P2 purinergic receptor mRNA in rat and human sinoatrial node and other heart regions.

It is known that adenosine 5'-triphosphate (ATP) is a cotransmitter in the heart. Additionally, ATP is released from ischemic and hypoxic myocytes. Therefore, cardiac-derived sources of ATP have the potential to modify cardiac function. ATP activates P2X(1-7) and P2Y(1-14) receptors; however, the presence of P2X and P2Y receptor subtypes in strategic cardiac locations such as the sinoatrial node has not been determined. An understanding of P2X and P2Y receptor localization would facilitate investigation of purine receptor function in the heart. Therefore, we used quantitative PCR and in situ hybridization to measure the expression of mRNA of all known purine receptors in rat left ventricle, right atrium and sinoatrial node (SAN), and human right atrium and SAN. Expression of mRNA for all the cloned P2 receptors was observed in the ventricles, atria, and SAN of the rat. However, their abundance varied in different regions of the heart. P2X(5) was the most abundant of the P2X receptors in all three regions of the rat heart. In rat left ventricle, P2Y(1), P2Y(2), and P2Y(14) mRNA levels were highest for P2Y receptors, while in right atrium and SAN, P2Y(2) and P2Y(14) levels were highest, respectively. We extended these studies to investigate P2X(4) receptor mRNA in heart from rats with coronary artery ligation-induced heart failure. P2X(4) receptor mRNA was upregulated by 93% in SAN (P < 0.05), while a trend towards an increase was also observed in the right atrium and left ventricle (not significant). Thus, P2X(4)-mediated effects might be modulated in heart failure. mRNA for P2X(4-7) and P2Y(1,2,4,6,12-14), but not P2X(2,3) and P2Y(11), was detected in human right atrium and SAN. In addition, mRNA for P2X(1) was detected in human SAN but not human right atrium. In human right atrium and SAN, P2X(4) and P2X(7) mRNA was the highest for P2X receptors. P2Y(1) and P2Y(2) mRNA were the most abundant for P2Y receptors in the right atrium, while P2Y(1), P2Y(2), and P2Y(14) were the most abundant P2Y receptor subtypes in human SAN. This study shows a widespread distribution of P2 receptor mRNA in rat heart tissues but a more restricted presence and distribution of P2 receptor mRNA in human atrium and SAN. This study provides further direction for the elucidation of P2 receptor modulation of heart rate and contractility.

(-)-CGP12177 increases contractile force through beta1l-adrenoceptors but not through beta3-adrenoceptors in human right atrial myocardium

(-)-CGP12177 is a non-conventional partial agonist that causes modest and transient increases of contractile force in human atrial trabeculae (Kaumann and Molenaar, 2008). These effects are markedly increased and maintained by inhibition of phosphodiesterase PDE3. As verified with recombinant receptors, the cardiostimulant effect of (-)-CGP12177 is mediated through a site at the beta1-adrenoceptor with lower affinity (beta1LAR) compared to the site through which (-)-CGP12177 antagonizes the effects of catecholamines (beta1HAR). However, in a recent report it was proposed that the positive inotropic effects of CGP12177 are mediated through beta3-adrenoceptors (Skeberdis et al 2008). We therefore investigated whether the effects of (-)-CGP12177 on human atrial trabeculae are antagonized by the beta3-adrenoceptor-selective antagonist L-748,337 (1 microM). (-)-CGP12177 (200 nM) caused a stable increase in force which was significantly reduced by the addition of (-)-bupranolol (1 microM), P = 0.002, (basal 4.45 ± 0.78 mN, IBMX (PDE inhibitor) 5.47 ± 1.01 mN, (-)-CGP12177 9.34 ± 1.33 mN, (-)-bupranolol 5.79 ± 1.08 mN, n = 6) but not affected by the addition of L-748,337 (1 microM), P = 0.12, (basal 4.48 ± 1.32 mN, IBMX 7.15 ± 2.28 mN, (-)-CGP12177 12.51 ± 3.71 mN, L-748,337 10.90 ± 3.49 mN, n = 6). Cumulative concentration-effect curves for (-)-CGP12177 were not shifted to the right by L-748,337 (1 microM). The –logEC50M values of (-)-CGP12177 in the absence and presence of L-748,337 were 7.21±0.09 and 7.41±0.13, respectively (data from 25 trabeculae from 8 patients, P=0.2) The positive inotropic effects of (-)-CGP12177 (IBMX present) were not antagonized by L-748,337 but were blunted by (-)-bupranolol (1 microM). The results rule out an involvement of beta3-adrenoceptors in the positive inotropic effects (-)-CGP12177 in human right atrial myocardium and are consistent with mediation through beta1LAR. Kaumann A and Molenaar P (2008) Pharmacol Ther 118, 303-336 Skeberdis VA et al (2008) J Clin Invest, 118, 3219-3227

The highs (B1H) and lows (B1L) of human heart B1-adrenoceptors (AR)

The 1AR has two binding sites which can be activated to cause cardiostimulation. The first, termed, 1HAR (high affinity site of 1AR) is activated by noradrenaline and adrenaline and is blocked by relatively low concentrations of β-blockers including carvedilol (Kaumann and Molenaar, 2008). The other, termed, 1LAR (low affinity site of 1AR) has lower affinity for noradrenaline and adrenaline and is activated by some β-blockers including CGP12177 and pindolol, at higher concentrations than those required to block the receptor (Kaumann and Molenaar, 2008). (-)-CGP12177 is a non-conventional partial agonist that causes modest and transient increases of contractile force in human atrial trabeculae (Kaumann and Molenaar, 2008). These effects are markedly increased and maintained by inhibition of phosphodiesterase PDE3. The stimulant effects of (-)-CGP12177 at human β1ARs was verified with recombinant receptors (Kaumann and Molenaar, 2008). However, in a recent report it was proposed that the positive inotropic effects of CGP12177 are mediated through 3ARs in human right atrium (Skeberdis et al 2008). This proposal was not consistent with the lack of blockade of (-)-CGP12177 inotropic effects or increases in L-type Ca2+ current (ICa-L ) by the β3AR blocker 1 μM LY748,337 (Christ et al, 2010). On the otherhand, (-)-CGP12177 increases in inotropic effects and ICa-L were blocked by (-)-bupranolol 1-10 μM (Christ et al, 2010). Chronic infusion of (-)-CGP 12177 (10 mg/Kg/24 hours) for four weeks in an aortic constriction mouse model of heart failure caused an increase in left ventricular wall thickness, fibrosis and inflammation-related left ventricular gene expression levels. Christ T et al (2010) Br J Pharmacol, In press Kaumann A and Molenaar P (2008) Pharmacol Ther 118, 303-336 Skeberdis VA et al (2008) J Clin Invest, 118, 3219-3227

The Heart of the South American Rattlesnake, Crotalus durissus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Heart failure-induced skeletal myopathy in spontaneously hypertensive rats

Background: Although skeletal muscle atrophy and changes in myosin heavy chain (MyHC) isoforms have often been observed during heart failure, their pathophysiological mechanisms are not completely defined. In this study we tested the hypothesis that skeletal muscle phenotype changes are related to myogenic regulatory factors and myostatin/follistatin expression in spontaneously hypertensive rats (SHR) with heart failure. Methods: After developing tachypnea, SHR were subjected to transthoracic echocardiogram. Pathological evidence of heart failure was assessed during euthanasia. Age-matched Wistar-Kyoto (WKY) rats were used as controls. Soleus muscle morphometry was analyzed in histological sections, and MyHC isoforms evaluated by electrophoresis. Protein levels were assessed by Western blotting. Statistical analysis: Student's t test and Pearson correlation. Results: All SHR presented right ventricular hypertrophy and seven had pleuropericardial effusion. Echocardiographic evaluation showed dilation in the left chambers and left ventricular hypertrophy with systolic and diastolic dysfunction in SHR. Soleus weight and fiber cross sectional areas were lower (WKY 3615±412; SHR 2035±224 μm2; P < 0.001), and collagen fractional volume was higher in SHR. The relative amount of type I MyHC isoform was increased in SHR. Myogenin, myostatin, and follistatin expression was lower and MRF4 levels higher in SHR. Myogenin and follistatin expression positively correlated with fiber cross sectional areas and MRF4 levels positively correlated with I MyHC isoform. Conclusion: Reduced myogenin and follistatin expression seems to participate in muscle atrophy while increased MRF4 protein levels can modulate myosin heavy chain isoform shift in skeletal muscle of spontaneously hypertensive rats with heart failure. © 2012 Elsevier B.V.

Stitched to the heart--till intervention do us part

The case report describes the situation where a venous infusion catheter was inadvertently stitched to the lateral wall of the right atrium during valve replacement. A dual percutaneous approach was used to first sever the catheter at the suture and then remove both ends safely. The risk of tearing the suture which would have resulted in tamponade had to be avoided.

Postmortem radiology of fatal hemorrhage: measurements of cross-sectional areas of major blood vessels and volumes of aorta and spleen on MDCT and volumes of heart chambers on MRI

OBJECTIVE: Autopsy determination of fatal hemorrhage as the cause of death is often a difficult diagnosis in forensic medicine. No quantitative system for accurately measuring the blood volume in a corpse has been developed. MATERIALS AND METHODS: This article describes the measurement and evaluation of the cross-sectional areas of major blood vessels, of the diameter of the right pulmonary artery, of the volumes of thoracic aorta and spleen on MDCT, and of the volumes of heart chambers on MRI in 65 autopsy-verified cases of fatal hemorrhage or no fatal hemorrhage. RESULTS: Most cases with a cause of death of "fatal hemorrhage" had collapsed vessels. The finding of a collapsed superior vena cava, main pulmonary artery, or right pulmonary artery was 100% specific for fatal hemorrhage. The mean volumes of the thoracic aorta and of each of the heart chambers and the mean cross-sectional areas of all vessels except the inferior vena cava and abdominal aorta were significantly smaller in fatal hemorrhage than in no fatal hemorrhage. CONCLUSION: For the quantitative differentiation of fatal hemorrhage from other causes of death, we propose a three-step algorithm with measurements of the diameter of the right pulmonary artery, the cross-sectional area of the main pulmonary artery, and the volume of the right atrium (specificity, 100%; sensitivity, 95%). However, this algorithm must be corroborated in a prospective study, which would eliminate the limitations of this study. Quantitative postmortem cross-sectional imaging might become a reliable objective method to assess the question of fatal hemorrhage in forensic medicine.

Sodium pump reduction correlates with aortic clamp time in pediatric heart surgery

Myocardial depression after cardiac surgery is modulated by cardiopulmonary bypass (CPB) and the underlying heart disease. The sodium pump is a key component for myocardial function. We hypothesized that the change in sodium pump expression during CPB correlates with intraoperative and postoperative laboratory and clinical parameters in neonates and children with various congenital heart defects. Sodium pump isoforms alpha1 (ATP1A1) and alpha3 (ATP1A3) mRNA expression in right atrial myocardium, excised before and after CPB, was quantified. Groups were assigned according to presence (VO group, n = 8) or absence (NO group, n = 8) of right atrial volume overload. CPB and aortic clamp time correlated with postoperative troponin-I values and ICU stay. ATP1A1 (P = 0.008) and ATP1A3 (P = 0.038) mRNA expression were significantly reduced during CPB. Longer aortic clamp times were associated with lower postoperative ATP1A1 (P = 0.045) and ATP1A3 (P = 0.002) mRNA expression. Low postoperative ATP1A1 (P = 0.043) and ATP1A3 (P = 0.002) expressions were associated with high troponin-I values. These results were restricted to the VO group. No correlation of sodium pump mRNA expression was found with the duration of ICU stay or ventilation. The postoperative troponin-I and clinical parameters correlated with the length of CPB, regardless of volume overload. In contrast, only dilated right atrium seemed to be susceptible to CPB in terms of sodium pump expression, showing a reduction during the operation and a correlation of sodium pump with postoperative troponin-I values.

Beneficial cardiovascular effects of endothelin ET(A) receptor blockade in established long-term heart failure after myocardial infarction

Although experimental prevention studies have suggested therapeutic potential of endothelin (ET) antagonists for the treatment of heart failure, the results of clinical trials using ET antagonists on top of standard heart failure medications have been largely disappointing. This experimental study investigated the effects of chronic ET(A) receptor blockade in long-term survivors of myocardial infarction who had developed stable chronic heart failure in the absence of other treatments. Systolic blood pressure, heart rate, organ weights of the right atrium and ventricle, and the lungs were determined, and tissue ET-1 peptide levels were measured in cardiac tissue, lung, and aorta. The results show that chronic blockade of ET(A) receptors stabilizes systolic blood pressure and reverses the heart failure-induced weight increases of right heart chambers and lung. The changes observed occurred independently of tissue ET-1 concentrations and heart rate, suggesting mechanisms independent of local cardiac or pulmonary ET-1 synthesis, which are yet to be identified.

Irrigated-tip catheter ablation of intraatrial reentrant tachycardia in patients late after surgery of congenital heart disease.

OBJECTIVES The aim of this study was to evaluate irrigated-tip catheter for ablation of intraatrial reentrant tachycardias late after surgical repair of congenital heart disease. BACKGROUND In congenital heart disease patients, the right atrium can be markedly enlarged with areas of low blood flow. Radiofrequency (RF) lesion creation may be hampered by insufficient electrode cooling at sites with low blood flow. METHODS Thirty-six consecutive patients with intraatrial reentrant tachycardia refractory to antiarrhythmic therapy from two centers were included in the study. Entrainment pacing and electroanatomic mapping (CARTO) were used to delineate reentrant circuits and critical isthmus sites. RF ablation was performed using an irrigated-tip catheter (Navistar Thermocool). RESULTS Fifty-two intraatrial reentrant tachycardia circuits were identified, and 48 were targeted with RF ablation. RF ablation was performed using a mean of 13 +/- 11 irrigated RF applications per tachycardia isthmus with a mean power of 36 +/- 8 W. In a historical control group of congenital heart disease patients managed with conventional catheter ablation, the number of lesions per isthmus was higher (23 +/- 11) and mean power was lower (27 +/- 14 W). Acute success was achieved in 45 intraatrial reentrant tachycardias (94% of targeted tachycardias and 87% of all tachycardias). After a mean follow-up of 17 +/- 7 months, 33 (92%) of 36 patients were free of recurrence. Five patients (14%) developed paroxysmal atrial fibrillation. CONCLUSIONS The combination of modern techniques including electroanatomic mapping and catheter irrigation allows safe and highly effective ablation of intraatrial reentrant tachycardia in patients with surgically repaired congenital heart disease.

Rat heart: A site of oxytocin production and action

We report here that the rat heart is a site of oxytocin (OT) synthesis and release. Oxytocin was detected in all four chambers of the heart. The highest OT concentration was in the right atrium (2128 ± 114 pg/mg protein), which was 19-fold higher than in rat uterus but 3.3-fold lower than in the hypothalamus. OT concentrations were significantly greater in the right and left atria than in the corresponding ventricles. Furthermore, OT was released into the effluent of isolated, perfused rat heart (34.5 ± 4.7 pg/min) and into the medium of cultured atrial myocytes. Reverse-phase HPLC purification of the heart extracts and heart perfusates revealed a main peak identical with the retention time of synthetic OT. Southern blots of reverse transcription–PCR products from rat heart revealed gene expression of specific OT mRNA. OT immunostaining likewise was found in atrial myocytes and fibroblasts, and the intensity of positive stains from OT receptors paralleled the atrial natriuretic peptide stores. Our findings suggest that heart OT is structurally identical, and therefore derived from, the same gene as the OT that is primarily found in the hypothalamus. Thus, the heart synthesizes and processes a biologically active form of OT. The presence of OT and OT receptor in all of the heart’s chambers suggests an autocrine and/or paracrine role for the peptide. Our finding of abundant OT receptor in atrial myocytes supports our hypothesis that OT, directly and/or via atrial natriuretic peptide release, can regulate the force of cardiac contraction.

Carvedilol blocks beta(2)- more than beta(1)-adrenoceptors in human heart

Objective: To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart and beta(2)-adrenoceptors. Methods: The positive inotropic effects of noradrenaline (in the presence of the beta(2)-selective antagonist ICI118551) and adrenaline (in the presence of the beta(1)-selective antagonist CGP20712), mediated through beta(1)- and beta(2)-adrenoceptors, respectively, were investigated in atrial and ventricular trabeculae. The patch-clamp technique was used to investigate effects of noradrenaline and adrenaline on L-type Ca2+ current in human atrial myocytes. Results: Carvedilol was a 13-fold more potent competitive antagonist of the effects of adrenaline at 1 2-adrenoceptors (-logK(B) = 10.13 +/- 0.08) than of noradrenaline at beta(1)-adrenoceptors (-logK(B) = 9.02 +/- 0.07) in human right atrium. Chronic carvedilol treatment of patients with non-terminal heart failure reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline 5.6-fold and 91.2-fold, respectively, compared to beta(1)-blocker-treated patients, consistent with persistent preferential blockade of beta(2)-adrenoceptors. In terminal heart failure carvedilol treatment reduced 1.8-fold and 25.1-fold the sensitivity of right ventricular trabeculae to noradrenaline and adrenaline, respectively, but metoprolol treatment did not reduce the sensitivity to the catecholamines. Increases of current (I-Ca,I-L) produced by noradrenaline and adrenaline were not different in atrial myocytes obtained from non-terminal heart failure patients treated with metoprolol or carvedilol, consistent with dissociation of both beta-blockers from the receptors. Conclusions: Carvedilol blocks human cardiac beta(2)-adrenoceptors more than beta(1)-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of beta-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.

BACKGROUND: Although we know much about the molecular makeup of the sinus node (SN) in small mammals, little is known about it in humans. The aims of the present study were to investigate the expression of ion channels in the human SN and to use the data to predict electrical activity. METHODS AND RESULTS: Quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence were used to analyze 6 human tissue samples. Messenger RNA (mRNA) for 120 ion channels (and some related proteins) was measured in the SN, a novel paranodal area, and the right atrium (RA). The results showed, for example, that in the SN compared with the RA, there was a lower expression of Na(v)1.5, K(v)4.3, K(v)1.5, ERG, K(ir)2.1, K(ir)6.2, RyR2, SERCA2a, Cx40, and Cx43 mRNAs but a higher expression of Ca(v)1.3, Ca(v)3.1, HCN1, and HCN4 mRNAs. The expression pattern of many ion channels in the paranodal area was intermediate between that of the SN and RA; however, compared with the SN and RA, the paranodal area showed greater expression of K(v)4.2, K(ir)6.1, TASK1, SK2, and MiRP2. Expression of ion channel proteins was in agreement with expression of the corresponding mRNAs. The levels of mRNA in the SN, as a percentage of those in the RA, were used to estimate conductances of key ionic currents as a percentage of those in a mathematical model of human atrial action potential. The resulting SN model successfully produced pacemaking. CONCLUSIONS: Ion channels show a complex and heterogeneous pattern of expression in the SN, paranodal area, and RA in humans, and the expression pattern is appropriate to explain pacemaking.

Human atrial beta1L-adrenoceptor but not beta3-adrenoceptor activation increases force and Ca2+ current at physiological temperature

BACKGROUND AND PURPOSE It has been proposed that BRL37344, SR58611 and CGP12177 activate b3-adrenoceptors in human atrium to increase contractility and L-type Ca2+ current (ICa-L). b3-adrenoceptor agonists are potentially beneficial for the treatment of a variety of diseases but concomitant cardiostimulation would be potentially harmful. It has also been proposed that (-)-CGP12177 activates the low affinity binding site of the b1-adrenoceptor in human atrium. We therefore used BRL37344, SR58611 and (-)-CGP12177 with selective b-adrenoceptor subtype antagonists to clarify cardiostimulant b-adrenoceptor subtypes in human atrium. EXPERIMENTAL APPROACH Human right atrium was obtained from patients without heart failure undergoing coronary artery bypass or valve surgery. Cardiomyocytes were prepared to test BRL37344, SR58611 and CGP12177 effects on ICa-L. Contractile effects were determined on right atrial trabeculae. KEY RESULTS BRL37344 increased force which was antagonized by blockade of b1- and b2-adrenoceptors but not by blockade of b3-adrenoceptors with b3-adrenoceptor-selective L-748,337 (1 mM). The b3-adrenoceptor agonist SR58611 (1 nM–10 mM) did not affect atrial force. BRL37344 and SR58611 did not increase ICa-L at 37°C, but did at 24°C which was prevented by L-748,337. (-)-CGP12177 increased force and ICa-L at both 24°C and 37°C which was prevented by (-)-bupranolol (1–10 mM), but not L-748,337. CONCLUSIONS AND IMPLICATIONS We conclude that the inotropic responses to BRL37344 are mediated through b1- and b2-adrenoceptors. The inotropic and ICa-L responses to (-)-CGP12177 are mediated through the low affinity site b1L-adrenoceptor of the b1-adrenoceptor. b3-adrenoceptor-mediated increases in ICa-L are restricted to low temperatures. Human atrial b3-adrenoceptors do not change contractility and ICa-L at physiological temperature.

Inflow cannula design for biventricular assist devices

Cardiovascular diseases are a leading cause of death throughout the developed world. With the demand for donor hearts far exceeding the supply, a bridge-to-transplant or permanent solution is required. This is currently achieved with ventricular assist devices (VADs), which can be used to assist the left ventricle (LVAD), right ventricle (RVAD), or both ventricles simultaneously (BiVAD). Earlier generation VADs were large, volume-displacement devices designed for temporary support until a donor heart was found. The latest generation of VADs use rotary blood pump technology which improves device lifetime and the quality of life for end stage heart failure patients. VADs are connected to the heart and greater vessels of the patient through specially designed tubes called cannulae. The inflow cannulae, which supply blood to the VAD, are usually attached to the left atrium or ventricle for LVAD support, and the right atrium or ventricle for RVAD support. Few studies have characterized the haemodynamic difference between the two cannulation sites, particularly with respect to rotary RVAD support. Inflow cannulae are usually made of metal or a semi-rigid polymer to prevent collapse with negative pressures. However suction, and subsequent collapse, of the cannulated heart chamber can be a frequent occurrence, particularly with the relatively preload insensitive rotary blood pumps. Suction events may be associated with endocardial damage, pump flow stoppages and ventricular arrhythmias. While several VAD control strategies are under development, these usually rely on potentially inaccurate sensors or somewhat unreliable inferred data to estimate preload. Fixation of the inflow cannula is usually achieved through suturing the cannula, often via a felt sewing ring, to the cannulated chamber. This technique extends the time on cardiopulmonary bypass which is associated with several postoperative complications. The overall objective of this thesis was to improve the placement and design of rotary LVAD and RVAD inflow cannulae to achieve enhanced haemodynamic performance, reduced incidence of suction events, reduced levels of postoperative bleeding and a faster implantation procedure. Specific objectives were: * in-vitro evaluation of LVAD and RVAD inflow cannula placement, * design and in-vitro evaluation of a passive mechanism to reduce the potential for heart chamber suction, * design and in-vitro evaluation of a novel suture-less cannula fixation device. In order to complete in-vitro evaluation of VAD inflow cannulae, a mock circulation loop (MCL) was developed to accurately replicate the haemodynamics in the human systemic and pulmonary circulations. Validation of the MCL’s haemodynamic performance, including the form and magnitude of pressure, flow and volume traces was completed through comparisons of patient data and the literature. The MCL was capable of reproducing almost any healthy or pathological condition, and provided a useful tool to evaluate VAD cannulation and other cardiovascular devices. The MCL was used to evaluate inflow cannula placement for rotary VAD support. Left and right atrial and ventricular cannulation sites were evaluated under conditions of mild and severe heart failure. With a view to long term LVAD support in the severe left heart failure condition, left ventricular inflow cannulation was preferred due to improved LVAD efficiency and reduced potential for thrombus formation. In the mild left heart failure condition, left atrial cannulation was preferred to provide an improved platform for myocardial recovery. Similar trends were observed with RVAD support, however to a lesser degree due to a smaller difference in right atrial and ventricular pressures. A compliant inflow cannula to prevent suction events was then developed and evaluated in the MCL. As rotary LVAD or RVAD preload was reduced, suction events occurred in all instances with a rigid inflow cannula. Addition of the compliant segment eliminated suction events in all instances. This was due to passive restriction of the compliant segment as preload dropped, thus increasing the VAD circuit resistance and decreasing the VAD flow rate. Therefore, the compliant inflow cannula acted as a passive flow control / anti-suction system in LVAD and RVAD support. A novel suture-less inflow cannula fixation device was then developed to reduce implantation time and postoperative bleeding. The fixation device was evaluated for LVAD and RVAD support in cadaveric animal and human hearts attached to a MCL. LVAD inflow cannulation was achieved in under two minutes with the suture-less fixation device. No leakage through the suture-less fixation device – myocardial interface was noted. Continued development and in-vivo evaluation of this device may result in an improved inflow cannulation technique with the potential for off-bypass insertion. Continued development of this research, in particular the compliant inflow cannula and suture-less inflow cannulation device, will result in improved postoperative outcomes, life span and quality of life for end-stage heart failure patients.