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A description of prolonged preservation of the heart prior to transplantation

He is currently pursuing his PhD at the University of Glasgow.

An overview of different methods of myocardial protection currently employed peri-transplantation

His research interests surround primary graft dysfunction in heart transplantation. Click here to view Vessel Plus 2017;1: Abstract Myocardial protection is integral to the functioning of hearts in day to day cardiac surgery. However, due to the longer ischaemic times, it becomes pivotal in the management of organs during transplantation. There are many different strategies employed to ensure diligent and judicious myocardial protection during donor management, transportation of the heart and the post-operative period.

Given the limited supply of organs and the increasing waiting lists for heart transplants worldwide, it has become an area of renewed interest with many innovations and inventions using the principles of basic sciences to improve outcomes of transplanted hearts. The heart procurement process encompasses several of the different myocardial protection strategies in tandem to provide the greatest benefit to the recipients.

This review looks at the different modalities employed, which include different types of cardioplegia, the role of biomarkers, the cutting-edge novel therapies, hormonal therapies and ischaemic conditioning strategies. Myocardial protection, cardiac surgery, cardiac transplantation Introduction Cardiac surgery is a rapidly evolving specialty when compared to other forms of surgery.

In the 19th century, professor Theodor Billroth, one of the pioneers of modern abdominal surgery once stated: In 1951, Russian physiologist Vladimar Petrovich Demikhov performed the first thoracic transplants recorded. He transplanted the heart and lungs of a male dog into a 3-year-old female dog. The dog survived 6 days exhibiting normal behaviour but succumbed to respiratory complications.

A description of prolonged preservation of the heart prior to transplantation

This was the first recorded history of any animal surviving any length of time with a transplanted heart supporting its circulation[ 2 ]. Norman Shumway from the University of Minnesota was well known for his work on myocardial protection.

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Along with Lillehei, they would later lead the team that refined the technique of orthotopic heart transplantation. They reported a series of orthotopic heart transplantations in dogs and perfected a method that had been use previously by Cass and Brock by preserving the recipient atrial cuffs[ 3 ]. They had also first introduced the idea of cold cardioplegia. These experiments were successful but Shumway that host immunologic mechanisms were destroying the graft and survival could be prevented by addressing these[ 4 ].

Shumway searched for biomarkers to monitor transplant rejection. Initial experiments with enzymes hypertensin I were unsuccessful. He settled on electrocardiography as a monitor but noted its limitations and pointed out that atrial fibrillation within 7-21 days of transplant was an early sign of rejection[ 5 ].

After working with transplant nephrologists, he assessed the potential benefits of immunosuppression 6-mercaptopurine, azathioprine, and prednisolone and increased survival by up to 250 days in dogs receiving orthotopic transplants. Christiaan Barnard extended their pioneering work. The number of heart transplants performed worldwide continued to increase until the shortage of donors in the 1990s became a limiting factor[ 8 ].

  • The results were consistent with non-inferiority of OCS vs;
  • Allopurinol with glutathione act as antioxidants[ 40 , 41 ];
  • Following preservation, the OCS group demonstrated acceptable lactate profiles and all hearts out of this group were successfully transplanted whereas none of the hearts in the SOC group could be weaned off bypass.

This was included standardizing protocols which includes insertion of a pulmonary artery catheter and performance of cardiac output studies, weaning other vasopressors and commencing arginine vasopressin, and administration of hormone replacement.

This included tri-iodothyronine, methylprednisolone and insulin. Despite recent advances, myocardial protection during heart transplantation remains a challenging avenue. With the increasing usage of borderline donor hearts as described, we review some of the myocardial protection strategies and potential markers for perioperative myocardial infarction. Cardioplegia Ringer first noted the relationship between potassium and sodium concentration and the heart rate in 1883[ 11 ].

Experimentations with potassium citrate were initially unsuccessful due to the excessive osmolality due to the high-concentration potassium citrate[ 12 ]. Most cardioplegic solutions today employ a more physiological osmolality and potassium concentration.

Cardioplegic solutions are defined as intracellular and extracellular solutions based on the concentrations of sodium and potassium ions. Extracellular solutions contain high levels of potassium, magnesium and sodium, while intracellular solutions contain low electrolyte levels.

A description of prolonged preservation of the heart prior to transplantation

This reduction in membrane potential resting state prevents generation of action potentials. Extracellular cardioplegia on the other hand works by preventing repolarization of myocytes.

Potassium rich perfusate in the extracellular space reduces the membrane voltage difference causing depolarization. Intracellular calcium sequestration occurs via active transport across an ATP-dependent pump allowing relaxation of the myocardium in diastole. Repolarization however is prevented by the high potassium concentration of the cardioplegic solution. Both intracellular and extracellular a description of prolonged preservation of the heart prior to transplantation solutions have similar long-term outcomes[ 14 ].

Norman Shumway first noted the use of topical hypothermia to reduce myocardial metabolic requirements in 1960 when chemical cardioplegia fell out of favour[ 15 ]. Clinical cardioplegia was reintroduced in the 1970s by using a low-sodium solution by Bretschneider et al. Blood was later introduced as medium for cardioplegia by Buckberg as it was later discovered that reperfusion injuries occurred in crystalloid cardioplegia due to the associated influence of calcium and oxygen as described by Buckberg[ 21 ] and Hearse et al.

There are intracellular and extracellular types of crystalloid cardioplegia which have become the gold standard for cardiac preservation [Table 1] [ 23 ]. They reported good results provided the ischaemic times were less than 4 h.

Cold HTK solution was infused at low perfusion pressure after procurement and the donor heart was placed in a sterile bag containing HTK solution. The heart was covered with ice-cold saline for topical cooling and packed in a container filled with ice. There were 4 deaths 8. They concluded that HTK was superior due to the reduced pumping time albeit with a higher post-operative inotrope score.

HTK is an intracellular type of cardioplegic solution. It lowers concentrations of sodium and calcium thereby inducing cardiac arrest by deprivation of extracellular sodium thus preventing depolarisation of the action potential. Calcium channels open leading to increased cytosolic calcium and potentially aggravating cellular injury, indirectly reducing the calcium concentration.

Histidine in the HTK solution, acts as a buffer enhancing the efficiency of anaerobic glycolysis. This has been quoted by several sources to be its primary advantage, with its buffering capacity allowing effective myocardial preservation. Tryptophan stabilises the cell membranes. Mannitol, an osmotic diuretic is added to reduce cellular oedema as it has free radical scavenging properties thus reducing the extent of ischaemic injury[ 27 ].

Addition of a buffer and reduction of calcium concentrations resulted in the formation of No. In a rat model, Plegisol was shown to be superior to its predecessor with lower rates of post-operative ventricular fibrillation, increased left ventricular pressure and recovery of aortic flow[ 29 ]. Addition of procaine in this solution reduces the incidence of post-declamping ventricular fibrillation. There were no other between-group differences[ 31 ].

  • Brain natriuretic peptide BNP is actively synthesized and released from cardiac myocytes in response to ischaemia and inflammation[ 62 ];
  • Multiple studies have since been done to study the effect of glucose-potassium-insulin GKI on myocyte function;
  • Shumway searched for biomarkers to monitor transplant rejection;
  • Follow up data shows patients are still making a good recovery at 176, 91, and 77 days after transplantation;
  • Ischaemic conditioning has garnered a lot of interest in recent times with almost 500 articles published every year, and 53 clinical trials phase I to IV available on PubMed.

Eurocollins Collins et al. The predecessor to the Eurocollins solution, Collins solution, provided reliable preservation and was the organ preservation fluid of choice in abdominal organ transplantation especially renal preservation. Collins solution a description of prolonged preservation of the heart prior to transplantation a high potassium content alongside a glucose osmotic barrier.

Despite achieving relatively long storage times for abdominal organs, hearts were more susceptible to ischaemic injury and the low protective properties of glucose compounded by the acidotic conditions resulting from glucose conversion to lactate resulted in the addition of mannitol or sucrose instead of glucose as the impermeant[ 33 ]. Euro-Collins solution however fell out of favour due to the variability of recovery of hearts at non-uniform temperatures[ 34 ].

Prior to its introduction, abdominal organs preserved in Collins solution would have limited ischaemic tolerance of about 8 h. Belzer and Southard developed UW solution initially to prolong liver and pancreas preservation. Their initial experiments of canine pancreases were encouraging and used it for liver and kidneys with similarly encouraging results[ 36-38 ].

It contains lactobionate and raffinose, which are metabolically inert, making it suitable for multiorgan usage. Both these substances which are osmotically active prevent organ oedema. Addition of adenosine provides precursor of an energy source ATP.

Allopurinol with glutathione act as antioxidants[ 4041 ]. Celsior Dr Menasche and colleagues developed Celsior solution[ 44 ]. They utilised lactobionate and mannitol as impermeants.

Celsior also uses histidine as a buffer and glutamate as an energy substance alongside magnesium to stabilise calcium levels. Unlike UW which has a high potassium content, Celsior had a lower potassium content and a high sodium concentration. In canine models, Celsior had a similar cardioprotective profile as UW. Higher concentrations of potassium results in increase coronary vascular resistance secondary to endothelial distension[ 4546 ]. De Santo et al.

They followed up 200 consecutive heart recipients with 73 in the high-risk group defined as 2 or more of the following: There was no difference noted between the two groups in terms of 1-year mortality, hospital mortality, histological findings and patterns of enzyme release[ 47 ].

Comparison of cardioplegic solutions Lee et al. In their cohort of 31 patients, they demonstrated non-inferiority to other approaches. The theoretical benefits include the quick initial arrest from StH alongside the prolonged effect of HTK alongside its buffering mechanism. The effectiveness of HTK has resulted in lower CK and lactate dehydrogenase levels in non-transplant cardiac surgery [Table 2] [ 4849 ].

Comparison of studies comparing cardioplegic agents Comparisons between the different crystalloid cardioplegia solutions are difficult to extrapolate due to the lack of direct comparisons. Several smaller animal studies however do suggest potential superiority of HTK cardioplegia over the rest. Biomarkers Cardiac troponins have largely replaced cardiac muscle enzymes CK-MB for the diagnosis of myocardial infarction.

Cardiac troponin T cTnT and troponin I cTnI are cardiac regulatory proteins that control the calcium mediated interaction between actin and myosin. The role of post-operative troponin release as a prognostic factor for mid- and short-term all-cause mortality after adult cardiac surgery is accepted albeit cut-off values are difficult to establish due to the variety of timing of the Tn testing, Tn subunit and Tn assays[ 59 ].

Its prognostic value in a transplant setting however has not been clearly understood. CK-MB and troponin I are released immediately after transplantation and depends on myocardial ischaemic damage, which is related to ischaemic time[ 60 ].

Data from 362 consecutive recipients were collated over 11 years. Target outcomes included factors determining troponin release, early graft failure, rise in creatinine and operative death. This study depicted the largest group of adult cardiac transplantation patients who had cTnI levels correlated with perioperative morbidity and mortality reported in the literature thus far.

The pattern of troponin release observed was similar to that reported by Minami. Factors that predicted this rise included previous cardiac surgery, left ventricular hypertrophy, increased ischaemic time and transplant status 2B. Troponin proteins are intracellular proteins released primarily from cardiac myocytes undergoing cellular necrosis.