THE GRANOV-GOOR INDEX (GGI): A New Algorithm for the Assessment of LV Systolic Dysfunction – LVSD

According to AHA and ACC reports, some 400,000 Americans succumb annually, unnecessarily, suddenly and unexpectedly to asymptomatic coronary artery disease.  We developed an ambulatory apparatus for the personal kit of the family doctor, which is suitable for assessing covert signs that are emitted by these asymptomatic coronary conditions, including the largest single killer of man – the Hibernating Myocardium (HM).  With the advent of this new, simple and cost-effective technology, the risks of Sudden Cardiac Death (SCD) can now be surveilled by the medical centers as well as by the family doctors in the community.

For additional information, please contact mailto:info@nimedical.co.il

An improved method for preventing Sudden Cardiac Death (SCD) by timely detection of the Hibernating Myocardium and other coronary conditions through a new algorithm for assessing Left Ventricular Systolic Dysfunction (LVSD).

The Calamity of Asymptomatic Coronary Artery Disease and the Hibernating Myocardium

•  Half a century has passed since the introduction in the sixties of coronary revascularization as a therapeutic measure for the sequellae of Coronary Artery Disease (CAD) [1-3].
•     According to the 2007 Update of the American Heart Association - AHA [2], despite the availability of revascularization, CAD causes one of every 5 deaths in the US, killing more people than any other single human ailment.
• Of the 650,000 who die annually of CAD, there are 300,000-350,000 asymptomatic individuals who succumb to Sudden Cardiac Death (SCD).  Two-thirds of these are incurred by the Hibernating Myocardium [4], which is the largest single killer of man.
• 57,000 additional cases are asymptomatic subjects who develop unrecognized systolic Heart Failure (HF) which, when discovered, is too late for salvation [2].
• However, once any of these over 400,000 asymptomatic yet vulnerable patients have been diagnosed, their prognosis is excellent, because coronary revascularization is a particularly appropriate mode of therapy for the various forms of asymptomatic CAD [5-11].
  

The NICaS CSWe introduce here our new impedance ambulatory tool, the NICaS CS (Non-Invasive Cardiac System – Cardiac Surveyor), with its unique algorithm for detecting Left Ventricular Systolic Dysfunction (LVSD) [12-14].  Since HM is one of the etiologies of LVSD, the Granov-Goor Index (GGI) is the key algorithm for the search for asymptomatic HM.

The Hibernating Myocardium

• Hibernating Myocardium (HM) is the term that was used by Rahimtoola to coin the diagnostic title of the most lethal cardiac disease in America, which accounts for approximately 250,000 annual Sudden Cardiac Deaths (SCD) [3].
• Four features are displayed in HM: 1) Impairment of the contractile power of the Left Ventricle at rest, called LV Systolic Dysfunction (LVSD) [16-19]; 2) LVSD of the HM differs from several other types of LVSD conditions in that it is a result of chronic ischemia which is induced by stenosis in the regional coronary arterial branch [11,20]; 3) The hibernated myocardium is viable, but has undergone structural alterations, including electrical irritability, with a tendency to generate lethal ventricular fibrillation [11,20]; 4) The earlier revascularization of the regional coronary branch is performed, the higher the prospects of restoring the original pre-ischemic state, with cure [10,11,14,16].
• With the advent of the NICaS CS, the prognosis of adults in the community who sustain asymptomatic HM will be radically improved.  A 4-5 minute annual follow-up test provides a 70-80% probability of detecting an obscure Asymptomatic LVSD (ALVSD) condition, if there is one [12-14].  Subsequently, the diagnosis of HM which is made by imaging technologies [21-24] leads to revascularization, and a high likelihood of cure.
  
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The Risks of Hibernating Myocardium and Benefits of Revascularization

•  The following are data from a meta-analysis by Allman et al [10], where comparisons were made between revascularization versus medical treatment in patients with LVSD, with or without hibernation.

• Therapeutic Options                        Annual Mortality

         A) revascularization in hibernation                3.2%
         B) medical therapy in hibernation                 16%
         C) revascularization in non-hibernation        7.7%
         D) medical therapy in non-hibernation         6.2%

• The NICaS CS is destined to search for the asymptomatic Hibernating Myocardium while it is still in its pre-clinical phase.

The Search for the Life-Threatening Hibernating Myocardium

• 70% of LVSD cases have a background of CAD [25], and in 50% of asymptomatic LVSD (ALVSD) individuals who sustain CAD, there is hibernation [24].
• As hibernation is age-related [15,20], and as the prevalence of asymptomatic HM is 2-4-fold that of the symptomatic HM [25], the prevalence of asymptomatic HM between the ages of 60-75 is 4-7.5%.
• According to Rahimtoola, the “golden time” for revascularization is in the early stage of the hibernation, when patients only have wall motion abnormalities, and remodeling either has not occurred, or is only minimal [16].
• The results of our trial indicate that the ideal timing for revascularization is the pre-clinical phase of the ALVSD, a timing which is overlapping with Rahimtoola’s “Golden Time” [16] and with Framingham’s  threshold 40%<55% [19].
• Hence with a result of the GGI<9.7-10.0, the patient should have a further workup to verify whether hibernation is present or not [14].

The Granov-Goor Index

The Granov-Goor Index (GGI) was designed to assess Asymptomatic Left Ventricular Systolic Dysfunction (ALVSD).  This algorithm is based on the following formula:

GGI=ΔR/R x α x HR x kHR

(where ΔR is the impedance change during the cardiac cycle(Ω), R is the basal resistance(Ω), α is the time interval (seconds) between opening of the aortic valve (the beginning of the systolic impedance change) and peak systolic value of the ΔR,HR is heart rate  and kHR is correcting factor for HR if HR>90 kHR=90/HR or if HR<60 kHR=60/HR)

The GGI algorithm provides a yes or no (Boolean) reply, and when the GGI<9.7-10.0, the LVEF<55%, which is a condition of LV dysfunction [12-14,19].

The equation of the GGI is a fraction of the following original Frinerman algorithm of the NICaS technology for measuring the cardiac output [15]:

SV = ΔRρL2(α+β) Kw x HF / RR1β

(where SV is the cardiac stroke volume (MI), ρ is the blood electrical resistivity (Ω cm), L is the patient’s height (CM), Kw is a correcting factor for body weight, HF is the hydration factor related to the body water composition, and (α+β)/β is the ratio of the systolic time plus the diastolic time divided by the diastolic time of the ΔR waveform).

 
The rationale behind the formulation of the GGI was the desire to identify the measured value of the isolated α character.

The Crucial Role of the α Character in the Granov-Goor Index

• The α parameter pertains to the hemodynamic interval that begins with the opening of the aortic valve and terminates with the peak impedance change which demarcates the peak systolic volume of the systemic arterial tree [28].  The result of α, therefore, is determined by an equilibrium between the contractile force of the heart and by the elasticity of the distending arterial tree [29].
• The hemodynamic characteristics of the α parameter were conceived in the forties by Holzer [30], and its reliability was recently reaffirmed by Hardy’s MRI studies [29].
• As a measure of the arterial distensibility, the α is recognized as an energy parameter.  Therefore, not only is a positive GGI result a sign of subnormal LVEF, but as an algorithm that measures a contractile energy factor, a positive result independently implies that a pre-clinical phase of heart failure (HF) has begun [29].

Reliability of the GGI Results

• The GGI algorithm was appraised in a Helsinky-approved trial at the Wolfson Medical Center, Tel Aviv University.  Comparisons were made between the GGI and echocardiography, which was performed using GE Vivid 7 (GE Vingmed Ultrasound A/S, Norway).  EF was calculated using the biplane Simpson technique.
• In a report of 254 patients [13], sensitivity was 88.9%, specificity 97.1%, and negative and positive predictive values were 98% and 87%, respectively.  The Pearson correlation, r=0.7544, p<0.0001 and 95% Confidence Interval for r=0.6960 to 0.803.
• By the time the FDA Committee approved the validity of the GGI, 301 individuals had already been tested [31]. Sensitivity – 88%, specificity –  98%, positive and negative predictive values were 90% and 97%, respectively.
• This trial confirmed the validity of the criteria of the upper and lower limits of the Framingham threshold of 40%<55% [19] as the true boundaries of the pre-clinical phase of ALVSD.
• In this trial, however, individuals were encountered whose LVEF<40%, and who were in CHF, but they were asymptomatic.  This is the same kind of patient population as in the SOLVD [4] trial, who should be categorized as spurious ALVSD.  Their outlook for revascularization was unpredictable.

Management of CHF by the NICaS CS

• The accuracy of measurements of Cardiac Output (CO) results in patients treated for Congestive Heart Failure (CHF) is critical for survival.
• Comparisons between the NICaS CS and the gold standard Thermodilution (TD) results reveal a limit of agreement of ±1.0 lit/min – 20% disparity between the two methods [15,32].
• This degree of accuracy of the NICaS CS is in accordance with the FDA required standard of bioequivalence [33].
• In 3 independent clinical trials where the CO results of Thoracic Impedance Cardiography (TIC) were compared with TD, the Bland-Altman limits of agreement with 2SD were ±2.2 lit/min – 44% disparity between the two technologies [34-36], revealing precisely half the accuracy of the NICaS CS.

The Sudden Cardiac Death of Silent Ischemia

• In the remaining one-third of the asymptomatic individuals with CAD who succumb to Sudden Cardiac Death (SCD), the underlying disorder is silent ischemia [4,5].  Death here is incurred by a sudden and unexpected coronary occlusion, resulting in a massive acute infarction.
• The search by the NICaS CS for signs of silent ischemia is based on searching for Transient cardiac Ischemic Attacks (TcIA).
• There are two hemodynamic sequellae of a transient ischemic event:  A) Peripheral arterial vasoconstriction with a rising Systemic Vascular Resistance (SVR) (or Total Peripheral Resistance – TPR) [37-43]; B) An instant decline of the LVEF [38].  It has not been determined whether this transient, reactive LV dysfunction is due to the rising SVR or to the myocardial ischemia.

Intellectual Property & Regulatory Status

Patents:  US Patents 5,469,859 and 5,735,284; 3 additional new patents are pending
Regulatory Status:

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Cardiac arrest, Prevention of Cardiac arrest, sudden cardiac death (SCD), Coronary artery disease CAD , Mortality of CAD, Myocardial ischemia, coronary revascularization. Heart attack myocardial infarction