ORIGINAL ARTICLE

END-DIASTOLIC LEFT VENTRICULAR PRESSURE REDUCTION IN ISCHEMIC HEART FAILURE INDUCED BY RAMIPRIL ALONE AND RAMIPRIL + CARVEDILOL: A DOPPLER-ECHOCARDIOGRAPHIC STUDY

Federico Cacciapuoti MD; Antonietta Buonomo MD; Fulvio Cacciapuoti; Rodolfo Grella MD; Diana Lama, MD; *Maria D’Avino MD; Paola Bolognino, MD Department of Internal Medicine, Second University of Naples, Naples, Italy

 Abstract
     Method
     Result
 Introduction
 Materials
 Statistical analysis
 Results
 Discussion

 CONCLUSION

 References
 COURT OF THE MYRTLES

Abstract

Method             Result

Method

Thirty-four patients affected by Ischemic Heart Failure (IHF) were evaluated by Echocardiography (E).
 They had reduced Ejection Fraction % (EF%) evaluated by the cube volume-formula and evident from a decrease of V.max. of E wave and an increase of V. max. of A wave of mitral doppler inflow pattern, with reversal of E/A wave ratio. In addition, an increase of Iso-Volumic Relaxation Time (IVRT) and E wave Deceleration Time (DT) were present, while the pulmonary veins flow-pattern reflected increased End Diastolic Left Ventricular Pressure (EDLVP). Patients were treated with Ramipril (Group I) or Ramipril and Carvedilol (Group II). These drugs were given concommitant with other drugs (Digitalis, Diuretics, Antiplatelets and Nitrates). M-Mode and 2D-Echo were performed one week after the end of therapy.

Result

The echocardiographic parameters were evaluated in all patients at baseline and compared with those obtained respectively after Ramipril (Group I) and Ramipril + Carvedilol (Group II). Results showed a rise of LVESV and a decrease of LVEDV with progressive increase of EF% (from 30 to 40%). This change was also displayed by an increase of V. max. of E and a little decrease of A waves V. max. of mitral pattern (without inversion of their ratio in the Group I) and a similar but more evident change of V. max. of both waves, with reversal of E/A ratio in Group II. Conclusion: Ramipril, given with conventional drugs, resulted in poor reduction of EDLVP whereas the combination of Ramipril + Carvedilol added to conventional therapy, induced a more evident functional reduction of this hemodynamic parameter. Heart Views. 2002;3 (1): 28-33 © 2002 Gulf Heart Association

Key Words:

   Ischemic Heart Failure    End Diastolic Left Ventricular Pressure  
    Echocardiography Ramipril   Carverdilol   

Introduction

schemic Heart Failure (IHF) induces an abnormal elevation of End Diastolic Left Ventricular Pressure (EDLVP) dependent both on the reduced left ventricular diastolic relaxation (with reduced filling) and the increase in peripheral vascular resistance. 
This last is due to activation of the neuro-endocrine system, a mechanism counterbalancing the reduced stroke volume (1-3). Activation of the renin-angiotensin system and the sympathetic nervous system results in an increase in preload and afterload, which at least initially increases cardiac contractility. 
However, persistent activation of the neuroendocrine system is deleterious and leads to ventricular remodelling. 
Therefore, it is necessary to minimize or block this neurohormonal activation and/or its peripheral effects with pharmacologic therapy.
 Interventions which inhibit, antagonize, or otherwise favorably modulate neurohormonal activation such as ACE inhibition and beta-blockade produce improved outcomes in heart failure patients (4-6). Among several b-blockers, Carvedilol seems to be the more useful because it blocks a1 and b2-receptors (7,8), inducing vasodilatation, increase in ejection fraction (EF), and decrease in EDLVP  

(9,10). Among ACE-inhibitors, Ramipril is one of the most useful in reducing or minimizing the Renin-Angiotensin-Aldosterone-System (RAAS.) secretion (11,12). The objective of this study was to verify if, in patients with IHF and already treated with conventional therapy, the addition of Ramipril and/or Carvedilol, is able to reduce EDLVP and if this change is evident using Doppler Echocardiography (2DEcho) parameters.

Materials

end-systolic-diameter (LVESD). Left ventricular volumes (LVEDV, LVESV) using the cube-formula were obtained. The ejection fraction % (EF%) was evaluated according to the following formula:

                LVEDV - LVESV
EF% = __________________ x 100
                       LVEDV

Mitral inflow parameters recorded by two-dimensional Doppler echocardiography (2D-Echo) were: maximum Velocity (V. max.) of E and A waves and E/A ratio (13). The isovolumic relaxation time (IVRT) and the deceleration time (DT) of E wave were also evaluated. 
The pattern of pulmonic vein flow was recorded in all patients (14). At the time of the study, all patients were already receiving Digitalis (0.125 or 0.25 mg. per os/day), Furosemide (12.5 or 25 mg per os/day), an antiplatelet drug, and nitrates. 
The ACE inhibitor Ramipril, (2.5 mg. per os/day) was given to 16 patients at random and constituted Group I. 
In the remaining 18 patients, combined Ramipril + Carvedilol were added and constituted Group II. Carvedilol, under guidance of arterial pressure and heart rate, was added incrementally from 3.125 mg b.i.d to 25 mg b.i.d over a period of 40 days. One week after the initiation of therapy, M-mode and 2D-Echo parameters were repeated and recorded.

Statistical analysis

The values of LVEDV, LVESV and EF% obtained in basal conditions in all patients and

those recorded in each group were compared with those obtained in groups I and II. V. max. of E and A waves, their ratio (E/A), and the values of IVRT and DT were recorded at baseline and were compared with groups I and II.
 Finally, the systolic-diastolic pattern of pulmonary venous flow was measured basally in all patients and compared with that recorded after Ramipril (Group I) and Ramipril + Carvedilol (Group II). For all parameters evaluated, the Student t-test for unpaired data was used. 
A p<0.05 value was considered significant.

Results

In two patients in Group II, it was impossible to give Carvedilol because it induced an excessive reduction of the arterial pressure (in one) and bronchospasm (in the other).
 In addition, in one patient in Group II, the maximum dose of 25 mg. b.i.d was not achieved because the maximum dose tolerated was 25 mg. in the morning and 6.25 mg in the afternoon. Therefore, the number of patients was 16 in Group 1 and 16 in Group II. 
Table I shows the baseline value ±1SD of LVEDV and the mean values achieved in Groups I and II. This parameter increased from baseline 289.4±17 ml to 293.4±18 ml in Group I and to 314.5±19 ml in Group II, with a p <0.05 and p <0.01 respectively. On the contrary, the mean value of LVESV decreased from basal conditions (201.3±18 ml) in patients treated with Ramipril alone (189.8±19 ml) and in those who received Ramipril + Carvedilol (186.3±17 ml). Differences were significant, with a p <0.05 (in Group I) and p <0.01 (in group II). EF% under basal conditions was 30.0±1.4% and increased to 35.3±1.3% in Group I, p <0.05. Group II patients (Ramipril + Carvedilol), EF% reached 40.6±1.8%, p <0.01). In basal conditions, the value of V. max. of E wave was 0.82±0.12 m/sec.; the mean of V. max. of A wave was 0.91±0.15 m/sec.; E/A ratio was 0.91±0.14. (fig.1). After treatment with Ramipril alone (Group I) , V. max. of E wave was 0.83±0.13 m/sec.; V. max. of A wave was 0.90±0.5 m/sec and E/A wave ratio was 0.94±0.7. 
In Group 1 "mitral" parameter differences with respect to the baseline values were not significant (N.S.).
 After Ramipril + Carvedilol (Group II) the mean of E wave was 0.87±0.12 m/sec; V. max. of A wave was 0.81±0.6 cm/sec; the mean value of E/A wave ratio was1.07±0.4. (fig.2). As opposed to Group I patients, the difference in values in mitral parameters in Group II patients was statistically significant (p <0.05 for V.max. of E wave; p <0.01 for V. max. of A wave and p <0.01 for E/A wave ratio).

Tab. II. Doppler-echocardiographic results of pattern of pulmonary venous flows recorded at baseline and after Ramipril alone (I group) and Ramipril + Carvedilol (II group).

The mean of IVRT was 65±0.8 msec. and the mean value of E wave DT was 165±1.4 msec in basal conditions. After Ramipril (Group I) IVRT resulted of 72±1.4 msec and DT of E wave was 174±2 msec. Differences in respect to the basal values were significant (p <0.05). In Group II patients the mean was 84±1.4 msec and 186±1 msec respectively, with a p <0.01 .
The basal mean value of the pulmonary venous pattern and those recorded after Ramipril (Group I) and Ramipril + Carvedilol (Group II) is shown in Table II. In basal conditions, the mean of systolic pulmonary vein flow (S) was 0.76±0.13 msec. A mean value of 0.44±0.14 msec was achieved for the diastolic wave (D) and 0.25±0.10 msec was measured for the diastolic reverse flow (A wave) (fig.3). In Group I, the systolic wave (S) was 0.67±0.10 msec (p <0.05); the diastolic wave (D) was 0.53±0.13 msec (p <0.05); the reverse diastolic wave (A) was 0.18±0.11 msec. (p <0.01). Finally, in Group II, the pulmonary venous flow showed a systolic wave (S) equal to 0.68±0.7 msec.; a diastolic wave (D)= to 0.57±0.8 msec. and a reverse diastolic wave (A) of 0.23±0.8 msec (fig.4).

Discussion

t is common knowledge that the pattern and V max of E and A waves of diastolic mitral flow and their ratio depends on a lot of factors that make difficult their comparison in different subjects affected by the same disease. These difficulties depend on: the position of the sample volume between the mitral leaflets (16), on the cardiac rhythm (17), on the P-R interval (18) and on the age (19). In addition, it seems dependent also on the heart rate. Decubitus can also influence the E/A ratio (20). Finally, the changes of V. max. of E or A waves can be a consequence of variable loads on the left ventricle, rather than on its diastolic function.
 IVRT, E wave DT and the values of pulmonary venous flow are less dependent on these factors. 
In order to minimize these difficulties, we have enrolled the patients affected by IHF only, within a certain age limit (41 to 55 years), and all patients were in sinus rhythm with a P-R interval between 0.16 and 0.20 sec. The ultrasonographic evaluation was standardized and performed in the left lateral decubitus of 20°, placing the sample volume between the mitral leaflets. 
The increased EF% obtained after both treatments (Ramipril or Ramipril + Carvedilol) is likely due to the reduction of LVESV (with the rise of V. max. of E wave) and to the increase in LVEDV (with reduction of V. max. of A wave) (21). 
But, this last effect was greater than the first and, consequently the EF% increased. 
The rise of V. max. of E wave (due to the passive emptying of left atrium into left ventricle) depends on the highest pressure difference between the left atrium and the left ventricle at early diastole; the decrease of V. max. of A wave (due to the active emptyng of left atrium into left ventricle) is due to the reduced pressure difference between left atrium and the left ventricle at end diastole.
 In addition, the decrease in vascular resistance (induced by Ramipril and/or Carvedilol) also facilitates the emptying of left ventricle during systole (22,23).
After Ramipril alone, there were no significant changes in V. max. of E and A waves and E/A ratio, but these were more evident (with reversal of E/A ratio) in patients receiving Ramipril and Carvedilol (group II). Ramipril:
 ACE-inhibitors decreases serum-concentration of Angiotensin II and reduces afterload with consequent reduction of EDLVP. In the AIRE study, Ramipril given to patients with clinical evidence of heart failure due to ischemia reduced mortality, stroke or reinfarction, and delayed progression to more severe heart failure. These results were recently confirmed by the extension of the study, which also showed prolongation of survival (25). Carvedilol: There are various classes of b-blockers with varying activity. First class b-blockers (i.e. Propranolol) are absolutely not used because of its negative inotropic effect that is superimposed to the peripheral vasoconstriction, which is a consequence of a2-receptor blockade. Second class b-blockers (i.e. Metoprolol or Bisoprolol) are well-tolerated because they do not act on peripheral resistance.
 Finally, third class b-blocker (i.e., Carvedilol) achieves excellent results, especially in patients with hypokinesia and dilatation of the left ventricle, because they block both cardiac (blocks b1-receptors) and peripheral actions (26). Its simultaneous effect on b1-b2 and a1-receptors results in positive inotropic action and peripheral vasodilatation. The adrenergic effect of this drug is of type b1>a1>b2 (27). Its cardiac action has been reported to be due to blockade of b-receptors, whereas the peripheral vasodilation is due to a1-receptor blockade (28-31). 
The administration of Carvedilol in increasing doses induces a progressive increase in ventricular performance and a progressive reduction of heart failure symptoms, both at rest and after effort (32,33). Finally, the pulmonary venous pattern of the impaired relaxation recorded in our patients in basal conditions showed a significant lowering of V. max. of S wave and an increase of D and A waves after the addition of two drugs ( to traditional therapy. These changes depend on the true decrease of EDLVP but not on the pseudo-normalization of the Doppler mitral patterns.

CONCLUSION

Some drugs such as Ramipril and/or Carvedilol, added to conventional therapy for IHF in NYHA II-III class, seem to reduce EDLVP and increaseEF% in these patients. 
These effects seem mainly due to the reduction of peripheral resistance with consequent increase of the left ventricular cavity during systole.
These changes are responsible for the reduction of EDLVP evident by Mono 2D and Doppler echocardiography.

References

1. Francis GS., Cohn JN., Johnson G., et al. :Plasma nor- epinephrine, 
    plasma renin activity and congestive heart failure. Relations to survival and the
    effects of therapy in V-HeFT II follow-up. Circulation 1993;87(suppl.IV): 40-48.

2. Bonow RO.: Left ventricular diastolic dysfunction as cause of 
    congestive heart failure. Mechanisms and management. Ann. 
    Intern. Med. 1992;117:172B-178B.

3. Swedberg K., Sharpe N.: The value of angiotensin converting enzyme inhibitors for 
    the treatment of patients with left ventricular dysfunction, heart failure or after 
    acute myocardial infarction.Eur.  Heart J. 1996;17:1306-1311.

4. Waagstein F., Hjalmarson A., Varnuskas E., et al.:
    Effect of chronic beta-adrenergic receptor blockade in congestive 
    cardiomyopathy.Br. Heart J. 1975;37:1022-1036.

5. Swedberg K., Hjalmarson A., Waagstein F., et al.:Beneficial effects 
    of long-term beta-blockade in congestive cardiomyopathy. Br. Heart . 
   1980; 44:117-133.

6. Yusuf S.; Garg R.; Conachie D. : 
    Effect of Angiotensin- converting enzyme inhibitors in left ventricular 
    dysfunction : results of the studies of left ventricular dysfunction in the context of 
    the similar trials. J. Cardiovacs.Pharmacol. 1993; 22 (suppl.9) S28-S35.

7. Colucci WS., Packer M., Bristow MR., et al.:
    Carvedilol inhibits clinical progression in patients with mild symptoms of 
    heart failure.Circulation 1996; 94:2800-2806.

8. Das Gupta P., Jain D., Lahiri A., et al.: Long-term efficacy and safety of 
    carvedilol, a new b-blocking agent with vasaodilating properties in patients with 
    chronic ischemic heart disease. Drug Invest. 1992; 4:263-272.

9. Mauser M., Voelker W., Ickrath O., et al.: Acute hemodynamic effects of
    the vasodilating b-blocker carvedilol compared to a combination of nifedipine 
    and propranolol in patients with coronary artery disease.Z. Kardiol. 1989;78:726-731.

10. Nagakawa Y., Akedo Y., Kaku S.,et al.: Effects of carvedilol on 
      common arterial flow, peripheral hemodynamics and hemoreologic variables 
      in hypertension. Eur. J. Clin. Pharmacol. 1990 ;10 (suppl.1):114-116.

11. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
      effect of Ramipril on mortality of survivors of acute myocardial infarction with 
      clinical evidence of ‎heart failure. Lancet 1993;342:821-828.

12. Hall AS.; Murray GD.; Ball SG. For AIREX study Investigators: 
      follow-up study of patients nononly allocated Ramipril or placebo for 
      heart failure after acute myocardial infarction. AIRE extension (AIREX) Study.
      Lancet 1997;349:1493-1497.

13. Nishimura RA., et al.: Assessment of diastolic function of the heart: 
      background and current applications of Doppler echocardiography. 
      Part I and II: Physiologic and pathophysologic features.
      Mayo Clin. Proc. 1989;64:71-81.

14. American Society of echocardiography Committee on standards, subcommittee 
     on quantitation of two-dimensional echocardiograms:
     recommendations for quantitations of the left ventricle
     by tw-dimensional echocardiography. J. Am. Soc.
     Echocardiogr. 1989;2:361-367.

15. Bristow MR., Gilbert EM., Abraham WT., et al.: 
      Carvedilol produces dose-related improvements in left ventricular function 
      and survival in subjects with chronic heart failure. Circulation 1996;94:2807-2816.

16. Ding ZP., et al.: Effect of sample volume location on 
      Doppler-derived transmitral inflow velocity values. 
      J. Am. Soc. Echocardiogr.1991;4:451-464.

17. Galderisi M., Benjamin EJ., Evans JC., et al.: Impact of heart rate and
      PR interval on Doppler indexes of left ventricular diastolic filling in
      an elderly cohort (the Framingham Heart Study). Am. J. Cardiol. 1993;72:1183-1187.

18. Cacciapuoti F., D’Avino M., Lama D., et al.: Progressive impairment of
      left ventricular diastolic filling with advancing age. Doppler echocardiographic study. 
      J. Am. Geriatr.Soc. 1992;40:245-250.

19. Klein AL., Burstow DJ., Tajik AJ., Zachariah PK., Bailey KR., Seward JB.: 
      Effects of age on left ventricular dimensions and filling dynamics in 117 
      normal patients. Mayo Clin.- Proc. 1994;69:212-224.

20. Tanabe K., Ishibashi Y., Ohta T., et al.:
      Effect of left and right lateral decubitus positions on mitral flow pattern by
      Doppler echocardiography in congestive heart failure. 
      Am. J. Cardiol. 1993;71:751-753.

21. Ohn M., Cheng CP., Little WC: Mechanism of altered filling patterns 
      of left ventricular filling during the development of congestive heart failure.
      Circulation 1994;89:2241-2250.

22. Nishimura RA., Appleton CP.: “Diastology”:beyond E and A. J. Am. Coll. 
      Cardiol. 1996;27:372-374.

23. Masuyama T., Popp AR.: Doppler evaluation of left ventricular filling
      in congestive heart failure. Eur. J. Cardiol. 1997;18:1548- 1556.

24. Hall AS.; Ball SG.: ACE-inhibitors after myocardial infarction. Lancet 1989;2:1527.

25. Cleland JGF.; Erhardt L.; Murray G.; Hall AS.; Ball SG.; on behalf of the
      AIRE Study Investigators: Effect of ramipril on morbidity and mode of 
      death among survivors of acute myocardial infarction:
      a report from Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
      Eur. Heart J. 1997;18:41-51.

26. Von Mollendorff E., Abshagen U., Akpan W., et al.:
      Clinical pharmacologic investigations with carvedilol, a new b- blocker with 
      direct vasodilator activity. Clin. Pharmacol. Ther.1986;39: 677-682.

27. Tomlison B., Bompart F., Graham BR., et al.: Vasodilating mechanism and 
      response to physiological pressure stimuli of acute doses of carvedilol 
      compared with labetalol, propranolol and hydralazine.Drugs 
      1988; 36 (suppl.6): 37-47.

28. Yoshikawa T., Port JD., Asano K., Chidiak P., Bouvier M., Dutcher
      D., Roden RL., Minobe WA., Tremmel RD., Bristow MR.: 
      Cardiac adrenergic receptor effects of carvedilol. 
      Eur. Heart J. 1996;17(Suppl):8 –16.

29. Bristow MR., Larrabee P., Minobe W., Roden R., Skerl RL., Klein J.,
      Handwerger D., Port JD.,Muller-Beckmann B.:
      Receptor pharmacology of carvedilol in the human heart. J. Cardiovasc. 
      Pharmacol. 1992;19 (suppl):S68-S80.

30. Bristow MR., Larrabee P., Muller-Beckmann B., Minobe W., Roden R., 
      Skerl RL., Klein J., Handwerger D.: 
      Effects of carvedilol on adrenergic receptor pharmacology in human 
      ventricular myocardium and lymphocytes. Clin. Invest. 1992;70:105S-113S.

31. Metra M., Nardi M Giubboni R., Dei Cas L.: Effects of short-and 
      long-term carverdilol administration on rest exercise hemodynamic variables, 
      exercise capacity and clinical conditions in patients 
      with idiopatic dilated cardiomyopathy. J. Am. Coll. Cardiol. 1994; 24, 1678-1687.

32. Di Lenarda A., Gilbert EM., Olsen SL., Mealey PC., Bristow MR.:
      Acute hemodynamic effects of carvedilol versus metoprolol in
      idiopatic dilated cardiomyopathy. J. Am. Coll. Cardiol. 1991;17:142A.

33. Olsen SL., Gilbert EM., Renlund DG., Mealey PC., Taylor DO., Yanowitz FD.,
      Bristow MR.: Carvedilol improves left ventricular function and symptoms 
      in heart failure: a double-bind randomized study J. Am. Coll. 
      Cardiol. 1995;25:1225-1231.

COURT OF THE MYRTLES

Correspondence to: Federico Cacciapuoti MD, Cattedra di Medicina Interna, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli (S.U.N.), Piazza L. Miraglia, 280138-Napoli-Italy. Tel. 081/5665022 *XII Div. Medicina P.O. “A. Cardarelli”-Napoli