that is used to partially or completely replace the function of a failing heart.

The function of VADs differs from that of artificial cardiac pacemakers. Some

VADs are intended for short term use, typically for patients recovering from

heart attacks or heart surgery, while others are intended for long-term use,

typically for patients suffering from advanced congestive heart failure.

VADs are distinct from artificial hearts, which are designed to completely

take over cardiac function and generally require the removal of the patient's

heart. VADs are designed to assist either the right or left ventricle, or

both at once. The type that is used depends primarily on the underlying

heart disease and the pulmonary arterial resistance that determines the load on

the right ventricle. LVADs are most commonly used, but when

pulmonary arterial resistance is high, right ventricular assistance may become

necessary. Long term VADs are normally used to keep patients alive with a good

quality of life while they wait for a heart transplantation. However, LVADs

are sometimes used as destination therapy, meaning they will never undergo

heart transplant, and sometimes as a bridge to recovery.

In the last few years, VADs have improved significantly in terms of

providing survival and quality of life among recipients.

Design = Pumps=

The pumps used in VADs can be divided into two main categories – pulsatile

pumps, that mimic the natural pulsing action of the heart, and continuous flow

pumps. Pulsatile VADs use positive displacement pumps. In some of these

pumps, the volume occupied by blood varies during the pumping cycle, and if

the pump is contained inside the body then a vent tube to the outside air is

required. Continuous flow VADs are smaller and

have proven to be more durable than pulsatile VADs. They normally use either

a centrifugal pump or an axial flow pump. Both types have a central rotor

containing permanent magnets. Controlled electric currents running through coils

contained in the pump housing apply forces to the magnets, which in turn

cause the rotors to spin. In the centrifugal pumps, the rotors are shaped

to accelerate the blood circumferentially and thereby cause it

to move toward the outer rim of the pump, whereas in the axial flow pumps

the rotors are more or less cylindrical with blades that are helical, causing

the blood to be accelerated in the direction of the rotor's axis.

An important issue with continuous flow pumps is the method used to suspend the

rotor. Early versions used solid bearings; however, newer pumps, some of

which are approved for use in the EU, use either electromagnetic suspension or

hydrodynamic suspension. These pumps contain only one moving part.

History The first successful implantation of a

left ventricular assist device was completed in 1966 by Dr. Michael E.

DeBakey to a 37-year-old woman. A paracorporeal circuit was able to

provide mechanical support for 10 days after the surgery. The first successful

long-term implantation of an artificial LVAD was conducted in 1988 by Dr.

William F. Bernhard of Boston Children's Hospital Medical Center and Thermedics,

Inc of Woburn, MA under a National Institutes of Health research contract

which developed Heart-mate, an electronically controlled assist device.

This was funded by a three year $6.2 million contract to Thermedics and

Children's Hospital, Boston MA from the National Heart and Lung and Blood

Institute, a program of NIH. The early VADs emulated the heart by using a

"pulsatile" action where blood is alternately sucked into the pump from

the left ventricle then forced out into the aorta. Devices of this kind include

the HeartMate IP LVAS, which was approved for use in the US by the Food

and Drug Administration in October 1994. These devices are commonly referred to

as first generation VADs. More recent work has concentrated on

continuous flow pumps, which can be roughly categorized as either

centrifugal pumps or axial flow impeller driven pumps. These pumps have the

advantage of greater simplicity resulting in smaller size and greater

reliability. These devices are referred to as second generation VADs. A side

effect is that the user will not have a pulse, or that the pulse intensity will

be seriously reduced. Third generation VADs suspend the

impeller in the pump using either hydrodynamic or electromagnetic

suspension, thus removing the need for bearings and reducing the number of

moving parts to one. Another technology undergoing clinical

trials is the use of trans cutaneous induction to power and control the

device rather than using percutaneous cables. Apart from the obvious cosmetic

advantage this reduces the risk of infection and the consequent need to

take preventative action. A pulsatile pump using this technology has CE Mark

approval and is in clinical trials for US FDA approval.

A very different approach in the early stages of development is the use of an

inflatable cuff around the aorta. Inflating the cuff contracts the aorta

and deflating the cuff allows the aorta to expand – in effect the aorta becomes

a second left ventricle. A proposed refinement is to use the patient's

skeletal muscle, driven by a pacemaker, to power this device which would make it

truly self-contained. However a similar operation was tried in the 1990s with

disappointing results. In any case, it has substantial potential advantages in

avoiding the need to operate on the heart itself and in avoiding any contact

between blood and the device. This approach involves a return to a

pulsatile flow. Peter Houghton was the longest surviving

recipient of a VAD for permanent use. He received an experimental Jarvik 2000

LVAD in June 2000. Since then, he completed a 91-mile charity walk,

published two books, lectured widely, hiked in the Swiss Alps and the American

West, flew in an ultra-light aircraft, and traveled extensively around the

world. He died of acute renal failure in 2007 at the age of 69.

Studies and outcomes = Recent developments=

In July 2009 in England, surgeons removed a donor heart that had been

implanted in a toddler next to her native heart, after her native heart had

recovered. This technique suggests mechanical assist device, such as an

LVAD, can take some or all the work away from the native heart and allow it time

to heal. In July 2009, 18-month follow-up results

from the HeartMate II Clinical Trial concluded that continuous-flow LVAD

provides effective hemodynamic support for at least 18 months in patients

awaiting transplantation, with improved functional status and quality of life..

Heidelberg University Hospital reported in July 2009 that the first

HeartAssist5, known as the modern version of the DeBakey VAD, was

implanted there. The HeartAssist5 weighs 92 grams, is made of titanium and

plastic, and serves to pump blood from the left ventricle into the aorta.

A phase 1 clinical trial is underway, consisting of patients with coronary

artery bypass grafting and patients in end-stage heart failure who have a left

ventricular assist device. The trial involves testing a patch, called

Anginera(TM) that contains cells that secrete hormone-like growth factors that

stimulate other cells to grow. The patches are seeded with heart muscle

cells and then implanted onto the heart with the goal of getting the muscle

cells to start communicating with native tissues in a way that allows for regular

contractions. In September 2009, a New Zealand news

outlet, Stuff, reported that in another 18 months to two years, a new wireless

device will be ready for clinical trial that will power VADs without direct

contact. If successful, this may reduce the chance of infection as a result of

the power cable through the skin. The National Institutes of Health

awarded a $2.8 million grant to develop a "pulse-less" total artificial heart

using two VADS by Micromed, initially created by Michael DeBakey and George

Noon. The grant was renewed for a second year of research in August 2009. The

Total Artificial Heart was created using two HeartAssist5 VADs, whereby one VAD

pumps blood throughout the body and the other circulates blood to and from the

lungs. HeartWare International announced in

August 2009 that it had surpassed 50 implants of their HeartWare Ventricular

Assist System in their ADVANCE Clinical Trial, an FDA-approved IDE study. The

study is to assess the system as bridge-to-transplantation system for

patients with end-stage heart failure. The study, Evaluation of the HeartWare

LVAD System for the Treatment of Advance Heart Failure, is a multi-center study

that started in May 2009. On June 27, 2014 Hannover Medical School

in Hannover, Germany performed the first human implant of HeartMate III under the

direction of Professor Axel Haverich M.D., chief of the Cardiothoracic,

Transplantation and Vascular Surgery Department and surgeon Jan Schmitto,

M.D., Ph.D. On January 21, 2015 a study was

published in Journal of American College of Cardiology suggesting that long-term

use of LVAD may induce heart regeneration. This may explain the

bridge to recovery phenomenon first described by the Yacoub group in NEJM in

2009. The majority of VADs on the market today

are somewhat bulky. The smallest device approved by the FDA, the HeartMate II,

weighs about 1 pound and measures 3 inches. This has proven particularly

important for women and children, for whom alternatives would have been too

large. One device gained CE Mark approval for

use in the EU and began clinical trials in the US. As of June 2007 these pumps

had been implanted in over 100 patients. In 2009, Ventracor was placed into the

hands of Administrators due to financial problems and was later that year

liquidated. No other companies purchased the technology, so as a result the

VentrAssist device was essentially defunct. Around 30–50 patients worldwide

remain supported on VentrAssist devices as of January 2010.

The Heartware HVAD works similarly to the VentrAssist – albeit much smaller

and not requiring an abdominal pocket to be implanted into. The device has

obtained CE Mark in Europe, and FDA approval in the U.S. Recently, it was

shown that the Heartware HVAD can be implanted through limited access without

sternotomy. In a small number of cases left

ventricular assist devices, combined with drug therapy, have enabled the

heart to recover sufficiently for the device to be able to be removed.

= HeartMate II LVAD pivotal study= A series of studies involving the use of

the of HeartMate II LVAD have proven useful in establishing the viability and

risks of using LVADs for bridge-to-transplantation and

destination therapy. The pilot trial for the HeartMate II

LVAS began in November 2003 and consisted of 46 study patients at 15

centers. Results included 11 patients supported for more than one year and

three patients supported for more than two years.

The HeartMate II pivotal trial began in 2005 and included the evaluation of

HeartMate II for two indications: Bridge to transplantation and destination

therapy, or long-term, permanent support. Thoratec Corp. announced that

this was the first time the FDA had approved a clinical trial to include

both indications in one protocol. A multicenter study in the United States

from 2005 to 2007 with 113 patients showed that significant improvements in

function were prevalent after three months, and a survival rate of 68% after

twelve months. Based on one-year follow up data from

the first 194 patients enrolled in the trial, the FDA approved HeartMate II for

bridge-to-transplantation. The trial provided clinical evidence of improved

survival rates and quality of life for a broad range of patients.

Eighteen-month follow up data on 281 patients who had either reached the

study end-point or completed 18 months of post-operative follow-up showed

improved survival, less frequent adverse events and greater reliability with

continuous flow LVADS compared to pulsatile flow devices. Of the 281

patients, 157 patients had undergone transplant, 58 patients were continuing

with LVADs in their body and seven patients had the LVAD removed because

their heart recovered; the remaining 56 had died. The results showed that the

NYHA Class of heart failure the patients had been designated had significantly

improved after six months of LVAD support compared to the pre-LVAD

baseline. Although this trial involved bridge-to-transplant indication, the

results provide early evidence that continuous flow LVADs have advantages in

terms of durability and reliability for patients receiving mechanical support

for destination therapy. Following the FDA approval of HeartMate

II LVAD for bridge-to-transplantation purposes, a post-approval study was

undertaken to assess the efficacy of the device in a commercial setting. The

study found that the device improved outcomes, both compared to other LVAD

treatments and baseline patients. Specifically, HeartMate II patients

showed lower creatinine levels, 30-day survival rates were considerably higher

at 96%, and 93% reached successful outcomes.

= HARPS= The Harefield Recovery Protocol Study is

a clinical trial to evaluate whether advanced heart failure patients

requiring VAD support can recover sufficient myocardial function to allow

device removal. HARPS combines an LVAD with conventional oral heart failure

medications, followed by the novel β2 agonist clenbuterol. This opens the

possibility that some advanced heart failure patients may forgo heart

transplantation. To date, 73% of patients who underwent

the combination therapy regimen demonstrated sufficient recovery to

allow explantation and avoid heart transplantation; freedom from recurrent

heart failure in surviving patients was 100% and 89% at one and four years after

explantation, respectively; average ejection fraction was 64% at 59 months

after explantation – all patients were NYHA Class I; and no significant adverse

effects were reported with clenbuterol therapy.

= REMATCH= The REMATCH clinical trial began in May

1998 and ran through July 2001 in 20 cardiac transplant centers around the

USA. The trial was designed to compare long-term implantation of left

ventricular assist devices with optimal medical management for patients with

end-stage heart failure who require, but do not qualify to receive cardiac

transplantation. As a result of the clinical outcomes, the device received

FDA approval for both indications, in 2001 and 2003, respectively.

The trial demonstrated an 81% improvement in two-year survival among