease (CHD) by echocardiographic strain rate imaging (SRI).Methods: Thirty-four subjects without heart and lung disease (control group) and seventy-five patients with CHD between 25 and 83 years of age with isolated diastolic dysfunction and no contraindications for ACEI,βblocker and spironolactone were enrolled in this study. The patients with CHD were randomized to combination of ACEI andβblocker (C+M group, 38 patients) or combination of ACEI,βblocker and spironolactone (C+M+S group, 37 patients, spironolactone 40mg/d) for 6 months. Left atrial dimension(LAD), left ventricular end diastolic and systolic dimension, interventricular septal thickness(IVST), left ventricular posterior wall thickness(LVPWT) were measured by echocardiography. Left ventricular mass index (LVMI) was calculated from the above mentioned left ventricular parameters. Measurements of left ventricular end-diastolic volume ,end-systolic volume and ejection fraction was obtained by biplane Simpson's method. E/A ratio were calculated according to the early diastolic peak filling velocity of mitral inflow (E) and to late diastolic peak filling velocity (A). Peak systolic strain rate (SRs), peak early diastolic strain rate (SRe) and and peak late diastolic strain rate (SRa) in each segment of left ventricle were measured by tissue Doppler mode. The parameters mentioned above were determined at baseline 1st month, 3rd month and 6th months after randomization.Results: LAD at 6-month follow-up was 36.84±3.50mm in two-drug combination (C+M) group, 34.86±3.18mm in three-drug combination (C+M+S) group and 30.40±2.92mm in control group. The difference of LAD among the groups was significant (P<0.01). There was no significant difference in other conventional echocardiographic parameters. Although LAD in the group of three-drug combination was smaller than in the group of two-drug combination, LAD in three-drug combination (C+M+S) group was larger than in control group at 6th month. The parameters of SRI in control group were better than (C+M) and (C+M+S) group. However, compared with the (C+M) group, SRe reflecting the early ventricular diastolic function was improved in C+M+S group six months later(P<0.05).The baseline characteristics of the two groups with coronary heart disease were equally distributed. The E/A ratio averaged 0.74 in the (C+M) group and 0.75 in the (C+M+S) group at 6th month. There was significant difference within groups (P<0.05). The increase in E/A ratio implicated that the left ventricular inflow and filling function in the early diastole was improved. The decrease of IVST, LVPWT and LVMI in (C+M+S) group showed that the ventricular mass became less after six-month treatment.The indexes related to the systolic (SRs) and diastolic (SRe) functions were improved after treatment in two groups with coronary heart disease. However, the SRe was significantly higher in ventricular basal segments of posterior septum, lateral wall, anterior septum and mid segments of lateral wall, anterior wall, anterior septum and posterior wall in (C+M+S) group than in (C+M) group.No serious side-effect which influenced continued treatment was found in the combinative use of ACE inhibitor,β-blocker and spironolactone in long term.Conclusions: The combination of ACE inhibitor andβ-blocker significantly improved the ventricular diastolic function in patients with coronary heart disease. The additive aldosterone inhibitor spironolactone in the background of combination of ACE inhibitor andβ-blocker made the isolated diastolic dysfunction better and the safety was promotive in the long term application. Part 3 Effect of spironolactone, captopil and carvedilol on hemodynamics and remodeling after left ventricular injury in ratsObjective: To evaluate the effect of spironolactone, captopil and carvedilol on hemodynamics and remodeling of injury left ventricles in rats.Methods: Wistar rats (male) were cryoinjuried on the free left ventricular wall for 15 seconds to establish the myocardial necrosis model. There were 96 survived rats after 24 hours of the operation. Except 12 rats which were enrolled in Sham group, 84 rats were randomly divided into control group(22 rats), spironolactone group(22 rats), captopil and carvedilol group(20 rats), combinative group (20 rats, captopil+ carvedilol+spironolactone). There were 76 rats survived and 20 death after 14 weeks. 12 rats were in Sham group and 54 rats in control group or other treated groups complying with the requirement of myocardial necrosis. Systolic pressure, diastolic pressure and mean pressure in aorta, heart rate, left ventriclular end-diastolic pressure (LVEDP), maximum and minimum dp/dt in left ventricles were measured after 14 weeks of the drug administration. Then, the time constant of isovolumic pressure decay was calculated. The collagen content and the ratio of typeⅠandⅢcollagen in non-necrosis zone were determined. Cardiac actual weight, left ventricular actual weight, the diameter and area of left ventricular necrosis were measured after the rats were killed.Results: Compared with control group(2.94±0.30mg/g), relative cardiac weight in Sham group(2.33±0.27mg/g) and three-drug administration group(2.43±0.17mg/g) was lower (P<0.05). There were not significantly different in LVEDP and the time constant between Sham group and the drug administration groups, but the parameters in these groups were better than in control group(P<0.05). The time constant in Sham group and three-drug combination group were better than in spironolactone group and captopil+carvedilol group(P<0.05). The collagen content and the ratio of typeⅠandⅢcollagen in non-necrosis zone were lower in Sham group and each of treated groups than control group. The levels of the collagen content and the ratio of typeⅠandⅢcollagen in non-necrosis zone in three-drug combined group were lower than spironoloactone group and captopil+carvedilol group.Conclusion: The cardiac hemodynamic parameters and ventricular remodeling in rats with the myocardiac injury are improved by the use of spironolactone, captopil and carvedilol. Spironolactone cooperates with other neurohormonal antagonists in the improvement of cardiac function and remodeling.In conclusion, our research results indicated that:1. The left ventricular dysfunction was related to the severity of coronary artery stenosis in patients with coronary heart disease. The more the severity of coronary lesion was, the more serious ventricular diastolic dysfunction was. The serious and wide range of stenosis may impair the systolic function.2. Our research from both clinical observation and animal models demostrated that ACE inhibitor andβ-blocker contributed to the improvement of left ventricular diastolic dysfunction. Adding spironolactone to ACE inhibitors andβ-blocker made further ventricular diastolic function improvement and reduced ventricle remodeling in coronary heart disease.