New pharmacologic therapies for acute heart failure

Miguel Tavares, MD; Eva Rezlan, MD; Irina Vostroknoutova, MD; Hosni Khouadja, MD; Alexandre Mebazaa, MD, PhD

Crit Care Med 2008; 36[Suppl.]:S112S120)

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Outline

Targeting the Increased Vascular Tone in Heart Failure Targeting Sodium and Water Retention and Renal Impairment Targeting the Abnormal Myocyte Calcium Cycling in Heart Failure: Istaroxime Targeting the Arterial-Ventricular Coupling: Levosimendan

Introduction(1)

the limitations of high-dose diuretics and vasodilators inotropes, regardless of the dose used, have a detrimental effect on mortality new agents are under investigation for the treatment of pulmonary and systemic congestion and restoration of cardiac output in the setting of acute heart failure syndromes.

Introduction(2)

The new therapeutic approach is based on two goals: 1.short-term improvement in symptoms 2.long-term improvement of cardiac function. new therapeutic strategies aim to act at the cellular level to improve vessel and heart functions, with minimal side effects, together with improved sodium and water balance.

Introduction(3)

major determinant of survival in AHFS is the level of systolic blood pressure at admission Patients with high systolic blood pressure and predominant signs of pulmonary congestion very often have preserved systolic left ventricular function. These patients are usually treated with diuretics and vasodilators, such as nitroglycerin, nitroprusside, and nesiritide.

Introduction(4)

normal or low systolic blood pressure, have a lower left ventricular ejection fraction and frequent signs of organ hypoperfusion. Those patients are more likely to receive inotropes and have the highest in-hospital mortality rate among AHFS patients.

Introduction(5)

several studies demonstrated that standard care can improve dyspnea by 50% within the first 24 hrs . It is therefore reasonable to assume that there is room for new agents to further reduce the incidence of dyspnea in AHFS patients.

Introduction(6)

AHFS carries one of the highest mortality rates in medicine: 20% at 6 months . This could be related to 1.increased filling pressures 2.and/or decreased cardiac output 3.neurohormonal mechanisms, such as the sympathetic nervous system, the reninangiotensin system, and vasopressin

Increased Vascular Tone - Natriuretic peptide (1)

Natriuretic peptide (NP) hormones (ANP, BNP, CNP, and urodilatin) ANP and BNP, are both produced in atrial and ventricular myocytes in response to increased stretching of the cardiac wall generally cause vasodilation, inhibition of the renin-angiotensin-aldosterone system (RAAS), and reduction in blood pressure without affecting fluid volume.

Increased Vascular Tone - Natriuretic peptide (2)

CNP is produced both in brain and endothelial cells it acts locally in vascular smooth muscle cells, regulating vascular tone and pressure. Urodilatin is produced in the kidney acts in a paracrine fashion on collecting ducts, resulting in reduced Na resorption and thereby increased natriuresis and

Increased Vascular Tone - Natriuretic peptide (3)

Conclusion:NP to restore hemodynamic balance and fluid homeostasis

(Circ J2005; 69:283290) In a 6-yr open-label study of 3,777 patients with AHFS treated with 0.085 g/kg/min carperitide (ANP)for 65 hrs

82% of patients experienced clinical improvement

Increased Vascular Tone - Natriuretic peptide (4)

BNP was approved in the United States in 2001 for the treatment of AHFS patients with dyspnea at rest or with minimal activity.
(PRECEDENT study Circ J2005; 69:283290)

BNP reduced or had a neutral effect on ventricular ectopy and did not cause ventricular or supraventricular arrhythmias in patients with decompensated heart failure

Increased Vascular Tone - Natriuretic peptide (5)

(The VMAC study JAMA 2002; 287:15311540)

VMAC showed that BNP decreased PAOP and improved self evaluation of dyspnea at 3 hrs after initiation of study drug compared with placebo, Although there was marked hemodynamic improvement, including a decrease in filling pressures, the use of BNP has not been translated into long-term improvement in clinical outcome.

Increased Vascular Tone - Natriuretic peptide (6)

The primary pharmacodynamic effects of urodilatin are preload and afterload reduction due to vasodilatation of peripheral veins and arteries and increased diuresis and natriuresis. These effects result from its direct action on vascular smooth muscle cells, causing dilation of renal, pulmonary, and coronary arterial vessels, and from inhibition of sodium resorption in the renal tubules, inducing diuresis and natriuresis.

Increased Vascular Tone - Natriuretic peptide (7)

(Clin Sci (Lond) 1997; 92:397407) (Clin Pharmacol Ther1998; 64:7386) (Am J Physiol 1999; 276:R684R695)

urodilatin increased the renal filtration fraction increased the fractional excretion of sodium the rate of urinary sodium excretion down-regulating effect on the RAAS that inhibits aldosterone secretion from the

Increased Vascular Tone - Endothelin Receptor Antagonism(1)

ET is potent arterial and venous vasoconstriction mediated predominantly by the vascular smooth muscle cell ETA receptors . Plasma ET-1 levels are increased in acute and chronic heart failure, pulmonary hypertension, systemic hypertension, and all forms of acute coronary syndromes. ET-1 could instigate, in heart failure patients, deleterious long-term vascular

Sodium and Water Retension - Vasopressin Receptor Antagonist(1)

Increased vasopressin release is one of the postulated mechanisms for this imbalance. In heart failure, the decreases in effective blood volume and arterial filling would be sensed by the aortic and carotid sinus baroreceptors, resulting in stimulation of vasopressin release

Sodium and Water Retension - Vasopressin Receptor Antagonist(2)

Vasopressin receptor antagonism has the potential to directly address an important component of the pathophysiologic state that is driving the clinical signs of both hyponatremia and volume overload in heart failure. Clinical data have shown the ability of this agents to mobilize fluid and increase serum sodium levels in heart failure patients.

Sodium and Water Retension - Vasopressin Receptor Antagonist(3)

Vasopressin receptor antagonism increased urine volume, accompanied by an acute, significant reduction in body weight, and it can also reduced hyponatremia Vasopressin receptor antagonism tended to reduce mortality in patients with renal dysfunction and significantly reduced mortality in patients with severe systemic congestion.

Sodium and Water Retension - Vasopressin Receptor Antagonist(4)

Vasopressin Receptor Antagonist, in addition to standard therapy including diuretics, improved dyspnea and reduced body weight without serious adverse events.
(Circulation 2001; 104:24172423) (Circulation 2003; 107:26902696) (JAMA 2004; 291:19631971) (JAMA 2007; 297:13321343)

Sodium and Water Retension - Adenosine Antagonists

Adenosine-1-receptor blockade improves glomerular filtration by direct effect on afferent arterioles increased natriuresis with preserved glomerular filtration rate in New York Heart Association class III and IV patients because adenosine might attenuate left ventricular (LV) hypertrophy, inhibiting its effects might worsen LV hypertrophy.

Abnormal Myocyte Calcium Cycling: Istaroxime(1)

contraction is due to an activation of myofibrillar proteins by Ca2 originating from sarcoplasmic reticulum (SR) Ca2-induced Ca2 release.(L-type Ca2 channels ) Myocyte relaxation is due to pumping of Ca2 back into the SR due to a Ca2adenosine triphosphatase (ATPase) called SERCA. SERCA is activated by high-cytoplasmic free Ca2

Abnormal Myocyte Calcium Cycling: Istaroxime(2)

In cardiac myocytes from failing hearts: 1) decreased expression of SERCA 2) a Ca2 leak out of the SR during diastole through ryanodine. This is associated with an increased activity/ expression of the Na-Ca2 exchanger that extrudes Ca2 out of the cell during diastole in exchange for entry of Na.

Abnormal Myocyte Calcium Cycling: Istaroxime(3)

Istaroxime (PST-2744) is a Na/K-ATPase inhibitor not related to digitalis that also increases SERCA. The increase in SERCA induce a higher magnitude and rate of Ca2 reuptake . It decreased LV end-diastolic volume and pressure and LV end-systolic volumes, while LV ejection fraction increase. istaroxime reduced LV end-diastolic wall stress and modestly changed myocardial oxygen consumption, unlike classic

Abnormal Myocyte Calcium Cycling: Istaroxime(4)

In summary, istaroxime seems to be an interesting drug that might combine beneficial effects on both diastolic and systolic LV function.

the Arterial-Ventricular Coupling: Levosimendan(1)

It differs from classic inotropes because of its ability to improve myocardial efficiency without increasing myocardial oxygen demand, its antistunning properties, its effects on coronary blood flow. Beneficial effects of levosimendan may also be related to a vasodilatory effect, which may decrease right and left ventricular afterload

the Arterial-Ventricular Coupling: Levosimendan(2)

Many clinical trials support a beneficial effect of levosimendan on short-term hemodynamic and clinical signs in patients with AHFS. (Kivikko et al). reported a 30% increase in cardiac output and a 33% decrease in PAOP after a 24-hr infusion in class IIIIV heart failure patients.

the Arterial-Ventricular Coupling: Levosimendan(3)

In countries where it is available, early levosimendan infusion can be considered for patients who remain symptomatic with dyspnea at rest despite initial therapy particularly those with history of chronic heart failure, chronically treated with beta blockers . Levosimendan has also been used to restore right ventricular function in patients after cardiac surgery and acute respiratory distress syndrome

SUMMARY

Although some contend that no innovation exists concerning acute heart failure, this review shows that many new agents are in preclinical and often clinical phases with realistic hope. Indeed, drugs like BNP or levosimendan have shown interesting beneficial effects on acute heart failure. Those results need to be confirmed. More important, many new agents need to be tested in phase III trials either alone, on the top of traditional therapy, or combined with agents from other classes.