According to Myerburg and Costellanos, the introduction of cardiac revascularization to medicine (coronary artery bypass grafting [CABG]) almost 50 years ago led to a decline in the age-adjusted mortality from coronary artery disease (CAD),1 but brought no change to the fraction of coronary deaths that are sudden and unexpected.1 Of the 650,000 who die annually in the US of CAD, 300,000–350,000 succumb to sudden cardiac death (SCD),1,2 and another 57,000 to end-stage systolic congestive heart failure (CHF).3 This prognostic picture has not changed since the era before the introduction of revascularization by CABG operations in the late 1960s. With the new technology described here, the responsibility for timely diagnosis of asymptomatic CAD can be transferred from costly medical institutions to primary care physicians (PCPs) in the community. This alternative strategy of cost-effective early diagnosis will facilitate at long last the completion of the revolution of revascularization that began half a century ago.
Three consecutive models of the current technology were developed, the first being the Non-Invasive Cardiac System (NICaS). This was an impedance cardiographic (ICG) monitor for non-invasive measurement of the cardiac output (CO) and its derivatives.4 The electrode configuration includes one electrode at the patient’s wrist and the other at an ankle. Unlike the thoracic ICG (TIC), where the algorithm is based on the first derivatives of the impedance change (dR/dt), in the NICaS the algorithm is based on the ΔR as is. In addition, this algorithm is distinguished by the inclusion of a number of correcting coefficients:
SV = ΔRρL2 (α + β)KwxHF
where SV is the cardiac stroke volume (ml), ΔR is the resistance change during the cardiac cycle (Ω), R is the basal resistance (Ω), R1 is a corrected basal R (Ω), ρ is the blood electrical resistivity (Ω cm), L is the patient’s height (cm), Kw is a correcting factor for bodyweight, HF is the hydration factor related to the body water composition, 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, and (α+β)/β is the ratio of the systolic time plus the diastolic time divided by the diastolic time of the ΔR waveform.
A crucial character in this formula is the α, which is determined by the strength of the cardiac contractility (left ventricular [LV] function) and the elasticity of the arterial tree. In normal conditions, some of the energy of the LV contraction produces forward blood flow during systole, and the majority is briefly stored as potential energy in the distended arteries for the diastolic phase.5
This original NICaS monitor was upgraded to the NICaS 2004 Slim model for two reasons: to introduce to medicine a cost-effective, ambulatory tool that can be used by any doctor, anywhere, in the diagnosis, prevention, and management of systolic CHF; and to upgrade the accuracy and reliability of the cardiac output (CO)/cardiac index (CI) results and their derivatives. Comparison of the results of the NICaS Slim 2004 (approved by the US Food and Drug Administration [FDA] in July 2007) versus the other ICG technologies reveals a limit of agreement (two standard deviations [2SD]) between the NICaS 2004 and gold standard thermodilution (TD) of ±1.0l/minute-1 (a 20% disparity),6,7 whereas the limit of agreement (2SD) of the BioZ versus TD is ±2.2l/minute-1 (a 44% disparity),8–10 and the 2SD limit of agreement of whole body electrical bioimpedance (WBEB) versus TD is ±1.5l/minute-1 (a 34% disparity).11
Cardiac Index as a Presenting Sign of Asymptomatic Left Ventricular Systolic Dysfunction
The evolution of the final model, the NICaS CS (Cardiac Surveyor), was circumstantial. The NICaS CS has been approved by the US Food and Drug Administration (FDA) 510(K) No. K080941 (July 2009). During the developmental progress of the NICaS 2004 Slim in 2005–2006, the interim variants of the technology were tested on three company employees, two of whom then underwent revascularization.
This was a 54-year-old male with insulin-dependent diabetes and old Q-wave in leads III and AVF, who was otherwise asymptomatic. In his first test, a subnormal CI was noted (see Figure 1). After the fourth study, elective coronary angiography was performed, and Case 1 underwent urgent CABG x 4 operation. Post-operatively, Case 1 noticed a significant improvement in his physical condition, and his CI stabilized at around 2.5l/minute/m2.
This was a 73-year-old asymptomatic male, eight years post-CABG (x 2). During the first six months of investigative testing, Case 2 underwent four NICaS tests, which revealed a gradual decline in his CI from 3.8 to 2.13l/minute/m2 (see Figure 1). As he was asymptomatic, the decline in the CI was attributed to a technical incompetence of the NICaS.
Frustrated, and preparing to abandon the entire project, Case 2 suddenly and unexpectedly developed a stormy clinical picture of acute myocardial infarction (MI). A profound ST-segment elevation in leads II, III, AVF, and RV (V3R, V4R), and reciprocal ST depression in leads I and AVL, were observed on electrocardiogram (ECG) performed in the ambulance. During the emergent percutaneous coronary intervention (PCI), a nearly occlusive thrombus of the orifice of the dominant right coronary artery, which perfused 80% of the entire heart, was aspirated, followed by stenting.
After returning to work, it was incidentally noticed that both cases revealed a gradual improvement in their CI results (see Figure 1), indicating that both had had asymptomatic left ventricular systolic dysfunction (ALVSD) that was associated with the regenerative reserve of a viable (hibernating) myocardium.12–16
The Impedance Algorithm for Assessment of Asymptomatic Left Ventricular Systolic Dysfunction
At that time, five ICG algorithms were recognized for non-invasive assessment of LVSD. All were based on systolic time intervals (STI), including the Heather index,17 velocity index,18 acceleration index, and the two systolic time interval (STI) indices.19,20 As the correlation coefficient between these algorithms and echocardiographic left ventricular ejection fraction (LVEF) ranged between 0.463 and 0.55 (p<0.001),18–20 the need was felt for a more specific algorithm for assessing ALVSD. Since the α character of the NICaS algorithm contained systolic and diastolic energy factors, a formula based on α was designed, called the Granov–Goor Index (GGI):
ΔR/R x α x HR
where ΔR/R and α are taken from the original NICaS algorithm, and HR is a correcting factor for the heart rate.
Based on the available data of the two above cases, it was determined that a GGI of 10.0 should be the cut-off value of the LV function, which is equivalent to an echocardiographic LVEF of 55%. This LVEF value was adopted from the Framingham Study.21 The retroactively calculated GGI results of the two cases are displayed in Figure 1.
At this point, a trial was started at the Wolfson Medical Center, Tel Aviv University, where comparisons were made between the GGI and 2D echocardiographic LVEF results.22 Of the 254 studies, normal values were displayed in 206 by both methods, and LV dysfunction in 39. There were six false-positive GGI and five false-negative results, revealing a GGI sensitivity of 88.9%, specificity of 97.1%, and negative and positive predictive values of 98 and 87%, respectively (p<0.0001).
It also transpired during that trial that the GGI algorithm provides a yes or no result (Boolean) for LVSD <55%. Therefore, not only is a positive GGI result a sign of subnormal LVEF, but as an algorithm that measures the contractile energy factor, a positive result should imply that a pre-clinical phase of heart failure (HF) has begun.
After obtaining the required license for the clinical application of the NICaS, a private clinic in Tel Aviv, Cardioguard, opened up for testing. Of the 518 individuals (234 males and 284 females) over 55 years of age who visited the clinic between June 2007 and December 2009, there were 28 (5.4%) with positive GGI results. This is in accordance with the recognized tendency for an age-related prevalence of ALVSD.23 Of these 28 cases, however, only 13 were fully studied. Of the remaining 15, three showed a clinical picture of CHF, 11 were unco-operative, and in one the test was abortive.
Of the 13 patients who completed the testing (see Table 1), 10 (1.9%) concluded with stenting.
An ambulatory cardiac diagnostic apparatus, the NICaS CS, is available for incorporation in the family doctor’s personal kit. This apparatus is to be used for the following purposes.
- Diagnosis of ALVSD: a GGI <10.0 raises suspicion of ALVSD. Since 30% of ALVSD conditions in the general population24 and 42% of those in CAD25 are associated with a viable (hibernating) myocardium, a positive GGI result obliges further diagnostic work-up to determine viability.
- The exceptionally high reliability of the CO/CI results renders this tool ideal for the management of CHF.
- Events of rising TPR and reduction in CI during monitoring of the CO/CI and their derivatives during night sleep (at home),26 as well as during mental stress tests,27 are indicative of silent ischemia and risk of SCD.