In this article, Dr. Peter Rentrop details the scientific journey of how a team of cardiologists challenged the prevailing understanding of heart attacks and developed a new treatment approach.
The cause of the heart attacks
He came to the emergency room of the University Hospital of Göttingen, Germany, on July 1, 1979, at 1:30 pm. Anxious, sweating, complaining of excruciating chest pain, shortness of breath, and nausea, Patient A was suffering a large heart attack (called an acute myocardial infarction). His electrocardiogram revealed the heart attack was still in its early stages.
This man was unaware that his case was of historical significance as the first patient to participate in a new model for treating acute myocardial infarctions. The team in Göttingen, a small University town in northern Germany, would reshape the treatment of heart attacks a second time.
The controversy among pathologists
As early as 1880, Dr Carl Weigert, a German pathologist, introduced the term myocardial infarction (“Die Infarcte des Herzmuskels”) in his description of heart muscle death. He attributed it to the abrupt cutting off of the blood supply to part of the heart muscle by a blood clot or thrombus obstructing an atherosclerotic coronary artery. It was known that atherosclerosis results from the deposition of fatty substances in the vessel wall. Dr James B. Herrick popularized and broadened these concepts among American physicians in his 1912 landmark paper.
By the 1930s, extensive research had confirmed Weigert’s and Herrick’s views. It provided evidence that the blood clots that obstructed coronary arteries formed in response to breakages of atherosclerotic blockages, an event called plaque rupture. The terms “heart attack” and “coronary thrombosis” were used interchangeably in the 1960s, illustrating the wide acceptance of these concepts.
This view was challenged, however, in the late 1950s and early 1960s, when prominent pathologists reported that they had found coronary artery thrombi only in a minority of infarct victims. In contrast, severe atherosclerotic coronary narrowing was present in all.
If heart attacks occurred in the absence of an occlusive coronary thrombus, a new explanation would be required. It was known that atherosclerotic narrowing of the coronary arteries could render blood flow and oxygen supply to the heart muscle insufficient when oxygen requirements increased, as during physical or emotional stress, or when blood pressure decreased. With these new findings, heart attacks in the absence of a coronary thrombus were attributed to a profound oxygen supply/ demand mismatch due to severe atherosclerotic coronary artery narrowing.
As a result, even the coronary thrombi found by some influential pathologists only in a minority of patients were no longer considered to be the cause of the heart attack but rather its consequence. Thrombi were reported to be primarily present in the coronary arteries of patients who had died from cardiogenic shock days or weeks after the onset of myocardial infarction. In cardiogenic shock, blood flow and pressure are low because a large infarct has weakened the heart severely. This Impairment of circulation was believed to slow down blood flow in severely narrowed coronary arteries to near stagnation. Stagnating blood clots eventually. Total coronary artery occlusion by such late blood clots was believed to be of no importance in the development of heart attacks.
Cardiologists generally accepted these views in the 1960s and 70s. Patients in coronary care units (introduced into hospitals in the late 1960s) were treated by managing dangerous irregularities of the heart rhythm and minimizing oxygen requirements of the heart. The patients were shielded from any excitement and administered pain medication. After surviving the acute phase, strict hospital bed rest for up to six weeks was maintained with the goal of promoting the replacement of the dead heart muscle by a firm scar. Cardiologists investigated a large number of drugs, hoping to limit damage to the heart muscle by reducing oxygen requirements.
Initial observations from in vivo angiograms
The Göttingen team, however, had been questioning the prevailing scientific explanations. Patient A would be the first patient to benefit from a treatment based on new evidence restoring Weigert’s original concept about what causes acute myocardial infarction. Coronary angiograms, i.e., X-ray images of the coronary circulation, which Dr Peter Rentrop, head of the research, performed within the first hours of acute myocardial infarction, had revealed total blockage of the infarct-related coronary artery in about 80% of patients. Filling defects in many of the obstructed coronary arteries had the appearance of blood clots.
A group in Spokane, Washington, which also had performed coronary angiograms before emergency coronary artery bypass surgery, reported similar observations. These novel findings were not compatible with the view that coronary blood clots occur only in a minority of patients and that they develop later, days after the onset of a heart attack. This prevailing view was based on autopsies of non-survivors, which, before coronary angiography, had been the only method available to investigate the coronary anatomy of infarct patients. Many autopsy series included patients who had died from sudden death. Sudden death has a low incidence of total coronary occlusion and turns out to be a different entity from acute myocardial infarction.
The Göttingen cardiologists had the good fortune of working with Dr. Dietrich Sinapius, an internationally renowned cardiac pathologist. He used advanced techniques to find a plaque rupture sealed by a blood clot in all non-surviving infarct patients. Dr. Rentrop’s findings in in vivo angiograms corresponded to these blood clots. The Göttingen cardiologists were now convinced that Weigert’s and Herrick’s abandoned view had been correct: heart attacks are caused by coronary thrombi.
Observations during the first Percutaneous Coronary Interventions
For the first time worldwide, and almost exactly one year prior to the admission of Patient A, on June 13, 1978, Dr Rentrop had reopened a totally blocked coronary artery by “mechanical” means in the Cath Lab in a patient experiencing a heart attack. The minimally invasive procedure he employed today is known as “Percutaneous Coronary Intervention” (PCI). PCI is carried out through the same kind of catheter as coronary angiography, in which a small plastic tube is advanced from an artery in the groin or wrist to the orifice of the coronary artery. In this first PCI during a heart attack, Dr Rentrop threaded a thin wire through the coronary catheter into the obstructed artery to perforate the blockage and restore blood flow to the downstream heart muscle.
The patient’s striking response to the restoration of blood flow was immediate alleviation of chest pain and normalization of the electrocardiogram (EKG). This success prompted him to develop this technique further. He had special wires and catheters manufactured to unblock coronary arteries, modifying a method called “Transluminal Recanalization.” Dr Charles Dotter introduced Transluminal Recanalization in 1964 to reopen occluded leg arteries with wires and catheters instead of performing surgery (much to the chagrin of American vascular surgeons who rejected the procedure).
The Göttingen team tested their modified Transluminal Recanalization method in 15 patients, the first proof-of-concept study of PCI as a treatment for acute myocardial infarction. They succeeded in reopening 9 of the 15 occluded infarct-related arteries. They noted that restoration of blood flow not only stopped the patients’ pain and normalized their EKG but also improved the contraction of the heart muscle segment affected by the heart attack.
Such improvement had not been reported with any medical treatment, and the Göttingen cardiologists did not see it in a group of 13 patients who had undergone acute angiography but received medical treatment without PCI. Repeat angiography several weeks after the heart attack, however, revealed a surprising finding in this medically treated group: five of the 13 initially occluded infarct-related arteries were now open. They drew three conclusions.
- Occluded infarct arteries frequently recanalize spontaneously.
- PCI can restore blood flow to the heart muscle more rapidly and in a greater percentage of patients than spontaneous recanalization would.
- Early restoration of blood flow by PCI may stop the progression of heart attacks and salvage heart muscle.
Observations during intracoronary medical interventions spark further controversies
It was tempting to attribute the frequent occurrence of spontaneous coronary artery recanalization to endogenous thrombolysis, which is the body’s well-known ability to dissolve blood clots. However, studies published by Drs Philip Oliva and John Breckinridge in 1977 and Attilo Maseri in 1978 suggested a different mechanism.
These investigators had reopened total coronary occlusions among infarct patients when they injected nitroglycerin through a coronary catheter directly into the obstructed artery. Nitroglycerin does not affect blood clots but dissolves coronary spasms. The researchers suggested that myocardial infarction is caused by spasms, which may result in thrombus deposition due to blood stagnation.
The Göttingen team decided to test this hypothesis with intracoronary administration of targeted medications. Drugs to dissolve blood clots, known as thrombolytic or fibrinolytic agents, were already available.
A promising treatment gets derailed.
Dr. William Smith Tillett had begun to develop streptokinase, the first of these agents, in 1933, coinciding with the general acceptance of Weigert’s and Herrick’s view that blood clots cause heart attacks. In 1958, Dr. Anthony P. Fletcher et al. from Dr Sol Sherry’s group administered intravenous streptokinase to 24 patients with acute myocardial infarction with the explicit goal of reducing infarct size by “the rapid dissolution of a coronary thrombus.” Blood chemicals they measured provided indirect evidence that blood flow to the infant area had been restored, and the hospital mortality of patients treated within 14 hours of symptom onset was strikingly low.
Remarkable as it may be, in spite of this promising 1958 study, thrombolytic therapy for acute myocardial infarction was not further investigated in the United States for more than 20 years except for one small pilot trial published in 1974. The impact of Fletcher’s and Sherry’s thrombolysis paper was immediately blunted by findings from the initial autopsy reports, which questioned the causative role of coronary thrombosis in acute myocardial infarction. “Cardiologists no longer stressed coronary thrombosis as the cause of acute infarct,” Sherry understated politely. Consequently, acute myocardial infarction was not among the conditions for which the Food and Drug Administration (FDA) approved thrombolytic therapy in 1977.
In Europe and Australia, intravenous infusion of streptokinase was investigated as a treatment for acute myocardial infarction during the 1960s and 1970s in 20 small, inconclusive trials. In a surprising twist, but in keeping with the new belief that heart attacks are not caused by occlusive coronary blood clots, the therapeutic rationale in these trials switched from lysis (dissolution) of such thrombi to reduction of myocardial oxygen demand. Streptokinase was known to decrease blood viscosity (thickness and stickiness of blood) by splitting large circulating proteins. Reducing blood viscosity decreases the workload of the heart, a main determinant of oxygen demand.
A second proposed mechanism suggests that streptokinase improves microcirculation by rapidly dissolving small blood clots in the tiny vessels surrounding the heart attack area, the so-called microthrombi. These microthrombi were thought to extend the area of heart muscle death by blocking blood flow from neighboring arteries to the infarct area.
As late as 1979, when the European Cooperative Study Group finally documented a survival benefit from an intravenous streptokinase infusion in a sufficient-sized trial, the investigators attributed this benefit exclusively to a reduction in myocardial oxygen demand and improved microcirculation. They did not even consider that thrombolytic therapy might help patients by dissolving an obstructive coronary thrombus.
Intracoronary streptokinase infusion combined with mechanical recanalization stops a heart attack.
Patient A:
The Göttingen team challenged these assumptions head-on in 1979 when they added selective intracoronary drug infusions to their protocol of acute coronary artery recanalization with PCI. This was the study in which Patient A decided to participate.
His coronary angiogram, performed two hours after onset of infarct symptoms, revealed total blockage of the left anterior descending artery, the largest vessel of his heart (figure 1). About half of his heart muscle did not contract. Nitroglycerin was injected into the occluded vessel using Oliva’s technique, but the obstruction remained unchanged. A wire was passed through the obstruction to recanalize the artery mechanically (figure 2). After pullback of the wire a thin recanalization canal became apparent through which the left anterior descending artery filled slowly and incompletely to its middle segment (figure 3). Streptokinase was immediately administered into the coronary artery as a bolus, followed by continuous infusion for 50 minutes. Within five minutes of the initiation of streptokinase therapy, Patient A reported that his excruciating chest pain had completely subsided. After completion of the streptokinase infusion, control angiography revealed enlargement of the recanalization canal and striking flow improvement with a brisk filling of the entire left anterior descending artery (figure 4).
Figure 1: Total occlusion of the left anterior descending artery (arrow), which persisted after intracoronary nitroglycerin.
Figure 2: Wire passed through total occlusion of the left anterior descending artery (arrow).
Figure 3: After mechanical recanalization, some dye reaches the middle segment of the left anterior descending artery.
Figure 4: Following intracoronary streptokinase infusion, brisk filling of the entire left anterior descending artery (arrows).
During aorto-coronary bypass surgery, performed the following day, no evidence of a myocardial infarct was apparent; all segments of the heart muscle contracted vigorously. Control angiography two weeks later confirmed marked improvement of heart muscle function.
It appeared that early recanalization had prevented the development of a large heart attack. While spasmolytic therapy with nitroglycerin had not contributed to recanalization, there was strong evidence suggesting the benefit of streptokinase therapy.
How intracoronary administration of streptokinase differs from the intravenous infusion technique used in all prior trials.
Local medication administration achieves a higher concentration at the site of the desired action. In experimental animals, the intracoronary administration of a thrombolytic agent dissolved coronary thrombi more rapidly than intravenous infusion. Dr Köstering of the Göttingen team had demonstrated the efficacy of local administration of a thrombolytic agent in dialysis-dependent renal patients.
He had recanalized occluded arteriovenous shunts by injecting small amounts of streptokinase into the thrombosed arteries. The dose for intracoronary streptokinase administration, calculated based on this experience, was a fraction of the amount required with intravenous infusion. Bleeding complications, the main risk of thrombolytic therapy, were expected to be minimized with this dose reduction.
The team felt encouraged to continue their investigation. However, they realized that their observations had not yet conclusively proved that a coronary thrombus could be dissolved by lysis because of the antecedent mechanical recanalization. Consequently, they changed their protocol, limiting it to pharmacological interventions and forgoing any form of PCI in their subsequent patients.
Two of the following three patients presented with subtotal occlusion and one with complete obstruction of the infant vessel, which responded to intracoronary nitroglycerin injection with transient flow restoration. Intracoronary streptokinase infusion was required to achieve permanent patency.
Intracoronary streptokinase infusion alone stops a heart attack by dissolving a blood clot.
Patient B:
The fifth patient of the series, a 57-year-old female, presented with a complete obstruction of her left anterior descending artery (LAD), which did not change after administration of nitroglycerin (figure 5).
Figure 5: Total occlusion. of the left anterior descending artery not recanalized by intracoronary nitroglycerin.
However, fifteen minutes after initiating the streptokinase infusion, the cardiologists noted sudden irregularities in her heartbeat, which they frequently had seen in experimental animals after a ligated (tied off) coronary artery was reopened.
The room fell silent when Dr. Rentrop performed repeat coronary angiography on this patient. Her left anterior descending artery was patent and filled briskly (figure 6).
Figure 6: Recanalization and brisk filling of the entire left anterior descending artery after 15 minutes of intracoronary streptokinase.
After another three minutes, she reported no more chest pain. Dr. Heiner Blanke, a member of the team usually not given to pathos, turned to the nurses and technicians in the cath lab and proclaimed, “Ladies and gentlemen, you have just witnessed medical history.”
He was correct. For the first time, restoration of blood flow, which could not be explained by any mechanism other than the dissolution of a blood clot with a thrombolytic drug, had been shown to stop a heart attack. Finally, the causative role of coronary thrombosis in acute myocardial infarction has been demonstrated conclusively. Moreover, the rapidity with which the streptokinase infusion alone had achieved reflow had far-reaching therapeutic implications.
Demonstrating the initial intracoronary interventions in acute myocardial infarction at the AHA meeting in Anaheim in 1979 caused a sea change.
The Göttingen investigators submitted an abstract summarizing their pilot trial to the 29th Annual Scientific Session of the American College of Cardiology in March 1980. However, this first report to establish the pathogenetic role of thrombus by intracoronary thrombolytic therapy was rejected after being reviewed by “10 nationally recognized cardiovascular experts”, reflecting the profound attachment of the cardiology community to their incorrect assumptions.
However, their abstract on acute coronary artery recanalization using PCI with Transluminal Recanalization, submitted for the preceding Annual Scientific Session of the American Heart Association in Anaheim, California, in November 1979, had been accepted. Anticipating rejection of his thrombolysis abstract, Dr Rentrop added its results to his presentation of Transluminal Recanalization. Dr. Rentrop’s 1979 Anaheim presentation became a watershed event.
After seeing angiograms demonstrating restoration of coronary blood flow by either transluminal recanalization or intracoronary streptokinase infusion for the first time (https://youtu.be/uVzysOX-wHc), many investigators worldwide immediately reproduced these interventions in their labs, including the leading proponents of the oxygen supply/demand hypothesis.
Life-saving treatment is approved with a delay of 30 years.
A series of publications from the Göttingen group, soon followed by studies from many other centers, finally re-established the causative role of coronary thrombosis, first demonstrated by Weigert in 1880, as mainstream thinking. It set the stage for introducing reperfusion therapies, i.e., treatment modalities to reestablish blood flow in heart attack patients.
The randomized Mount Sinai/NYU Reperfusion Trial, Drs K.Peter Rentrop and Frederick Feit co-principal investigators, confirmed that the only useful pharmacologic strategy for coronary artery recanalization during interventional angiography is lysis of an occlusive thrombus by administration of a thrombolytic agent. Other investigators documented a significant survival benefit of intracoronary streptokinase therapy. Intravenous streptokinase infusion was shown to achieve rapid reperfusion in 50% to 60% of patients.
While the reperfusion rate of intracoronary streptokinase infusion was higher, the much more straightforward and broadly applicable intravenous approach was also shown to reduce infarct mortality significantly. The FDA approved the use of streptokinase “when administered by either the intravenous or intracoronary route … for the lysis of intracoronary thrombi, the improvement of ventricular function, and the reduction of mortality associated with AMI” in November of 1987, 30 years after Fletcher’s and Sherry’s groundbreaking study.
Since its approval, thrombolytic therapy in acute myocardial infarction has saved millions of lives, a triumph of science. However, millions of patients lost their lives because this treatment was delayed by 30 years due to an error of science, a fact often overlooked today and a reason to be humble. Today’s scientific truths are tomorrow’s errors.