Invited Commentary

Right ventricular failure is a severe complication in cardiovascular medicine with high mortality typically occurring (e.g., in the course of acute pulmonary embolism, or during severe attacks of bronchial asthma, or in acute right coronary artery occlusion). However, right ventricular failure often also impairs left ventricular function due to inter-ventricular interaction and dyssynchrony. It has been suggested that the dilation of the right ventricle may change left ventricular geometry and thereby the left ventricular contractile efficiency.[1]

Clinical therapy of right ventricular failure is difficult and often not effective. An option that was shown experimentally is aortic constriction, which may improve inter-ventricular interaction and elevate coronary perfusion.[2] The new idea originating from these previous findings that was followed in the present study in this issue,[3] was that elevation of the afterload as aortic constriction may change left ventricular geometry and thereby indirectly improve ventriculo-ventricular interaction and right ventricular contractility.

Thus, the authors induced right ventricular failure by pulmonary banding and thereafter elevated afterload by application of norepinephrine or epinephrine. However, they had to circumvent the problem that this treatment would directly affect the heart. For that purpose the hearts were pharmacologically denervated by the application of propranolol and atropine. Under this condition, the idea was that a mainly vascular response with elevated afterload remains. Indeed the authors found (see Fig. 5 of the article) that norepinephrine restored cardiac output and right ventricular contractility indices.

This is in principle very interesting and seems to corroborate the theory that the dilation of the right ventricle may compress the left ventricle and thereby might alter left ventricular output as was also suggested from a patient study.[4]

The use of vasoconstrictors in this specific setting is—from a pharmacological point of view—problematic. The authors used in each animal i.v. application of propranolol and later on investigated the effects of norepinephrine and epinephrine. Since propranolol effects will follow the normal pharmacokinetics with a half-life time of about 3 hours (single dose), the effects of norepinephrine and epinephrine are overshadowed by this. Moreover, the effect of norepinephrine is altered since it normally will affect both alpha and beta adrenoceptors and under this protocol will be shifted more to an alpha adrenergic response. This must be taken into account since alpha-adrenoceptors are also present in the heart, and in particular in the rabbit heart,[5] [6] [7] which upon activation mediate phosphoinositide hydrolysis with subsequent production of inositol 1,4,5-trisphosphate (IP(3)) and diacylglycerol and PKC activation. The resulting positive inotropic effect typically is accompanied by a negative lusitropic effect.[8] This can indeed be seen in the data of the authors of the present article as left ventricular dP/dt max is clearly elevated under the influence of norepinephrine (Table 1 of the article).

Moreover, it was not confirmed in the present study that complete beta-adrenergic denervation was really achieved. However, the data in Table 1 show at least that there was no longer a positive chronotropic effect of epinephrine, which is in favor of the view that beta-adrenoceptors were widely blocked. It needs to be noted, however, that epinephrine also exerts alpha-adrenergic effects.

Thus, the interpretation of the present study is not easy and is overshadowed by the effects described above. However, in principle the idea is interesting, and if one looks at the effects of lower doses of norepinephrine (0.1 to 0.5 µg/kg/min), there is already a positive effect on right ventricular performance at doses that did not elevate left ventricular dP/dtmax. Thus, it seems that the concept of increasing afterload to improve right ventricular performance via a left-right-interventricular interaction might be efficient.

The merit in the present study is that the authors clearly have shown that right ventricular failure affects left ventricular performance, and that there is a good argument for afterload-enhancing therapies to be of possible relevance. For future studies on this, really interesting, idea I see two possibilities to circumvent the problem described above: either the use of a surgical denervation strategy, or the use of a different vasoconstrictor such as vasopressin or terlipressin, which do not directly interfere with cardiac adrenoceptors or M-cholinoceptors.

• References

• 1 Brookes C, Ravn H, White P, Moeldrup U, Oldershaw P, Redington A. Acute right ventricular dilatation in response to ischemia significantly impairs left ventricular systolic performance. Circulation 1999; 100 (7) 761-767
• 2 Belenkie I, Horne SG, Dani R, Smith ER, Tyberg JV. Effects of aortic constriction during experimental acute right ventricular pressure loading. Further insights into diastolic and systolic ventricular interaction. Circulation 1995; 92 (3) 546-554
• 3 Apitz C, Honjo O, Friedberg M et al. Beneficial effects of vasopressors on right ventricular function in experimental acute right ventricular failure in a rabbit model Thorac Cardiov Surg. 2011 Epub ahead of print
• 4 Gan CT, Lankhaar JW, Marcus JT , et al. Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 2006; 290 (4) H1528-H1533
• 5 Braun AP, Walsh MP. Cardiac alpha 1-adrenoceptors stimulate a high-affinity GTPase activity in sarcolemmal membranes from rabbit atrial and ventricular myocytes. Eur J Biochem 1993; 213 (1) 57-65
• 6 Dybvik T, Osnes JB, Skomedal T. Similar localisation of alpha1- and beta-adrenoceptors in rabbit heart in relation to sympathetic nerve endings. Eur J Pharmacol 1999; 381 (2-3) 135-140
• 7 Yang HT, Endoh M. ( + /-)-tamsulosin, an alpha 1A-adrenoceptor antagonist, inhibits the positive inotropic effect but not the accumulation of inositol phosphates in rabbit heart. Eur J Pharmacol 1996; 312 (3) 281-291
• 8 Endoh M. Cardiac alpha(1)-adrenoceptors that regulate contractile function: subtypes and subcellular signal transduction mechanisms. Neurochem Res 1996; 21 (2) 217-229